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Review

Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review

by
Robert Percy Marshall
1,*,
Jan-Niklas Droste
1,
Jürgen Giessing
2 and
Richard B. Kreider
3
1
Medical Department, RasenBallsport Leipzig GmbH, 04177 Leipzig, Germany
2
Faculty of Natural and Environmental Sciences, Institute of Sports Science, Universität Koblenz-Landau, 76829 Landau, Germany
3
Exercise & Sport Nutrition Lab, Human Clinical Research Facility, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843, USA
*
Author to whom correspondence should be addressed.
Nutrients 2022, 14(3), 529; https://doi.org/10.3390/nu14030529
Submission received: 14 December 2021 / Revised: 24 January 2022 / Accepted: 24 January 2022 / Published: 26 January 2022
(This article belongs to the Special Issue Creatine Supplementation for Health and Clinical Diseases)

Abstract

:
Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion’s survival and health particularly during stressful conditions such as ischemia and injury. This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn.

1. Introduction

Creatine (N-aminoiminomethyl-N-methyl glycine) is a naturally occurring and nitrogen containing compound synthesized from the amino acids glycine, methionine that is classified within the family of guanidine phosphagens [1,2]. About one half the daily need for creatine is obtained from endogenous synthesis while the remaining is obtained from the diet, primarily red meat, fish, or dietary supplements [3,4]. Creatine is mainly stored in the muscle (95%) with the remaining found in the heart, brain, and testes [3,4,5,6], with about 2/3 in the form of PCr and the remaining as free creatine [4,5,7]. The metabolic basis of creatine in health and disease has been recently reviewed in detail by Bonilla and colleagues [1] (see Figure 1). Briefly, adenosine triphosphate (ATP) serves as the primary source of energy in most living cells. Enzymatic degradation of ATP into adenosine diphosphate (ADP) and inorganic phosphate (Pi) liberates free energy to fuel metabolic activity. However, only a small amount of ATP is stored in the cell. Energy derived from the degradation of phosphocreatine (PCr) serves to resynthesize ADP and Pi back to ATP to maintain cellular function until glycolysis in the cytosol and oxidative phosphorylation in the mitochondria can produce enough ATP to meet metabolic demands. Creatine also plays an important role in shuttling Pi from the mitochondria into the cytosol to form PCr to help maintain cellular bioenergetics (i.e., Creatine Phosphate Shuttle) [8]. In this way, PCr can donate its phosphate to ADP, thereby restoring ATP for cellular needs leaving creatine in the cytosol to diffuse back into the mitochondria to shuttle the next phosphate to locations far from its production site [8]. The ATP stored in the cells is usually sufficient for energy depletion that lasts less than two seconds. However, another two to seven seconds of muscle contractions are fueled by depleting available PCr stores [9]. Together, the ATP–PCr energy system provides energy to fuel short-term explosive exercise. Increasing PCr and creatine in muscle provides an energy reserve to meet anaerobic energy needs, thereby providing a critical source of energy particularly during ischemia, injury, and/or in response to impaired mitochondrial function [8,10].
Numerous studies over the last three decades have shown that creatine monohydrate (CrM) supplementation (e.g., 4 × 5 g/day for 5–7 days or 3–6 g/day for 4–12 weeks) increases muscle creatine and PCr content by 20–40% [5,11,12,13,14,15] and brain creatine content by 5–15% [16,17,18,19,20,21]. Creatine monohydrate supplementation has been reported to safely improve high-intensity exercise performance by 10–20% leading to greater training adaptations in adolescents [22,23,24,25,26], young adults [27,28,29,30,31,32,33,34,35,36,37,38], and older individuals [21,39,40,41,42,43,44,45,46,47,48]. No clinically significant side effects have been reported other than a desired weight gain [49]. Additionally, there is little to no evidence that CrM causes anecdotal reports of bloating, gastrointestinal distress, disproportionate increase in water retention, increased stress on the kidneys, increased susceptibility to injury, etc. [49,50]. In fact, studies directly assessing whether creatine causes some of those issues found no or opposite effects. As a result, there has been interest in assessing whether CrM supplementation may benefit a number of clinical populations including conditions that impair mitochondrial function [6]. The rationale is that since CrM supplementation can increase high-energy phosphate availability and also has antioxidant, neuroprotective, anti-lactatic, and calcium-homoeostatic effects, increasing phosphagen availability may help improve cell survival and/or health outcomes in conditions in which mitochondrial function is compromised (e.g., ischemia, injury, and/or non-communicable chronic diseases). The purpose of this review is to examine the literature related to the role of CrM supplementation in the management of various conditions characterized by mitochondrial dysfunction and make recommendations about further work needed in this area.

2. Methods

The methodological basis of this narrative review is a selective literature search in the PubMed database, supplemented by a free Internet search (German and English). In a first explorative step, the search terms “creatine supplementation” and/or “mitochondrial dysfunction” and “creatine” and/or “mitochondrial disease” were used. After a first analysis of the searched literature identifying 68 articles, a new selective literature search was performed in the sources described above using the terms mentioned above, adding relevant cited sources and cross-references. Subsequently, titles, abstracts and finally full-text articles were examined by the scientific team with regard to the suitability of the articles in terms of content and, in a subsequent step, in terms of quality. After the qualitative criteria had been verified, the content exploration was carried out following thematic questions related to the role of creatine in context: (1) Ergogenic role in mitochondrial dysfunction; (2) Noncommunicable chronic diseases (NCD); (3) Cardiovascular disease and ischemic heart failure; (4) Traumatic and ischemic CNS injuries; (5) Neurodegenerative disorders; (6) Psychological disorders; and (7) Chronic Fatigue Syndrome, Post Viral Fatigue Syndrome and Long COVID.

3. Creatine’s Ergogenic Role in Mitochondrial Dysfunction

Although there is not clear definition of mitochondrial dysfunction, it generally refers to conditions that reduce the ability of the mitochondria to contribute to production of energy in the form of ATP. However, any alteration of normal mitochondrial function could be called “mitochondrial dysfunction” as well [51]. Mitochondrial dysfunction can be of primary origin through inheriting pathological altered mitochondrial DNA (mtDNA) or acquiring secondary dysfunction through aging and exposure to mtDNA damaging processes [52,53]. This can be due to traumatic ischemic (blood deficient) or anoxic (oxygen deficient) as well as chronic conditions. Most common reasons for mitochondrial dysfunction are hypoxia, overexpression of reactive oxygen species (ROS), and an alteration of the intracellular calcium homoeostasis. Since creatine supplementation increases the availability of PCr, it may help cells withstand ischemic challenges and/or offset energy deficits associated with mitochondrial dysfunction

3.1. Acute, Traumatic Mitochondrial Dysfunction

Figure 2 shows the schematic sequence of an acute traumatic mitochondrial dysfunction with possible subsequent ischemia. The mechanical forces of injury result in an influx of calcium, potassium, and sodium. A calcium gradient is created, which reduces mitochondrial function [54,55]. In addition, an injury can lead to short-term ischemia (hypoxia) due to swelling, edema formation, development of neuroinflammation, obstruction of vessels, or hemorrhage [56]. The resulting oxygen deficiency interrupts the respiratory chain in the mitochondria. In both cases, the cell must switch to the energetic emergency plan and produce energy glycolytically, thereby increasing lactate production [57,58,59,60,61]. Oxygen radicals are generated, causing oxidative stress. This leads to cell damage and ultimately to cell death (apoptosis) [62,63,64]. If sufficient creatine phosphate reserves are present, the cell can compensate short-term energy deficits. ATP-dependent calcium transporters can counteract the calcium gradient under consumption of ATP and PCr, maintain the cell milieu, and thus normalize mitochondrial function [65,66]. Oxygen radicals can be intercepted [67]. Even transient hypoxia of a few seconds can be counteracted by the body in this way [68]. There is evidence that creatine and cyclocreatine inhibit the mitochondrial–creatine kinase–adenine nucleotide translocator (Mi-Cr-ANT) complex and the mitochondrial permeability transition that is associated with ischemic injury and apoptosis [69]. Additionally, creatine enhances the ability of Mi-CK to shuttle ADP for oxidative phosphorylation and PCr formation, thereby decreasing mitochondrial membrane and production of reactive oxygen species (ROS) [70]. Since impairment in cellular energy production and increased oxidative stress are common features in several neuromuscular degenerative diseases, creatine supplementation may provide some therapeutic benefit [69,70]. In support of this premise, Sakellaris et al. [71,72] reported that oral administered creatine can be used as an additional supplement in treatment of acute mitochondrial dysfunction after brain injury. These studies showed clear improvement in clinical outcomes of patients with additional creatine-supplementation in comparison to no creatine-intake. Table 1 shows the level of evidence in humans that creatine supplementation may have a positive effect on treatment outcomes in patients with traumatic brain injury.

3.2. Chronic, Atraumatic Mitochondrial Dysfunction

Many chronic diseases such as cancer and age-related pathological conditions have been related to an altered mitochondrial function [73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101]. Chronic mitochondrial dysfunction is usually caused by slow changes in mitochondrial homeostasis eventually leading to an increase in ROS/NOS, glycolysis, and hyper-acidosis. There are multiple factors that directly damage mitochondrial function (Figure 3). Hypoxia is a common factor in conditions such as solid tumor, ischemia, or inflammation that leads to a depletion of oxygen and eventually through production of ROS to an alteration of intracellular proteins, lipids and DNA [89]. On the other hand, research was able to prove that malignant cells tend to create energy under glycolytic conditions although sufficient oxygen is provided. This pathological mechanism is called “Warburg Effect” [102,103]. This leads to an increase in cell acidity and an increase in ROS with damaging of DNA. Other factors leading to chronic mitochondrial dysfunction are toxic metals or reactive nitrogen species (NOS) [104]. An increase in ingested carbohydrates bigger than the individual needs leads to hyperinsulinemia. As a chronic condition, this will lead to an increase in receptor for advanced glycation end products (RAGE). Thus, nitrosative stress increases, manipulating mitochondrial function [105,106,107,108,109]. Increasing stress will lead to an intracellular accumulation of ammonium [110,111,112], ROS [113], lactate [114], ultimately inhibiting the Krebs cycle and oxidative metabolism.
Typical factors that lead to a disturbance in the cellular respiration are hypoxia, inflammation, viruses, mutations, oncogenes, age, radiation, and carcinogens [115]. The ultimate, most common denominators are reactive species which damage mtDNA. As soon as cellular defense systems such as antioxidants, intracellular energetic buffer, and enzymatic reactions are worn down, chronic alteration of cellular organelles begins [116]. As mentioned above, it is hard to differentiate in chronic mitochondrial dysfunction whether pathological conditions lead to hypoxia that produces ROS/NOS which eventually harms mtDNA or whether an altered mtDNA leads to an overexpression of ROS/NOS damaging itself [117]. It is widely accepted, however, that this chronic status is a vicious circle leading to a lethal cellular condition harming the host.
Magnetic resonance spectroscopy (MRS) is an analytical tool that detects electromagnetical signals that are produced by the atomic nuclei within the molecules. Thus, it can be used to (non-invasively) measure concentrations for specific molecules in tissue. This technique has extensively been used in neurological research to identify phosphorus and proton metabolites in tissue in vivo [118,119,120,121]. Using this, research was able to prove mitochondrial dysfunction in patients with bipolar disorders. These patients also suffered from an impaired energy production [122], increased levels of lactate (hyperacidotic state) [123] and PCr concentration [114,124,125]. Therefore, it was assumed that creatine supplementation could improve clinical outcome in cases of mitochondrial dysfunction. Creatine is able to buffer lactate accumulation by reducing the need for glycolysis [126], reducing ROS [127] and restoring calcium homeostasis. Table 2 presents an overview of the level of evidence for creatine supplementation for chronic, atraumatic mitochondrial dysfunction.

4. Noncommunicable Chronic Diseases (NCD)

Modern ways of (unhealthy) living like over nutrition, exposure to toxic substances, and sedentarism combined with an individual’s genetic background led to the development of NCD [90]. Four disease clusters are associated with NCD such as cardiovascular diseases, cancers, chronic pulmonary diseases, and diabetes mellitus [129]. NCD are associated with low-grade inflammation and an increase in oxidative stress [130]. Through the past decades, they have become the biggest health threat of modern society [131,132,133]. Lately, there has been a link established between NCD and mitochondrial dysfunction. Reduced oxygen consumption rates have been shown in cardiovascular diseases such as hypertension and atherosclerosis. Additionally, they suffer from calcium overload due to mitochondrial calcium mishandling and ROS overproduction [134,135,136,137]. Obesity [138,139,140,141] as well as diabetes mellitus [142,143,144,145,146,147,148,149] are associated with an increased mitochondrial fragmentation rate, impaired ATP production, as well as ROS overproduction and calcium mishandling. In regards to creatine and its connection to mitochondrial dysfunction, reduced levels were detected in human myocytes in diabetes mellitus [150], obesity [151], and hypertension [152]. Not surprisingly, NCD are the most common factors contributing to the development of an acute ischemic heart attack or acute ischemic brain disease (Figure 4).
Table 3 shows some of the studies that have been conducted on creatine supplementation in noncommunicable chronic diseases. Creatine’s benefits in physical activity and thus counteracting NCD development have been widely explained [20,153,154,155,156,157,158,159,160,161,162,163]. There is, however, substantial evidence for the beneficial effects of supplementation even without combining it with sports. The sole intake of creatine has been able to significantly lower blood lipids such as cholesterol and triglycerides, slow down the development of fatty liver, and lower the HbA1C in human and animal studies, thus improving the clinical outcome and progression of the metabolic syndrome [164,165,166].

5. Cardiovascular Disease and Ischemic Heart Failure

Optimal replenishment of creatine reserves was able (in experimental studies) to slow down disease progression of the other above mentioned NCD and cardiomyopathy. Therefore, creatine supplementation has been identified to be of special therapeutic interest in treatment of cardiovascular diseases and their course [167,168]. The heart has its own four creatine kinase (CK) isozymes, proving the importance of ensuring filled energy depots [169]. A gradual reduction of myocardial total creatine content has been shown on chronic heart failure in human as well as animal studies [170,171,172,173]. The ratio of PCr/ATP has been defined to better judge myocardial creatine metabolism [174]. Low ratios have been positively correlated with low contractile function, more severe heart failure symptoms, and a higher risk of mortality [175,176,177].
Creatine supplementation in patients with chronic heart failure and similar animal studies have not shown any beneficial effect on clinical outcome, neither on myocardial creatine concentrations [178,179,180]. The transmembrane Creatine-Transporter (CrT) seems to be the limiting factor in this matter [181]. Question remains if other creatine-analogues that pass intracellular without the need of CrT might prove of better help in cardiovascular diseases. The energy deficiency resulting from local hypoxia during an ischemic heart attack leads to mitochondrial dysfunction, which in turn can have arrhythmogenic consequences and lead to sudden cardiac death [182,183,184]. Therefore, it is not surprising that creatine plays a critical role during a cardiac ischemic event [185,186]. First in vitro studies allow the hypothesis that saturation of myocardial creatine stores may lead to protection in the event of a transient ischemic attack [49]. In this context, in animal studies, filled ATP stores have a positive inotropic, apoptosis-protective effect and counteract a post-ischemic inflammatory cascade [187].
Intravenous in vivo administration of phosphocreatine was able to confer significant myocardial protection after bypass surgery [188], resulting in a reduction in the incidence of ventricular fibrillation and myocardial infarction as well as arrhythmias [189]. The newly developed special form of creatine, cyclo-creatine, deserves special attention. After an oral loading phase prior to elective cardiac interventions (PCI, ACVB, HTX), cyclo-creatine has a similar protective effect against lethal events [183,187,190,191]. However, large-scale human studies have yet to confirm the initial promising results. Table 4 summarizes the level of evidence available on the role of creatine in cardiovascular disease and ischemic heart failure [187,188,189,190,191].

6. Traumatic and Ischemic Central Nervous System Injuries

Mitochondrial function and ATP production are crucial for the neuronal survival and excitability [193]. At the same time, however, mitochondrial dysfunction leads to the overproduction of ROS and neuronal apoptosis which is closely related to neurodegenerative diseases and cerebral ischemia [193,194,195,196,197]. Whereas earlier research mainly focused on mitochondrial bioenergetic roles, new studies have shown the importance of apoptotic signaling, mitochondrial biogenesis, and mitophagy in the development of cerebrovascular disease and stroke. Mitochondrial health is therefore essential for neurological survival and rehabilitation [198,199]. Reperfusion injury is another acute complication feared by medical doctors involving mitochondria and clinical outcomes [200,201]. Following reperfusion of the injured brain tissue, excessive ROS and calcium produced under hypoxic conditions are washed in the body’s periphery, causing damage on cellular and molecular level [202]. Intracellular calcium deregulation enhances neuronal cell death after stroke, giving the stability of the mitochondrial (calcium) permeability transition pore (mPTP) a special predictive measure [203].
The acute protective effects of creatine on the central nervous system (CNS) have long been known. Similar to the effect in the myocardium, energy buffering for short-term hypoxic conditions can be achieved by saturating intracellular PCr. This may lead to protection against ischemia and cell death, as well as calcium gradients created by mechanical stimuli [204,205,206]. In animal experiments, researchers were able to show that idiopathically caused brain damage and spinal cord injuries developed to a lesser extent after creatine oral administration [207,208]. Creatine supplementation also had a positive effect on infarct sizes after insult in ischemic mouse models [209]. These results suggest that creatine administration may lead to preventive CNS protection against concussions, traumatic brain injury, spinal cord injury, and insults [210].
Adding to the above-mentioned protective effects of Creatine during a hypoxic situation, special advantages of creatine on the CNS have been proven. The term excitotoxicity describes the destruction of neuronal cells due to pathological activation of its excitatory receptors [202]. Research was able to show that excitatory amino acids, such as Glutamate, become more neurotoxic when the cell’s energy levels are reduced by hypoxia [211]. Activation of the glutamate NMDA receptor correlates with reduced ATP and PCr levels [212]. Creatine was able to protect animal brain tissues from the apoptotic effects of excitatory amino acids [213,214]. Lastly, it was shown that Creatine stabilizes mPTP in rodent studies, thus protecting brain tissue from apoptosis and cell death [67]. Table 5 presents a summary of the level of evidence related to creatine supplementation for traumatic and ischemic CNS injuries [205,206,207].

7. Neurodegenerative Disorders

Ageing has been defined as a “progressive accumulation of changes with time that are associated with or responsible for the ever-increasing susceptibility to disease and death” [215]. Brain tissue is due to its high-energy demands especially vulnerable to mitochondrial deficits, ROS, hypoxia, and energy depletion [216,217]. Although ROS are of special need to neurons and brain tissue needed for synaptic plasticity, learning and memory function, their overproduction is closely related to nitration of proteins, mtDNA impairment and the development of neurodegenerative diseases, ageing, and cognitive deficits [218,219,220]. Insulin resistance and diabetes mellitus deteriorate these conditions and accelerate cognitive decline as well as incidence of neurogenerative diseases [221,222,223]. RAGE and ammonium level up the documented damage to mitochondria, neuronal cells, and brain tissue [224,225,226]. Alzheimer’s disease has already been named “type 3 diabetes“ [227]. Pathologically altered mitochondria have been shown to be swollen, have altered membrane potential, and reductions of ATP levels [228]. Therefore, mitochondrial protection and reduction of oxidative stress have been suggested to be of high therapeutic importance for the treatment of neurodegenerative disorders [229]. Anti-inflammatory nutrition, caloric restriction, as well as the use of supplements have been discussed to be improve mitochondrial functioning and cognition [230,231,232,233]. Various studies have also shown that creatine supplementation has a positive effect on cognition and brain function [234,235]. The effect was greater the more the participant was exposed to external stressors (e.g., hypoxia, sleep deprivation, etc.) [45,205] or the more complex the tasks were performed [236]. In this context, intake led to a lower need for sleep, earlier wake-up times, and improved sleep behavior [237].
Neurodegenerative diseases are usually characterized by the destruction or dysfunction of neurons in a specific brain area. Depending on the affected brain area, course, and severity, the forms of the disease differ. These include Alzheimer’s disease (MA), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington’s disease (MH), and Parkinson’s disease (MP). Impaired energy balance with mitochondrial dysfunction and oxidative stress are common to all diseases [238]. Similar findings have been made with intellectual disability-related diseases [239]. This bioenergetic deficit is thought to lead to apoptosis and necrosis and ultimately to neuronal degeneration [240]. Therefore, it is reasonable to assume that an improvement in mitochondrial health could enable a positive influence on the course of the disease. Table 6 provides a summary of the level of evidence related to the role of creatine supplementation for neurodegenerative disorders [45,234,236]. Initial studies suggest that creatine supplementation may be neuroprotective. For example, in 2013, Kley and coworkers [241] conducted a Cochrane review on the role of creatine monohydrate supplementation for treating muscle disorders. The researchers found sound evidence from randomized clinical trials that creatine supplementation increased strength and functional capacity in muscular dystrophy and idiopathic inflammatory myopathy while having no effect in patients with metabolic-related myopathies and McArdle disease. More long-term research is needed to evaluate the long-term effects of creatine in neurodegenerative diseases that impair muscle function.

8. Psychological Disorders

In the 1980s, a link was established between bioenergetic deficits and depression [190,242,243,244], bipolar disorders [114,245,246], and obsessive–compulsive disorders [247,248]. It is believed that there is an increase in energy demand with depletion of PCr stores at the onset of disease [124,249]. In clinical trials with depressed patients [250,251,252], a positive effect on subjective impairment after adjuvant creatine supplementation could be demonstrated. The higher the increase in cerebral PCr after creatine supplementation, the lower the depressive or manic symptoms [253]. The combination of antidepressants and creatine was more effective than simple pharmacological medication [254]. Creatine administration was even effective when drug therapy with SSRIs proved to be ineffective [255]. In this content, creatine has also been discussed as a potential therapeutic agent in the treatment of drug addiction and its psychic related disorders [256]. Positive effects of creatine supplementation have also been reported in post-traumatic stress disorders [257]. Schizophrenic and stress patients seem to gain no benefit from creatine intake. There is, however, ongoing debate on higher dosage for a needed benefit in these sub-groups [258]. Table 7 presents a summary of the literature related to the effects of creatine supplementation on individuals with psychological disorders [251,252,255].

9. Chronic Fatigue Syndrome, Post Viral Fatigue Syndrome, and Long COVID

Fatigue is the most characteristic symptom of an energy deficit. There does not, however, exist a proper definition of the fatigue syndrome [259]. Fibromyalgia is a similar pathological entity closely related to CFS. Initially thought to be purely a psychological problem, linking fatigue to depression or other psychiatric diseases, newer research has been able to prove a metabolic dysfunction causing the symptoms [99,260,261]. Linking this clinical state with mitochondrial dysfunction was first able when lowered mitochondrial ATP levels were shown using MRS on patients with fatigue syndrome [262]. Later muscle biopsies and serum biomarkers have been able to show reduced mitochondrial biomarkers [263,264]. These markers have been Carnitine and CoQ10 [265]. On a mitochondrial level fatty acid metabolism was altered, electron transport chain was disrupted, there was a greater need in glucose concentrations and higher levels of lactate were shown [266]. Higher creatinine excretion via urine was shown to correlate positively with fatigue and pain severity. Being the end product of creatine, this urine marker could imply a higher turnover and depletion of the body’s creatine storage [267]. More recent hypotheses state that these alterations have been caused by an activation of immune–inflammatory pathways due to viral infections (e.g., Epstein Barr, Q Fever, Ross River Infection) [268].
Long COVID is a persistent fatigue state after Sars-2-CoV-2 infection [269,270]. Interestingly, even asymptomatic patients exhibited raised biomarkers involved in inflammation and stress response [271]. Long COVID, Chronic Fatigue Syndrome, and Post Viral Fatigue Syndrome are believed to be the same entity [248,272]. Supplementation of guadinioacteic acid, a precursor of creatine, was able to attenuate several aspects of fatigue in fibromyalgia patients [273]. In combination of experimental findings as well as these first promising clinical outcomes, creatine might be an important key in the rehabilitation process of CFS and Long COVID patients [274]. Table 8 summarizes the available literature on the effects of the creatine precursor GAA on chronic fatigue and Post-COVID syndrome [274].

10. Conclusions

This review summarizes creatine’s impact on mitochondrial function besides restoring ATP-storage. Creatine monohydrate is one of the best-known nutrient supplements mainly being used for improvement of athletic performance. However, there is growing evidence for a broader therapeutic spectrum of this nitrogen–amino-compound. Various health-promoting effects on cell-metabolism after the intake of creatine have been shown. Its impact on mitochondrial integrity has become of special interest. Mitochondrial dysfunction has become a central pathological hallmark of non-communicable diseases. The supplementation of creatine monohydrate may have some synergistic effects in the treatment of CND. This seems to be directly related to its protective effects on mitochondria. Different from pharmaceutical products, the intake of creatine is safe age- and gender-independent with nearly no side-effects [49,50]. Although these findings are promising, much of the available data has been generated with in vitro or animal studies. Therefore, there is a need to conduct more clinical trials in humans to assess the potential therapeutic effects of creatine monohydrate supplementation on conditions influencing mitochondrial function.

Author Contributions

Conceptualization, R.P.M.; writing—original draft preparation, R.P.M.; writing—review and editing, R.P.M., J.-N.D., J.G., and R.B.K.; funding acquisition, R.P.M. All authors have read and agreed to the published version of the manuscript.

Funding

The APC of selected papers of this special issue are being funded by AlzChem, LLC. (Trostberg, Germany) who manufactures creatine monohydrate. The funders had no role in the writing of the manuscript, interpretation of the literature, or in the decision to publish the results.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors would like to thank all of the research participants, scholars, and funding agencies who have contributed to the research cited in this manuscript.

Conflicts of Interest

R.P.M. received financial support for presenting on creatine at industry sponsored scientific conferences. J.N.D. declares there is no financial and no non-financial conflict of interest. J.G. reports no conflict of interest. R.B.K. has conducted industry sponsored research on creatine, received financial support for presenting on creatine at industry sponsored scientific conferences, and has served as an expert witness on cases related to creatine. Additionally, he serves as Chair of the Scientific Advisory Board for AlzChem who sponsored this special issue.

References

  1. Bonilla, D.A.; Kreider, R.B.; Stout, J.R.; Forero, D.A.; Kerksick, C.M.; Roberts, M.D.; Rawson, E.S. Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review. Nutrients 2021, 13, 1238. [Google Scholar] [CrossRef]
  2. Candow, D.G.; Forbes, S.C.; Chilibeck, P.D.; Cornish, S.M.; Antonio, J.; Kreider, R.B. Effectiveness of Creatine Supplementation on Aging Muscle and Bone: Focus on Falls Prevention and Inflammation. J. Clin. Med. 2019, 8, 488. [Google Scholar] [CrossRef] [Green Version]
  3. Brosnan, M.E.; Brosnan, J.T. The role of dietary creatine. Amino Acids 2016, 48, 1785–1791. [Google Scholar] [CrossRef]
  4. Harris, R. Creatine in health, medicine and sport: An introduction to a meeting held at Downing College, University of Cambridge, July 2010. Amino Acids 2011, 40, 1267. [Google Scholar] [CrossRef] [Green Version]
  5. Harris, R.C.; Soderlund, K.; Hultman, E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin. Sci. 1992, 83, 367–374. [Google Scholar] [CrossRef] [Green Version]
  6. Kreider, R.B.; Stout, J.R. Creatine in Health and Disease. Nutrients 2021, 13, 447. [Google Scholar] [CrossRef]
  7. Hultman, E.; Soderlund, K.; Timmons, J.A.; Cederblad, G.; Greenhaff, P.L. Muscle creatine loading in men. J. Appl. Physiol. 1996, 81, 232–237. [Google Scholar] [CrossRef]
  8. Wallimann, T.; Tokarska-Schlattner, M.; Schlattner, U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids 2011, 40, 1271–1296. [Google Scholar] [CrossRef] [Green Version]
  9. Huertas, J.R.; Casuso, R.A.; Agustín, P.H.; Cogliati, S. Stay Fit, Stay Young: Mitochondria in Movement: The Role of Exercise in the New Mitochondrial Paradigm. Oxidative Med. Cell. Longev. 2019, 2019, e7058350. [Google Scholar] [CrossRef] [Green Version]
  10. Negro, M.; Avanzato, I.; D’Antona, G. Chapter 2.7—Creatine in Skeletal Muscle Physiology. In Nonvitamin and Nonmineral Nutritional Supplements; Nabavi, S.M., Silva, A.S., Eds.; Academic Press: Cambridge, MA, USA, 2019; pp. 59–68. [Google Scholar]
  11. Nelson, A.G.; Arnall, D.A.; Kokkonen, J.; Day, R.; Evans, J. Muscle glycogen supercompensation is enhanced by prior creatine supplementation. Med. Sci. Sports Exerc. 2001, 33, 1096–1100. [Google Scholar] [CrossRef]
  12. Tarnopolsky, M.A.; Parise, G. Direct measurement of high-energy phosphate compounds in patients with neuromuscular disease. Muscle Nerve 1999, 22, 1228–1233. [Google Scholar] [CrossRef]
  13. McKenna, M.J.; Morton, J.; Selig, S.E.; Snow, R.J. Creatine supplementation increases muscle total creatine but not maximal intermittent exercise performance. J. Appl. Physiol. 1999, 87, 2244–2252. [Google Scholar] [CrossRef]
  14. Greenhaff, P.L.; Bodin, K.; Soderlund, K.; Hultman, E. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am. J. Physiol. 1994, 266, E725–E730. [Google Scholar] [CrossRef]
  15. Greenwood, M.; Kreider, R.B.; Earnest, C.P.; Rasmussen, C.; Almada, A. Differences in creatine retention among three nutritional formulations of oral creatine supplements. J. Exerc. Physiol. Online 2003, 6, 37–43. [Google Scholar]
  16. Choi, J.K.; Kustermann, E.; Dedeoglu, A.; Jenkins, B.G. Magnetic resonance spectroscopy of regional brain metabolite markers in FALS mice and the effects of dietary creatine supplementation. Eur. J. Neurosci. 2009, 30, 2143–2150. [Google Scholar] [CrossRef] [Green Version]
  17. Lyoo, I.K.; Kong, S.W.; Sung, S.M.; Hirashima, F.; Parow, A.; Hennen, J.; Cohen, B.M.; Renshaw, P.F. Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate. Psychiatry Res. 2003, 123, 87–100. [Google Scholar] [CrossRef]
  18. Roschel, H.; Gualano, B.; Ostojic, S.M.; Rawson, E.S. Creatine Supplementation and Brain Health. Nutrients 2021, 13, 586. [Google Scholar] [CrossRef]
  19. Dolan, E.; Gualano, B.; Rawson, E.S. Beyond muscle: The effects of creatine supplementation on brain creatine, cognitive processing, and traumatic brain injury. Eur. J. Sport Sci. 2019, 19, 1–14. [Google Scholar] [CrossRef]
  20. Gualano, B.; Rawson, E.S.; Candow, D.G.; Chilibeck, P.D. Creatine supplementation in the aging population: Effects on skeletal muscle, bone and brain. Amino Acids 2016, 48, 1793–1805. [Google Scholar] [CrossRef]
  21. Rawson, E.S.; Venezia, A.C. Use of creatine in the elderly and evidence for effects on cognitive function in young and old. Amino Acids 2011, 40, 1349–1362. [Google Scholar] [CrossRef]
  22. Cornish, S.M.; Chilibeck, P.D.; Burke, D.G. The effect of creatine monohydrate supplementation on sprint skating in ice-hockey players. J. Sports Med. Phys. Fitness 2006, 46, 90–98. [Google Scholar]
  23. Dawson, B.; Vladich, T.; Blanksby, B.A. Effects of 4 weeks of creatine supplementation in junior swimmers on freestyle sprint and swim bench performance. J. Strength Cond. Res. 2002, 16, 485–490. [Google Scholar]
  24. Grindstaff, P.D.; Kreider, R.; Bishop, R.; Wilson, M.; Wood, L.; Alexander, C.; Almada, A. Effects of creatine supplementation on repetitive sprint performance and body composition in competitive swimmers. Int. J. Sport Nutr. 1997, 7, 330–346. [Google Scholar] [CrossRef]
  25. Juhasz, I.; Gyore, I.; Csende, Z.; Racz, L.; Tihanyi, J. Creatine supplementation improves the anaerobic performance of elite junior fin swimmers. Acta Physiol. Hung. 2009, 96, 325–336. [Google Scholar] [CrossRef]
  26. Silva, A.J.; Machado Reis, V.; Guidetti, L.; Bessone Alves, F.; Mota, P.; Freitas, J.; Baldari, C. Effect of creatine on swimming velocity, body composition and hydrodynamic variables. J. Sports Med. Phys. Fitness 2007, 47, 58–64. [Google Scholar]
  27. Kreider, R.B.; Ferreira, M.; Wilson, M.; Grindstaff, P.; Plisk, S.; Reinardy, J.; Cantler, E.; Almada, A.L. Effects of creatine supplementation on body composition, strength, and sprint performance. Med. Sci. Sports Exerc. 1998, 30, 73–82. [Google Scholar] [CrossRef]
  28. Stone, M.H.; Sanborn, K.; Smith, L.L.; O’Bryant, H.S.; Hoke, T.; Utter, A.C.; Johnson, R.L.; Boros, R.; Hruby, J.; Pierce, K.C.; et al. Effects of in-season (5 weeks) creatine and pyruvate supplementation on anaerobic performance and body composition in American football players. Int. J. Sport Nutr. 1999, 9, 146–165. [Google Scholar] [CrossRef]
  29. Bemben, M.G.; Bemben, D.A.; Loftiss, D.D.; Knehans, A.W. Creatine supplementation during resistance training in college football athletes. Med. Sci. Sports Exerc. 2001, 33, 1667–1673. [Google Scholar] [CrossRef]
  30. Hoffman, J.; Ratamess, N.; Kang, J.; Mangine, G.; Faigenbaum, A.; Stout, J. Effect of creatine and beta-alanine supplementation on performance and endocrine responses in strength/power athletes. Int. J. Sport Nutr. Exerc. Metab. 2006, 16, 430–446. [Google Scholar] [CrossRef] [Green Version]
  31. Chilibeck, P.D.; Magnus, C.; Anderson, M. Effect of in-season creatine supplementation on body composition and performance in rugby union football players. Appl. Physiol. Nutr. Metab. 2007, 32, 1052–1057. [Google Scholar] [CrossRef]
  32. Claudino, J.G.; Mezencio, B.; Amaral, S.; Zanetti, V.; Benatti, F.; Roschel, H.; Gualano, B.; Amadio, A.C.; Serrao, J.C. Creatine monohydrate supplementation on lower-limb muscle power in Brazilian elite soccer players. J. Int. Soc. Sports Nutr. 2014, 11, 32. [Google Scholar] [CrossRef] [Green Version]
  33. Kerksick, C.M.; Rasmussen, C.; Lancaster, S.; Starks, M.; Smith, P.; Melton, C.; Greenwood, M.; Almada, A.; Kreider, R. Impact of differing protein sources and a creatine containing nutritional formula after 12 weeks of resistance training. Nutrition 2007, 23, 647–656. [Google Scholar] [CrossRef]
  34. Kerksick, C.M.; Wilborn, C.D.; Campbell, W.I.; Harvey, T.M.; Marcello, B.M.; Roberts, M.D.; Parker, A.G.; Byars, A.G.; Greenwood, L.D.; Almada, A.L.; et al. The effects of creatine monohydrate supplementation with and without D-pinitol on resistance training adaptations. J. Strength Cond. Res. 2009, 23, 2673–2682. [Google Scholar] [CrossRef] [Green Version]
  35. Galvan, E.; Walker, D.K.; Simbo, S.Y.; Dalton, R.; Levers, K.; O’Connor, A.; Goodenough, C.; Barringer, N.D.; Greenwood, M.; Rasmussen, C.; et al. Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance. J. Int. Soc. Sports Nutr. 2016, 13, 12. [Google Scholar] [CrossRef] [Green Version]
  36. Volek, J.S.; Kraemer, W.J.; Bush, J.A.; Boetes, M.; Incledon, T.; Clark, K.L.; Lynch, J.M. Creatine supplementation enhances muscular performance during high-intensity resistance exercise. J. Am. Diet. Assoc. 1997, 97, 765–770. [Google Scholar] [CrossRef]
  37. Volek, J.S.; Mazzetti, S.A.; Farquhar, W.B.; Barnes, B.R.; Gomez, A.L.; Kraemer, W.J. Physiological responses to short-term exercise in the heat after creatine loading. Med. Sci. Sports Exerc. 2001, 33, 1101–1108. [Google Scholar] [CrossRef]
  38. Volek, J.S.; Ratamess, N.A.; Rubin, M.R.; Gomez, A.L.; French, D.N.; McGuigan, M.M.; Scheett, T.P.; Sharman, M.J.; Hakkinen, K.; Kraemer, W.J. The effects of creatine supplementation on muscular performance and body composition responses to short-term resistance training overreaching. Eur. J. Appl. Physiol. 2004, 91, 628–637. [Google Scholar] [CrossRef]
  39. Buford, T.W.; Kreider, R.B.; Stout, J.R.; Greenwood, M.; Campbell, B.; Spano, M.; Ziegenfuss, T.; Lopez, H.; Landis, J.; Antonio, J. International Society of Sports Nutrition position stand: Creatine supplementation and exercise. J. Int. Soc. Sports Nutr. 2007, 4, 6. [Google Scholar] [CrossRef] [Green Version]
  40. Kreider, R.B.; Wilborn, C.D.; Taylor, L.; Campbell, B.; Almada, A.L.; Collins, R.; Cooke, M.; Earnest, C.P.; Greenwood, M.; Kalman, D.S.; et al. ISSN exercise & sport nutrition review: Research & recommendations. J. Int. Soc. Sports Nutr. 2010, 7, 7. [Google Scholar] [CrossRef] [Green Version]
  41. Branch, J.D. Effect of creatine supplementation on body composition and performance: A meta-analysis. Int. J. Sport Nutr. Exerc. Metab. 2003, 13, 198–226. [Google Scholar] [CrossRef]
  42. Devries, M.C.; Phillips, S.M. Creatine supplementation during resistance training in older adults-a meta-analysis. Med. Sci. Sports Exerc. 2014, 46, 1194–1203. [Google Scholar] [CrossRef]
  43. Lanhers, C.; Pereira, B.; Naughton, G.; Trousselard, M.; Lesage, F.X.; Dutheil, F. Creatine Supplementation and Lower Limb Strength Performance: A Systematic Review and Meta-Analyses. Sports Med. 2015, 45, 1285–1294. [Google Scholar] [CrossRef]
  44. Wiroth, J.B.; Bermon, S.; Andrei, S.; Dalloz, E.; Hebuterne, X.; Dolisi, C. Effects of oral creatine supplementation on maximal pedalling performance in older adults. Eur. J. Appl. Physiol. 2001, 84, 533–539. [Google Scholar] [CrossRef]
  45. McMorris, T.; Mielcarz, G.; Harris, R.C.; Swain, J.P.; Howard, A. Creatine supplementation and cognitive performance in elderly individuals. Neuropsychol. Dev. Cogn. B Aging Neuropsychol. Cogn. 2007, 14, 517–528. [Google Scholar] [CrossRef]
  46. Rawson, E.S.; Clarkson, P.M. Acute creatine supplementation in older men. Int. J. Sports Med. 2000, 21, 71–75. [Google Scholar] [CrossRef]
  47. Tarnopolsky, M.A. Potential benefits of creatine monohydrate supplementation in the elderly. Curr. Opin. Clin. Nutr. Metab. Care 2000, 3, 497–502. [Google Scholar] [CrossRef]
  48. Aguiar, A.F.; Januario, R.S.; Junior, R.P.; Gerage, A.M.; Pina, F.L.; do Nascimento, M.A.; Padovani, C.R.; Cyrino, E.S. Long-term creatine supplementation improves muscular performance during resistance training in older women. Eur. J. Appl. Physiol. 2013, 113, 987–996. [Google Scholar] [CrossRef]
  49. Kreider, R.B.; Kalman, D.S.; Antonio, J.; Ziegenfuss, T.N.; Wildman, R.; Collins, R.; Candow, D.G.; Kleiner, S.M.; Almada, A.L.; Lopez, H.L. International Society of Sports Nutrition position stand: Safety and efficacy of creatine supplementation in exercise, sport, and medicine. J. Int. Soc. Sports Nutr. 2017, 14, 18. [Google Scholar] [CrossRef]
  50. Antonio, J.; Candow, D.G.; Forbes, S.C.; Gualano, B.; Jagim, A.R.; Kreider, R.B.; Rawson, E.S.; Smith-Ryan, A.E.; VanDusseldorp, T.A.; Willoughby, D.S.; et al. Common questions and misconceptions about creatine supplementation: What does the scientific evidence really show? J. Int. Soc. Sports Nutr. 2021, 18, 13. [Google Scholar] [CrossRef]
  51. Brand, M.D.; Nicholls, D.G. Assessing mitochondrial dysfunction in cells. Biochem. J. 2011, 435, 297–312. [Google Scholar] [CrossRef] [Green Version]
  52. Read, C.Y.; Calnan, R.J. Mitochondrial disease: Beyond etiology unknown. J. Pediatr. Nurs. 2000, 15, 232–241. [Google Scholar] [CrossRef]
  53. Cohen, B.H.; Gold, D.R. Mitochondrial cytopathy in adults: What we know so far. Clev. Clin. J. Med. 2001, 68, 625–642. [Google Scholar] [CrossRef] [Green Version]
  54. Giza, C.C.; Hovda, D.A. The Neurometabolic Cascade of Concussion. J. Athl. Train 2001, 36, 228–235. [Google Scholar] [CrossRef] [Green Version]
  55. Dean, A.; Philip, J.; Arikan, G.; Opitz, B.; Sterr, A. Potential for use of creatine supplementation following mild traumatic brain injury. Concussion 2017, 2, CNC34. [Google Scholar] [CrossRef] [Green Version]
  56. Gaetz, M. The neurophysiology of brain injury. Clin. Neurophysiol. 2004, 115, 4–18. [Google Scholar] [CrossRef] [Green Version]
  57. Brooke, N.S.; Ouwerkerk, R.; Adams, C.B.; Radda, G.K.; Ledingham, J.G.; Rajagopalan, B. Phosphorus-31 magnetic resonance spectra reveal prolonged intracellular acidosis in the brain following subarachnoid hemorrhage. Proc. Natl. Acad. Sci. USA 1994, 91, 1903–1907. [Google Scholar] [CrossRef] [Green Version]
  58. Abe, K.; Aoki, M.; Kawagoe, J.; Yoshida, T.; Hattori, A.; Kogure, K.; Itoyama, Y. Ischemic Delayed Neuronal Death. Stroke 1995, 26, 1478–1489. [Google Scholar] [CrossRef]
  59. Ankarcrona, M.; Dypbukt, J.M.; Bonfoco, E.; Zhivotovsky, B.; Orrenius, S.; Lipton, S.A.; Nicotera, P. Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995, 15, 961–973. [Google Scholar] [CrossRef] [Green Version]
  60. Fiskum, G.; Murphy, A.N.; Beal, M.F. Mitochondria in Neurodegeneration: Acute Ischemia and Chronic Neurodegenerative Diseases. J. Cereb. Blood Flow Metab. 1999, 19, 351–369. [Google Scholar] [CrossRef]
  61. Schinder, A.F.; Olson, E.C.; Spitzer, N.C.; Montal, M. Mitochondrial Dysfunction Is a Primary Event in Glutamate Neurotoxicity. J. Neurosci. 1996, 16, 6125–6133. [Google Scholar] [CrossRef] [Green Version]
  62. Béard, E.; Braissant, O. Synthesis and transport of creatine in the CNS: Importance for cerebral functions. J. Neurochem. 2010, 115, 297–313. [Google Scholar] [CrossRef] [Green Version]
  63. Rabinowitz, A.R.; Li, X.; Levin, H.S. Sport and nonsport etiologies of mild traumatic brain injury: Similarities and differences. Annu. Rev. Psychol. 2014, 65, 301–331. [Google Scholar] [CrossRef]
  64. Signoretti, S.; Lazzarino, G.; Tavazzi, B.; Vagnozzi, R. The pathophysiology of concussion. PM R 2011, 3, S359–S368. [Google Scholar] [CrossRef]
  65. Andres, R.H.; Ducray, A.D.; Schlattner, U.; Wallimann, T.; Widmer, H.R. Functions and effects of creatine in the central nervous system. Brain Res. Bull. 2008, 76, 329–343. [Google Scholar] [CrossRef]
  66. Gualano, B.; Roschel, H.; Lancha, A.H.; Brightbill, C.E.; Rawson, E.S. In sickness and in health: The widespread application of creatine supplementation. Amino Acids 2012, 43, 519–529. [Google Scholar] [CrossRef]
  67. Rae, C.D.; Bröer, S. Creatine as a booster for human brain function. How might it work? Neurochem. Int. 2015, 89, 249–259. [Google Scholar] [CrossRef]
  68. Perasso, L.; Spallarossa, P.; Gandolfo, C.; Ruggeri, P.; Balestrino, M. Therapeutic Use of Creatine in Brain or Heart Ischemia: Available Data and Future Perspectives. Med. Res. Rev. 2013, 33, 336–363. [Google Scholar] [CrossRef]
  69. O’Gorman, E.; Beutner, G.; Dolder, M.; Koretsky, A.P.; Brdiczka, D.; Wallimann, T. The role of creatine kinase in inhibition of mitochondrial permeability transition. FEBS Lett. 1997, 414, 253–257. [Google Scholar] [CrossRef] [Green Version]
  70. Meyer, L.E.; Machado, L.B.; Santiago, A.P.; Da-Silva, W.S.; De Felice, F.G.; Holub, O.; Oliveira, M.F.; Galina, A. Mitochondrial creatine kinase activity prevents reactive oxygen species generation: Antioxidant role of mitochondrial kinase-dependent ADP re-cycling activity. J. Biol. Chem. 2006, 281, 37361–37371. [Google Scholar] [CrossRef] [Green Version]
  71. Sakellaris, G.; Kotsiou, M.; Tamiolaki, M.; Kalostos, G.; Tsapaki, E.; Spanaki, M.; Spilioti, M.; Charissis, G.; Evangeliou, A. Prevention of complications related to traumatic brain injury in children and adolescents with creatine administration: An open label randomized pilot study. J. Trauma 2006, 61, 322–329. [Google Scholar] [CrossRef]
  72. Sakellaris, G.; Nasis, G.; Kotsiou, M.; Tamiolaki, M.; Charissis, G.; Evangeliou, A. Prevention of traumatic headache, dizziness and fatigue with creatine administration. A pilot study. Acta Paediatr. 2008, 97, 31–34. [Google Scholar] [CrossRef]
  73. Sosa, V.; Moliné, T.; Somoza, R.; Paciucci, R.; Kondoh, H.; Lleonart, M.E. Oxidative stress and cancer: An overview. Ageing Res. Rev. 2013, 12, 376–390. [Google Scholar] [CrossRef]
  74. Nicolson, G.L.; Ferreira, G.; Settineri, R.; Ellithorpe, R.R.; Breeding, P.; Ash, M.E. Mitochondrial Dysfunction and Chronic Disease: Treatment with Membrane Lipid Replacement and Other Natural Supplements. In Mitochondrial Biology and Experimental Therapeutics; Oliveira, P.J., Ed.; Springer International Publishing: Berlin/Heidelberg, Germany, 2018; pp. 499–522. [Google Scholar]
  75. Newell, C.; Leduc-Pessah, H.; Khan, A.; Shearer, J. Mitochondrial Dysfunction in Chronic Disease. In The Routledge Handbook on Biochemistry of Exercise; Routledge: Abingdon, UK, 2020. [Google Scholar]
  76. Victor, M.V.; Rocha, M.; Herance, R.; Hernandez-Mijares, A. Oxidative Stress and Mitochondrial Dysfunction in Type 2 Diabetes. Curr. Pharm. Des. 2011, 17, 3947–3958. [Google Scholar] [CrossRef]
  77. Picard, M.; Turnbull, D.M. Linking the Metabolic State and Mitochondrial DNA in Chronic Disease, Health, and Aging. Diabetes 2013, 62, 672–678. [Google Scholar] [CrossRef] [Green Version]
  78. Pieczenik, S.R.; Neustadt, J. Mitochondrial dysfunction and molecular pathways of disease. Exp. Mol. Pathol. 2007, 83, 84–92. [Google Scholar] [CrossRef]
  79. Madamanchi, N.R.; Runge, M.S. Mitochondrial Dysfunction in Atherosclerosis. Circ. Res. 2007, 100, 460–473. [Google Scholar] [CrossRef] [Green Version]
  80. Galvan, D.L.; Green, N.H.; Danesh, F.R. The hallmarks of mitochondrial dysfunction in chronic kidney disease. Kidney Int. 2017, 92, 1051–1057. [Google Scholar] [CrossRef]
  81. Cloonan, S.M.; Kim, K.; Esteves, P.; Trian, T.; Barnes, P.J. Mitochondrial dysfunction in lung ageing and disease. Eur. Respir. Rev. 2020, 29, 157. [Google Scholar] [CrossRef]
  82. Wei, P.Z.; Szeto, C.C. Mitochondrial dysfunction in diabetic kidney disease. Clin. Chim. Acta 2019, 496, 108–116. [Google Scholar] [CrossRef]
  83. Mansouri, A.; Gattolliat, C.-H.; Asselah, T. Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases. Gastroenterology 2018, 155, 629–647. [Google Scholar] [CrossRef] [Green Version]
  84. Fang, T.; Wang, M.; Xiao, H.; Wei, X. Mitochondrial dysfunction and chronic lung disease. Cell Biol. Toxicol. 2019, 35, 493–502. [Google Scholar] [CrossRef] [PubMed]
  85. López-Armada, M.J.; Riveiro-Naveira, R.R.; Vaamonde-García, C.; Valcárcel-Ares, M.N. Mitochondrial dysfunction and the inflammatory response. Mitochondrion 2013, 13, 106–118. [Google Scholar] [CrossRef] [PubMed]
  86. Castellani, R.; Hirai, K.; Aliev, G.; Drew, K.L.; Nunomura, A.; Takeda, A.; Cash, A.D.; Obrenovich, M.E.; Perry, G.; Smith, M.A. Role of mitochondrial dysfunction in Alzheimer’s disease. J. Neurosci. Res. 2002, 70, 357–360. [Google Scholar] [CrossRef] [PubMed]
  87. Sorrentino, V.; Menzies, K.J.; Auwerx, J. Repairing Mitochondrial Dysfunction in Disease. Annu. Rev. Pharmacol. Toxicol. 2018, 58, 353–389. [Google Scholar] [CrossRef]
  88. Abrigo, J.; Simon, F.; Cabrera, D.; Vilos, C.; Cabello-Verrugio, C. Mitochondrial Dysfunction in Skeletal Muscle Pathologies. Curr. Protein Pept. Sci. 2019, 20, 536–546. [Google Scholar] [CrossRef] [PubMed]
  89. Prakash, Y.S.; Pabelick, C.M.; Sieck, G.C. Mitochondrial Dysfunction in Airway Disease. Chest 2017, 152, 618–626. [Google Scholar] [CrossRef]
  90. Diaz-Vegas, A.; Sanchez-Aguilera, P.; Krycer, J.R.; Morales, P.E.; Monsalves-Alvarez, M.; Cifuentes, M.; Rothermel, B.A.; Lavandero, S. Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases? Endocr. Rev. 2020, 41, 491–517. [Google Scholar] [CrossRef]
  91. Novak, E.A.; Mollen, K.P. Mitochondrial dysfunction in inflammatory bowel disease. Front. Cell Dev. Biol. 2015, 3, 62. [Google Scholar] [CrossRef] [Green Version]
  92. Ballinger, S.W. Mitochondrial dysfunction in cardiovascular disease. Free Radic. Biol. Med. 2005, 38, 1278–1295. [Google Scholar] [CrossRef]
  93. Rosca, M.G.; Hoppel, C.L. Mitochondrial dysfunction in heart failure. Heart Fail. Rev. 2013, 18, 607–622. [Google Scholar] [CrossRef] [Green Version]
  94. Chistiakov, D.A.; Shkurat, T.P.; Melnichenko, A.A.; Grechko, A.V.; Orekhov, A.N. The role of mitochondrial dysfunction in cardiovascular disease: A brief review. Ann. Med. 2018, 50, 121–127. [Google Scholar] [CrossRef] [PubMed]
  95. Li, X.; Zhang, W.; Cao, Q.; Wang, Z.; Zhao, M.; Xu, L.; Zhuang, Q. Mitochondrial dysfunction in fibrotic diseases. Cell Death Discov. 2020, 6, 1–14. [Google Scholar] [CrossRef] [PubMed]
  96. Johri, A.; Beal, M.F. Mitochondrial Dysfunction in Neurodegenerative Diseases. J. Pharmacol. Exp. Ther. 2012, 342, 619–630. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Barot, M.; Gokulgandhi, M.R.; Mitra, A.K. Mitochondrial Dysfunction in Retinal Diseases. Curr. Eye Res. 2011, 36, 1069–1077. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Hu, F.; Liu, F. Mitochondrial stress: A bridge between mitochondrial dysfunction and metabolic diseases? Cell. Signal. 2011, 23, 1528–1533. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Myhill, S.; Booth, N.E.; McLaren-Howard, J. Chronic fatigue syndrome and mitochondrial dysfunction. Int. J. Clin. Exp. Med. 2009, 2, 1–16. [Google Scholar]
  100. Haas, R.H. Mitochondrial Dysfunction in Aging and Diseases of Aging. Biology 2019, 8, 48. [Google Scholar] [CrossRef] [Green Version]
  101. Kemp, G.J. Mitochondrial dysfunction in chronic ischemia and peripheral vascular disease. Mitochondrion 2004, 4, 629–640. [Google Scholar] [CrossRef]
  102. Liberti, M.V.; Locasale, J.W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem. Sci. 2016, 41, 211–218. [Google Scholar] [CrossRef] [Green Version]
  103. Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science 2009, 324, 1029–1033. [Google Scholar] [CrossRef] [Green Version]
  104. Zapelini, P.H.; Rezin, G.T.; Cardoso, M.R.; Ritter, C.; Klamt, F.; Moreira, J.C.F.; Streck, E.L.; Dal-Pizzol, F. Antioxidant treatment reverses mitochondrial dysfunction in a sepsis animal model. Mitochondrion 2008, 8, 211–218. [Google Scholar] [CrossRef] [PubMed]
  105. Molnár, A.G.; Kun, S.; Sélley, E.; Kertész, M.; Szélig, L.; Csontos, C.; Böddi, K.; Bogár, L.; Miseta, A.; Wittmann, I. Role of Tyrosine Isomers in Acute and Chronic Diseases Leading to Oxidative Stress—A Review. Curr. Med. Chem. 2016, 23, 667–685. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Ortiz, G.G.; Pacheco Moisés, F.P.; Mireles-Ramírez, M.; Flores-Alvarado, L.J.; González-Usigli, H.; Sánchez-González, V.J.; Sánchez-López, A.L.; Sánchez-Romero, L.; Díaz-Barba, E.I.; Santoscoy-Gutiérrez, J.F.; et al. Chapter One-Oxidative Stress: Love and Hate History in Central Nervous System. In Advances in Protein Chemistry and Structural Biology; Stress and Inflammation in Disorders; Donev, R., Ed.; Academic Press: Cambridge, MA, USA, 2017; Volume 108, pp. 1–31. [Google Scholar]
  107. Incalza, M.A.; D’Oria, R.; Natalicchio, A.; Perrini, S.; Laviola, L.; Giorgino, F. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vasc. Pharmacol. 2018, 100, 1–19. [Google Scholar] [CrossRef] [PubMed]
  108. Pall, M.L.; Levine, S. Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors. Sheng Li Xue Bao 2015, 67, 1–18. [Google Scholar]
  109. Moldogazieva, N.T.; Mokhosoev, I.M.; Mel’nikova, T.I.; Porozov, Y.B.; Terentiev, A.A. Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases. Oxidative Med. Cell. Longev. 2019, 2019, e3085756. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Bangsbo, J. Energy demands in competitive soccer. J. Sports Sci. 1994, 12, S5–S12. [Google Scholar] [CrossRef]
  111. Adeva, M.M.; Souto, G.; Blanco, N.; Donapetry, C. Ammonium metabolism in humans. Metabolism 2012, 61, 1495–1511. [Google Scholar] [CrossRef]
  112. Mutch, B.J.; Banister, E.W. Ammonia metabolism in exercise and fatigue: A review. Med. Sci. Sports Exerc. 1983, 15, 41–50. [Google Scholar] [CrossRef]
  113. Srinivasan, S.; Guha, M.; Kashina, A.; Avadhani, N.G. Mitochondrial Dysfunction and Mitochondrial Dynamics-The Cancer Connection. Biochim. Biophys. Acta 2017, 1858, 602–614. [Google Scholar] [CrossRef]
  114. Stork, C.; Renshaw, P.F. Mitochondrial dysfunction in bipolar disorder: Evidence from magnetic resonance spectroscopy research. Mol. Psychiatry 2005, 10, 900–919. [Google Scholar] [CrossRef] [Green Version]
  115. Devic, S. Warburg Effect-a Consequence or the Cause of Carcinogenesis? J. Cancer 2016, 7, 817–822. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Rani, V.; Deep, G.; Singh, R.K.; Palle, K.; Yadav, U.C.S. Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies. Life Sci. 2016, 148, 183–193. [Google Scholar] [CrossRef] [PubMed]
  117. Stepien, K.M.; Heaton, R.; Rankin, S.; Murphy, A.; Bentley, J.; Sexton, D.; Hargreaves, I.P. Evidence of Oxidative Stress and Secondary Mitochondrial Dysfunction in Metabolic and Non-Metabolic Disorders. J. Clin. Med. 2017, 6, 71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Mlynárik, V. Introduction to nuclear magnetic resonance. Anal. Biochem. 2017, 529, 4–9. [Google Scholar] [CrossRef] [PubMed]
  119. Prost, R.W. Magnetic resonance spectroscopy. Med. Phys. 2008, 35, 4530–4544. [Google Scholar] [CrossRef] [PubMed]
  120. Henning, A. Proton and multinuclear magnetic resonance spectroscopy in the human brain at ultra-high field strength: A review. Neuroimage 2018, 168, 181–198. [Google Scholar] [CrossRef]
  121. Porter, D.A.; Smith, M.A. Magnetic resonance spectroscopy in vivo. J. Biomed. Eng. 1988, 10, 562–568. [Google Scholar] [CrossRef]
  122. Bertolino, A.; Frye, M.; Callicott, J.H.; Mattay, V.S.; Rakow, R.; Shelton-Repella, J.; Post, R.; Weinberger, D.R. Neuronal pathology in the hippocampal area of patients with bipolar disorder: A study with proton magnetic resonance spectroscopic imaging. Biol. Psychiatry 2003, 53, 906–913. [Google Scholar] [CrossRef]
  123. Dager, S.R.; Friedman, S.D.; Parow, A.; Demopulos, C.; Stoll, A.L.; Lyoo, I.K.; Dunner, D.L.; Renshaw, P.F. Brain Metabolic Alterations in Medication-Free Patients with BipolarDisorder. Arch. Gen. Psychiatry 2004, 61, 450–458. [Google Scholar] [CrossRef] [Green Version]
  124. Kato, T.; Takahashi, S.; Shioiri, T.; Inubushi, T. Brain phosphorous metabolism in depressive disorders detected by phosphorus-31 magnetic resonance spectroscopy. J. Affect. Disord. 1992, 26, 223–230. [Google Scholar] [CrossRef]
  125. Kato, T.; Shioiri, T.; Murashita, J.; Hamakawa, H.; Takahashi, Y.; Inubushi, T.; Takahashi, S. Lateralized abnormality of high energy phosphate metabolism in the frontal lobes of patients with bipolar disorder detected by phase-encoded 31P-MRS. Psychol. Med. 1995, 25, 557–566. [Google Scholar] [CrossRef] [PubMed]
  126. Riesberg, L.A.; Weed, S.A.; McDonald, T.L.; Eckerson, J.M.; Drescher, K.M. Beyond muscles: The untapped potential of creatine. Int. Immunopharmacol. 2016, 37, 31–42. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Wyss, M.; Schulze, A. Health implications of creatine: Can oral creatine supplementation protect against neurological and atherosclerotic disease? Neuroscience 2002, 112, 243–260. [Google Scholar] [CrossRef]
  128. Guimarães-Ferreira, L.; Pinheiro, C.H.J.; Gerlinger-Romero, F.; Vitzel, K.F.; Nachbar, R.T.; Curi, R.; Nunes, M.T. Short-term creatine supplementation decreases reactive oxygen species content with no changes in expression and activity of antioxidant enzymes in skeletal muscle. Eur. J. Appl. Physiol. 2012, 112, 3905–3911. [Google Scholar] [CrossRef]
  129. Hunter, D.J.; Reddy, K.S. Noncommunicable Diseases. N. Engl. J. Med. 2013, 369, 1336–1343. [Google Scholar] [CrossRef] [Green Version]
  130. Peña-Oyarzun, D.; Bravo-Sagua, R.; Diaz-Vega, A.; Aleman, L.; Chiong, M.; Garcia, L.; Bambs, C.; Troncoso, R.; Cifuentes, M.; Morselli, E.; et al. Autophagy and oxidative stress in non-communicable diseases: A matter of the inflammatory state? Free Radic. Biol. Med. 2018, 124, 61–78. [Google Scholar] [CrossRef]
  131. Lozano, R.; Naghavi, M.; Foreman, K.; Lim, S.; Shibuya, K.; Aboyans, V.; Abraham, J.; Adair, T.; Aggarwal, R.; Ahn, S.Y.; et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012, 380, 2095–2128. [Google Scholar] [CrossRef]
  132. Murray, C.J.L.; Lopez, A.D. Measuring the Global Burden of Disease. N. Engl. J. Med. 2013, 369, 448–457. [Google Scholar] [CrossRef] [Green Version]
  133. World Health Organization. Noncommunicable Diseases: Progress Monitor 2020; World Health Organization: Geneva, Switzerland, 2020. [Google Scholar]
  134. Yu, E.P.K.; Reinhold, J.; Yu, H.; Starks, L.; Uryga, A.K.; Foote, K.; Finigan, A.; Figg, N.; Pung, Y.-F.; Logan, A.; et al. Mitochondrial Respiration Is Reduced in Atherosclerosis, Promoting Necrotic Core Formation and Reducing Relative Fibrous Cap Thickness. Arterioscler. Thromb. Vasc. Biol. 2017, 37, 2322–2332. [Google Scholar] [CrossRef] [Green Version]
  135. Shimizu, S.; Ishibashi, M.; Kumagai, S.; Wajima, T.; Hiroi, T.; Kurihara, T.; Ishii, M.; Kiuchi, Y. Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload. Int. J. Mol. Med. 2013, 31, 589–596. [Google Scholar] [CrossRef] [Green Version]
  136. Tang, Y.; Mi, C.; Liu, J.; Gao, F.; Long, J. Compromised mitochondrial remodeling in compensatory hypertrophied myocardium of spontaneously hypertensive rat. Cardiovasc. Pathol. 2014, 23, 101–106. [Google Scholar] [CrossRef] [PubMed]
  137. Walther, T.; Tschöpe, C.; Sterner-Kock, A.; Westermann, D.; Heringer-Walther, S.; Riad, A.; Nikolic, A.; Wang, Y.; Ebermann, L.; Siems, W.-E.; et al. Accelerated Mitochondrial Adenosine Diphosphate/Adenosine Triphosphate Transport Improves Hypertension-Induced Heart Disease. Circulation 2007, 115, 333–344. [Google Scholar] [CrossRef] [PubMed]
  138. Yu, T.; Robotham, J.L.; Yoon, Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc. Natl. Acad. Sci. USA 2006, 103, 2653–2658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Tormos, K.V.; Anso, E.; Hamanaka, R.B.; Eisenbart, J.; Joseph, J.; Kalyanaraman, B.; Chandel, N.S. Mitochondrial Complex III ROS Regulate Adipocyte Differentiation. Cell Metab. 2011, 14, 537–544. [Google Scholar] [CrossRef] [Green Version]
  140. Teodoro, J.S.; Rolo, A.P.; Duarte, F.V.; Simões, A.M.; Palmeira, C.M. Differential alterations in mitochondrial function induced by a choline-deficient diet: Understanding fatty liver disease progression. Mitochondrion 2008, 8, 367–376. [Google Scholar] [CrossRef] [Green Version]
  141. Galloway, C.A.; Lee, H.; Brookes, P.S.; Yoon, Y. Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 2014, 307, G632–G641. [Google Scholar] [CrossRef] [Green Version]
  142. Tubbs, E.; Chanon, S.; Robert, M.; Bendridi, N.; Bidaux, G.; Chauvin, M.-A.; Ji-Cao, J.; Durand, C.; Gauvrit-Ramette, D.; Vidal, H.; et al. Disruption of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Contributes to Muscle Insulin Resistance in Mice and Humans. Diabetes 2018, 67, 636–650. [Google Scholar] [CrossRef] [Green Version]
  143. Fazakerley, D.J.; Minard, A.Y.; Krycer, J.R.; Thomas, K.C.; Stöckli, J.; Harney, D.J.; Burchfield, J.G.; Maghzal, G.J.; Caldwell, S.T.; Hartley, R.C.; et al. Mitochondrial oxidative stress causes insulin resistance without disrupting oxidative phosphorylation. J. Biol. Chem. 2018, 293, 7315–7328. [Google Scholar] [CrossRef] [Green Version]
  144. Anderson, E.J.; Lustig, M.E.; Boyle, K.E.; Woodlief, T.L.; Kane, D.A.; Lin, C.-T.; Price, J.W.; Kang, L.; Rabinovitch, P.S.; Szeto, H.H.; et al. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J. Clin. Investig. 2009, 119, 573–581. [Google Scholar] [CrossRef]
  145. Gutiérrez, T.; Parra, V.; Troncoso, R.; Pennanen, C.; Contreras-Ferrat, A.; Vasquez-Trincado, C.; Morales, P.E.; Lopez-Crisosto, C.; Sotomayor-Flores, C.; Chiong, M.; et al. Alteration in mitochondrial Ca2+ uptake disrupts insulin signaling in hypertrophic cardiomyocytes. Cell Commun. Signal. 2014, 12, 68. [Google Scholar] [CrossRef] [Green Version]
  146. Tubbs, E.; Theurey, P.; Vial, G.; Bendridi, N.; Bravard, A.; Chauvin, M.-A.; Ji-Cao, J.; Zoulim, F.; Bartosch, B.; Ovize, M.; et al. Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Integrity Is Required for Insulin Signaling and Is Implicated in Hepatic Insulin Resistance. Diabetes 2014, 63, 3279–3294. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  147. Zhang, Z.; Wakabayashi, N.; Wakabayashi, J.; Tamura, Y.; Song, W.-J.; Sereda, S.; Clerc, P.; Polster, B.M.; Aja, S.M.; Pletnikov, M.V.; et al. The dynamin-related GTPase Opa1 is required for glucose-stimulated ATP production in pancreatic beta cells. Mol. Biol. Cell 2011, 22, 2235–2245. [Google Scholar] [CrossRef] [PubMed]
  148. Reinhardt, F.; Schultz, J.; Waterstradt, R.; Baltrusch, S. Drp1 guarding of the mitochondrial network is important for glucose-stimulated insulin secretion in pancreatic beta cells. Biochem. Biophys. Res. Commun. 2016, 474, 646–651. [Google Scholar] [CrossRef] [PubMed]
  149. Anello, M.; Lupi, R.; Spampinato, D.; Piro, S.; Masini, M.; Boggi, U.; Del Prato, S.; Rabuazzo, A.M.; Purrello, F.; Marchetti, P. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 2005, 48, 282–289. [Google Scholar] [CrossRef] [Green Version]
  150. Scheuermann-Freestone, M.; Madsen, P.L.; Manners, D.; Blamire, A.M.; Buckingham, R.E.; Styles, P.; Radda, G.K.; Neubauer, S.; Clarke, K. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation 2003, 107, 3040–3046. [Google Scholar] [CrossRef]
  151. Rider, O.J.; Francis, J.M.; Ali, M.K.; Holloway, C.; Pegg, T.; Robson, M.D.; Tyler, D.; Byrne, J.; Clarke, K.; Neubauer, S. Effects of catecholamine stress on diastolic function and myocardial energetics in obesity. Circulation 2012, 125, 1511–1519. [Google Scholar] [CrossRef] [Green Version]
  152. Lamb, H.J.; Beyerbacht, H.P.; Van der Laarse, A.; Stoel, B.C.; Doornbos, J.; Van der Wall, E.E.; De Roos, A. Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism. Circulation 1999, 99, 2261–2267. [Google Scholar] [CrossRef] [Green Version]
  153. Guescini, M.; Tiano, L.; Genova, M.L.; Polidori, E.; Silvestri, S.; Orlando, P.; Fimognari, C.; Calcabrini, C.; Stocchi, V.; Sestili, P. The Combination of Physical Exercise with Muscle-Directed Antioxidants to Counteract Sarcopenia: A Biomedical Rationale for Pleiotropic Treatment with Creatine and Coenzyme Q10. Oxidative Med. Cell. Longev. 2017, 2017, e7083049. [Google Scholar] [CrossRef] [Green Version]
  154. Alves, C.R.R.; Filho, C.A.A.M.; Benatti, F.B.; Brucki, S.; Pereira, R.M.R.; Pinto, A.L.d.S.; Lima, F.R.; Roschel, H.; Gualano, B. Creatine Supplementation Associated or Not with Strength Training upon Emotional and Cognitive Measures in Older Women: A Randomized Double-Blind Study. PLoS ONE 2013, 8, e76301. [Google Scholar] [CrossRef] [Green Version]
  155. Candow, D.G.; Forbes, S.C.; Chilibeck, P.D.; Cornish, S.M.; Antonio, J.; Kreider, R.B. Variables Influencing the Effectiveness of Creatine Supplementation as a Therapeutic Intervention for Sarcopenia. Front. Nutr. 2019, 6, 124. [Google Scholar] [CrossRef]
  156. Gualano, B.; Macedo, A.R.; Alves, C.R.; Roschel, H.; Benatti, F.B.; Takayama, L.; De Sa Pinto, A.L.; Lima, F.R.; Pereira, R.M. Creatine supplementation and resistance training in vulnerable older women: A randomized double-blind placebo-controlled clinical trial. Exp. Gerontol. 2014, 53, 7–15. [Google Scholar] [CrossRef] [PubMed]
  157. Lobo, D.M.; Tritto, A.C.; Da Silva, L.R.; De Oliveira, P.B.; Benatti, F.B.; Roschel, H.; Nieß, B.; Gualano, B.; Pereira, R.M.R. Effects of long-term low-dose dietary creatine supplementation in older women. Exp. Gerontol. 2015, 70, 97–104. [Google Scholar] [CrossRef] [PubMed]
  158. Pinto, C.L.; Botelho, P.B.; Carneiro, J.A.; Mota, J.F. Impact of creatine supplementation in combination with resistance training on lean mass in the elderly. J. Cach. Sarc. Muscle 2016, 7, 413–421. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  159. Gualano, B.; Artioli, G.G.; Poortmans, J.R.; Lancha Junior, A.H. Exploring the therapeutic role of creatine supplementation. Amino Acids 2010, 38, 31–44. [Google Scholar] [CrossRef]
  160. Candow, D.G.; Vogt, E.; Johannsmeyer, S.; Forbes, S.C.; Farthing, J.P. Strategic creatine supplementation and resistance training in healthy older adults. Appl. Physiol. Nutr. Metab. 2015, 40, 689–694. [Google Scholar] [CrossRef] [Green Version]
  161. De Sousa, M.V.; Da Silva Soares, D.B.; Caraça, E.R.; Cardoso, R. Dietary protein and exercise for preservation of lean mass and perspectives on type 2 diabetes prevention. Exp. Biol. Med. 2019, 244, 992–1004. [Google Scholar] [CrossRef]
  162. Barney, B.; Beck, G.R. Nutrition Interventions in Heart Failure. In Manual of Heart Failure Management; Bisognano, J.D., Earley, M.B., Baker, M.L., Eds.; Springer: Berlin/Heidelberg, Germany, 2009; pp. 207–217. [Google Scholar]
  163. Solis, M.Y.; Artioli, G.G.; Gualano, B. Potential of Creatine in Glucose Management and Diabetes. Nutrients 2021, 13, 570. [Google Scholar] [CrossRef]
  164. Gualano, B.; De Salles Painneli, V.; Roschel, H.; Artioli, G.G.; Neves, M.; De Sá Pinto, A.L.; Da Silva, M.E.R.; Cunha, M.R.; Otaduy, M.C.G.; Leite, C.D.C.; et al. Creatine in type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Med. Sci. Sports Exerc. 2011, 43, 770–778. [Google Scholar] [CrossRef]
  165. Earnest, C.P.; Almada, A.L.; Mitchell, T.L. High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women. Clin. Sci. 1996, 91, 113–118. [Google Scholar] [CrossRef]
  166. Deminice, R.; De Castro, G.S.F.; Francisco, L.V.; Da Silva, L.E.C.M.; Cardoso, J.F.R.; Frajacomo, F.T.T.; Teodoro, B.G.; Dos Reis Silveira, L.; Jordao, A.A. Creatine supplementation prevents fatty liver in rats fed choline-deficient diet: A burden of one-carbon and fatty acid metabolism. J. Nutr. Biochem. 2015, 26, 391–397. [Google Scholar] [CrossRef]
  167. Gupta, A.; Akki, A.; Wang, Y.; Leppo, M.K.; Chacko, V.P.; Foster, D.B.; Caceres, V.; Shi, S.; Kirk, J.A.; Su, J.; et al. Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved. J. Clin. Investig. 2012, 122, 291–302. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Wallis, J.; Lygate, C.A.; Fischer, A.; ten Hove, M.; Schneider, J.E.; Sebag-Montefiore, L.; Dawson, D.; Hulbert, K.; Zhang, W.; Zhang, M.H.; et al. Supranormal Myocardial Creatine and Phosphocreatine Concentrations Lead to Cardiac Hypertrophy and Heart Failure. Circulation 2005, 112, 3131–3139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Nascimben, L.; Ingwall, J.S.; Pauletto, P.; Friedrich, J.; Gwathmey, J.K.; Saks, V.; Pessina, A.C.; Allen, P.d. Creatine Kinase System in Failing and Nonfailing Human Myocardium. Circulation 1996, 94, 1894–1901. [Google Scholar] [CrossRef] [PubMed]
  170. Neubauer, S. The Failing Heart—An Engine Out of Fuel. N. Engl. J. Med. 2007, 356, 1140–1151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  171. Shen, W.; Spindler, M.; Higgins, M.A.; Jin, N.; Gill, R.M.; Bloem, L.J.; Ryan, T.P.; Ingwall, J.S. The fall in creatine levels and creatine kinase isozyme changes in the failing heart are reversible: Complex post-transcriptional regulation of the components of the CK system. J. Mol. Cell. Cardiol. 2005, 39, 537–544. [Google Scholar] [CrossRef] [PubMed]
  172. Lygate, C.A.; Fischer, A.; Sebag-Montefiore, L.; Wallis, J.; ten Hove, M.; Neubauer, S. The creatine kinase energy transport system in the failing mouse heart. J. Mol. Cell. Cardiol. 2007, 42, 1129–1136. [Google Scholar] [CrossRef]
  173. Liao, R.; Nascimben, L.; Friedrich, J.; Gwathmey, J.K.; Ingwall, J.S. Decreased Energy Reserve in an Animal Model of Dilated Cardiomyopathy. Circ. Res. 1996, 78, 893–902. [Google Scholar] [CrossRef]
  174. Zervou, S.; Whittington, H.J.; Russell, A.J.; Lygate, C.A. Augmentation of Creatine in the Heart. Mini Rev. Med. Chem. 2016, 16, 19–28. [Google Scholar] [CrossRef]
  175. Neubauer, S.; Krahe, T.; Schindler, R.; Horn, M.; Hillenbrand, H.; Entzeroth, C.; Mader, H.; Kromer, E.P.; Riegger, G.A.; Lackner, K. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation 1992, 86, 1810–1818. [Google Scholar] [CrossRef] [Green Version]
  176. Neubauer, S.; Horn, M.; Pabst, T.; Gödde, M.; Lübke, D.; Jilling, B.; Hahn, D.; Ertl, G. Contributions of 31P-magnetic resonance spectroscopy to the understanding of dilated heart muscle disease. Eur. Heart J. 1995, 16, 115–118. [Google Scholar] [CrossRef]
  177. Neubauer, S.; Horn, M.; Cramer, M.; Harre, K.; Newell, J.B.; Peters, W.; Pabst, T.; Ertl, G.; Hahn, D.; Ingwall, J.S.; et al. Myocardial Phosphocreatine-to-ATP Ratio Is a Predictor of Mortality in Patients with Dilated Cardiomyopathy. Circulation 1997, 96, 2190–2196. [Google Scholar] [CrossRef] [PubMed]
  178. Horn, M.; Remkes, H.; Dienesch, C.; Hu, K.; Ertl, G.; Neubauer, S. Chronic high-dose creatine feeding does not attenuate left ventricular remodeling in rat hearts post-myocardial infarction. Cardiovasc. Res. 1999, 43, 117–124. [Google Scholar] [CrossRef] [Green Version]
  179. McClung, J.; Hand, G.; Davis, J.; Carson, J. Effect of creatine supplementation on cardiac muscle of exercise-stressed rats. Eur. J. Appl. Physiol. 2003, 89, 26–33. [Google Scholar] [CrossRef] [PubMed]
  180. Bo, H.; Jiang, N.; Ma, G.; Qu, J.; Zhang, G.; Cao, D.; Wen, L.; Liu, S.; Ji, L.L.; Zhang, Y. Regulation of mitochondrial uncoupling respiration during exercise in rat heart: Role of reactive oxygen species (ROS) and uncoupling protein 2. Free Radic. Biol. Med. 2008, 44, 1373–1381. [Google Scholar] [CrossRef]
  181. Cao, F.; Zervou, S.; Lygate, C.A. The creatine kinase system as a therapeutic target for myocardial ischaemia–reperfusion injury. Biochem. Soc. Trans. 2018, 46, 1119–1127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  182. Hultman, J.; Ronquist, G.; Forsberg, J.O.; Hansson, H.E. Myocardial energy restoration of ischemic damage by administration of phosphoenolpyruvate during reperfusion. A study in a paracorporeal rat heart model. Eur. Surg. Res. 1983, 15, 200–207. [Google Scholar] [CrossRef] [PubMed]
  183. Osbakken, M.; Ito, K.; Zhang, D.; Ponomarenko, I.; Ivanics, T.; Jahngen, E.G.; Cohn, M. Creatine and cyclocreatine effects on ischemic myocardium: 31P nuclear magnetic resonance evaluation of intact heart. Cardiology 1992, 80, 184–195. [Google Scholar] [CrossRef]
  184. Sharov, V.G.; Saks, V.A.; Kupriyanov, V.V.; Lakomkin, V.L.; Kapelko, V.I.; Steinschneider, A.Y.; Javadov, S.A. Protection of ischemic myocardium by exogenous phosphocreatine. I. Morphologic and phosphorus 31-nuclear magnetic resonance studies. J. Thorac. Cardiovasc. Surg. 1987, 94, 749–761. [Google Scholar] [CrossRef]
  185. Balestrino, M.; Sarocchi, M.; Adriano, E.; Spallarossa, P. Potential of creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease. Amino Acids 2016, 48, 1955–1967. [Google Scholar] [CrossRef]
  186. ten Hove, M.; Lygate, C.A.; Fischer, A.; Schneider, J.E.; Sang, A.E.; Hulbert, K.; Sebag-Montefiore, L.; Watkins, H.; Clarke, K.; Isbrandt, D.; et al. Reduced Inotropic Reserve and Increased Susceptibility to Cardiac Ischemia/Reperfusion Injury in Phosphocreatine-Deficient Guanidinoacetate-N-Methyltransferase–Knockout Mice. Circulation 2005, 111, 2477–2485. [Google Scholar] [CrossRef] [Green Version]
  187. Elgebaly, S.A.; Wei, Z.; Tyles, E.; Elkerm, A.F.; Houser, S.L.; Gillies, C.; Kaddurah-Daouk, R. Enhancement of the recovery of rat hearts after prolonged cold storage by cyclocreatine phosphate. Transplantation 1994, 57, 803–806. [Google Scholar] [CrossRef] [PubMed]
  188. Cisowski, M.; Bochenek, A.; Kucewicz, E.; Wnuk-Wojnar, A.M.; Morawski, W.; Skalski, J.; Grzybek, H. The use of exogenous creatine phosphate for myocardial protection in patients undergoing coronary artery bypass surgery. J. Cardiovasc. Surg. 1996, 37, 75–80. [Google Scholar]
  189. Ruda, M.Y.; Samarenko, M.B.; Afonskaya, N.I.; Saks, V.A. Reduction of ventricular arrhythmias by phosphocreatine (Neoton) in patients with acute myocardial infarction. Am. Heart J. 1988, 116, 393–397. [Google Scholar] [CrossRef]
  190. Elgebaly, S.A.; Poston, R.; Todd, R.; Helmy, T.; Almaghraby, A.M.; Elbayoumi, T.; Kreutzer, D.L. Cyclocreatine protects against ischemic injury and enhances cardiac recovery during early reperfusion. Expert Rev. Cardiovasc. Ther. 2019, 17, 683–697. [Google Scholar] [CrossRef]
  191. Roberts, J.J.; Walker, J.B. Feeding a creatine analogue delays ATP depletion and onset of rigor in ischemic heart. Am. J. Physiol. Heart Circ. Physiol. 1982, 243, H911–H916. [Google Scholar] [CrossRef]
  192. Chida, K.; Otani, H.; Kohzuki, M.; Saito, H.; Kagaya, Y.; Takai, Y.; Takahashi, S.; Yamada, S.; Zuguchi, M. The Relationship between Plasma BNP Level and the Myocardial Phosphocreatine/Adenosine Triphosphate Ratio Determined by Phosphorus-31 Magnetic Resonance Spectroscopy in Patients with Dilated Cardiomyopathy. Cardiology 2006, 106, 132–136. [Google Scholar] [CrossRef]
  193. Russo, E.; Nguyen, H.; Lippert, T.; Tuazon, J.; Borlongan, C.V.; Napoli, E. Mitochondrial targeting as a novel therapy for stroke. Brain Circ. 2018, 4, 84–94. [Google Scholar] [CrossRef]
  194. Soustiel, J.F.; Zaaroor, M. Mitochondrial targeting for development of novel drug strategies in brain injury. Cent. Nerv. Syst. Agents Med. Chem. 2012, 12, 131–145. [Google Scholar] [CrossRef]
  195. Niizuma, K.; Endo, H.; Chan, P.H. Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival. J. Neurochem. 2009, 109, 133–138. [Google Scholar] [CrossRef] [Green Version]
  196. Niizuma, K.; Yoshioka, H.; Chen, H.; Kim, G.S.; Jung, J.E.; Katsu, M.; Okami, N.; Chan, P.H. Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 2010, 1802, 92–99. [Google Scholar] [CrossRef] [Green Version]
  197. Lin, M.T.; Beal, M.F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006, 443, 787–795. [Google Scholar] [CrossRef] [PubMed]
  198. He, Z.; Ning, N.; Zhou, Q.; Khoshnam, S.E.; Farzaneh, M. Mitochondria as a therapeutic target for ischemic stroke. Free Radic. Biol. Med. 2020, 146, 45–58. [Google Scholar] [CrossRef] [PubMed]
  199. Nguyen, H.; Zarriello, S.; Rajani, M.; Tuazon, J.; Napoli, E.; Borlongan, C.V. Understanding the Role of Dysfunctional and Healthy Mitochondria in Stroke Pathology and Its Treatment. Int. J. Mol. Sci. 2018, 19, 2127. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  200. Sanderson, T.H.; Reynolds, C.A.; Kumar, R.; Przyklenk, K.; Hüttemann, M. Molecular Mechanisms of Ischemia–Reperfusion Injury in Brain: Pivotal Role of the Mitochondrial Membrane Potential in Reactive Oxygen Species Generation. Mol. Neurobiol. 2013, 47, 9–23. [Google Scholar] [CrossRef] [Green Version]
  201. Chouchani, E.T.; Pell, V.R.; James, A.M.; Work, L.M.; Saeb-Parsy, K.; Frezza, C.; Krieg, T.; Murphy, M.P. A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury. Cell Metab. 2016, 23, 254–263. [Google Scholar] [CrossRef] [Green Version]
  202. Andrabi, S.S.; Parvez, S.; Tabassum, H. Ischemic stroke and mitochondria: Mechanisms and targets. Protoplasma 2020, 257, 335–343. [Google Scholar] [CrossRef]
  203. Nicholls, D.G. Mitochondrial calcium function and dysfunction in the central nervous system. Biochim. Biophys. Acta 2009, 1787, 1416–1424. [Google Scholar] [CrossRef] [Green Version]
  204. Blennow, K.; Hardy, J.; Zetterberg, H. The neuropathology and neurobiology of traumatic brain injury. Neuron 2012, 76, 886–899. [Google Scholar] [CrossRef] [Green Version]
  205. Turner, C.E.; Byblow, W.D.; Gant, N. Creatine supplementation enhances corticomotor excitability and cognitive performance during oxygen deprivation. J. Neurosci. 2015, 35, 1773–1780. [Google Scholar] [CrossRef]
  206. Zhu, S.; Li, M.; Figueroa, B.E.; Liu, A.; Stavrovskaya, I.G.; Pasinelli, P.; Beal, M.F.; Brown, R.H.; Kristal, B.S.; Ferrante, R.J.; et al. Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. J. Neurosci 2004, 24, 5909–5912. [Google Scholar] [CrossRef]
  207. Hausmann, O.N.; Fouad, K.; Wallimann, T.; Schwab, M.E. Protective effects of oral creatine supplementation on spinal cord injury in rats. Spin. Cord 2002, 40, 449–456. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  208. Sullivan, P.G.; Geiger, J.D.; Mattson, M.P.; Scheff, S.W. Dietary supplement creatine protects against traumatic brain injury. Ann. Neurol. 2000, 48, 723–729. [Google Scholar] [CrossRef]
  209. Prass, K.; Royl, G.; Lindauer, U.; Freyer, D.; Megow, D.; Dirnagl, U.; Stöckler-Ipsiroglu, G.; Wallimann, T.; Priller, J. Improved reperfusion and neuroprotection by creatine in a mouse model of stroke. J. Cereb. Blood Flow Metab. 2007, 27, 452–459. [Google Scholar] [CrossRef] [PubMed]
  210. Freire Royes, L.F.; Cassol, G. The Effects of Creatine Supplementation and Physical Exercise on Traumatic Brain Injury. Mini Rev. Med. Chem. 2016, 16, 29–39. [Google Scholar] [CrossRef] [PubMed]
  211. Novelli, A.; Reilly, J.A.; Lysko, P.G.; Henneberry, R.C. Glutamate becomes neurotoxic via the N-methyl-d-aspartate receptor when intracellular energy levels are reduced. Brain Res. 1988, 451, 205–212. [Google Scholar] [CrossRef]
  212. Tsuji, K.; Nakamura, Y.; Ogata, T.; Shibata, T.; Kataoka, K. Rapid decrease in ATP content without recovery phase during glutamate-induced cell death in cultured spinal neurons. Brain Res. 1994, 662, 289–292. [Google Scholar] [CrossRef]
  213. Carter, A.J.; Müller, R.E.; Pschorn, U.; Stransky, W. Preincubation with Creatine Enhances Levels of Creatine Phosphate and Prevents Anoxic Damage in Rat Hippocampal Slices. J. Neurochem. 1995, 64, 2691–2699. [Google Scholar] [CrossRef]
  214. Brustovetsky, N.; Brustovetsky, T.; Dubinsky, J.M. On the mechanisms of neuroprotection by creatine and phosphocreatine. J. Neurochem. 2001, 76, 425–434. [Google Scholar] [CrossRef]
  215. Harman, D. The aging process. Proc. Natl. Acad. Sci. USA 1981, 78, 7124–7128. [Google Scholar] [CrossRef] [Green Version]
  216. Grimm, A.; Friedland, K.; Eckert, A. Mitochondrial dysfunction: The missing link between aging and sporadic Alzheimer’s disease. Biogerontology 2016, 17, 281–296. [Google Scholar] [CrossRef]
  217. Leuner, K.; Hauptmann, S.; Abdel-Kader, R.; Scherping, I.; Keil, U.; Strosznajder, J.B.; Eckert, A.; Müller, W.E. Mitochondrial dysfunction: The first domino in brain aging and Alzheimer’s disease? Antiox. Redox Signal. 2007, 9, 1659–1675. [Google Scholar] [CrossRef] [PubMed]
  218. Bishop, N.A.; Lu, T.; Yankner, B.A. Neural mechanisms of ageing and cognitive decline. Nature 2010, 464, 529–535. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  219. Grimm, A.; Eckert, A. Brain aging and neurodegeneration: From a mitochondrial point of view. J. Neurochem. 2017, 143, 418–431. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  220. Geary, D.C. Mitochondrial Functioning and the Relations among Health, Cognition, and Aging: Where Cell Biology Meets Cognitive Science. Int. J. Mol. Sci. 2021, 22, 3562. [Google Scholar] [CrossRef] [PubMed]
  221. González-Reyes, R.E.; Aliev, G.; Ávila-Rodrigues, M.; Barreto, G.E. Alterations in Glucose Metabolism on Cognition: A Possible Link Between Diabetes and Dementia. Curr. Pharm. Des. 2016, 22, 812–818. [Google Scholar] [CrossRef] [PubMed]
  222. Shieh, J.C.-C.; Huang, P.-T.; Lin, Y.-F. Alzheimer’s Disease and Diabetes: Insulin Signaling as the Bridge Linking Two Pathologies. Mol. Neurobiol. 2020, 57, 1966–1977. [Google Scholar] [CrossRef] [PubMed]
  223. Cao, Y.; Yan, Z.; Zhou, T.; Wang, G. SIRT1 Regulates Cognitive Performance and Ability of Learning and Memory in Diabetic and Nondiabetic Models. J. Diabetes. Res. 2017, 2017, 7121827. [Google Scholar] [CrossRef]
  224. Jo, D.; Kim, B.C.; Cho, K.A.; Song, J. The Cerebral Effect of Ammonia in Brain Aging: Blood-Brain Barrier Breakdown, Mitochondrial Dysfunction, and Neuroinflammation. J. Clin. Med. 2021, 10, 2773. [Google Scholar] [CrossRef]
  225. Bustamante, J.; Czerniczyniec, A.; Lores-Arnaiz, S. Brain nitric oxide synthases and mitochondrial function. Front. Biosci. 2007, 12, 1034–1040. [Google Scholar] [CrossRef] [Green Version]
  226. Felipo, V.; Butterworth, R.F. Mitochondrial dysfunction in acute hyperammonemia. Neurochem. Int. 2002, 40, 487–491. [Google Scholar] [CrossRef]
  227. De la Monte, S.M.; Wands, J.R. Alzheimer’s Disease is Type 3 Diabetes—Evidence Reviewed. J. Diabetes Sci. Technol. 2008, 2, 1101–1113. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  228. Sripetchwandee, J.; Chattipakorn, N.; Chattipakorn, S.C. Links Between Obesity-Induced Brain Insulin Resistance, Brain Mitochondrial Dysfunction, and Dementia. Front. Endocrinol. 2018, 9, 496. [Google Scholar] [CrossRef] [PubMed]
  229. Müller, W.E.; Eckert, A.; Kurz, C.; Eckert, G.P.; Leuner, K. Mitochondrial dysfunction: Common final pathway in brain aging and Alzheimer’s disease—Therapeutic aspects. Mol. Neurobiol. 2010, 41, 159–171. [Google Scholar] [CrossRef]
  230. Kaliszewska, A.; Allison, J.; Martini, M.; Arias, N. The Interaction of Diet and Mitochondrial Dysfunction in Aging and Cognition. Int. J. Mol. Sci. 2021, 22, 3574. [Google Scholar] [CrossRef] [PubMed]
  231. Francis, H.M.; Stevenson, R.J. Potential for diet to prevent and remediate cognitive deficits in neurological disorders. Nutr. Rev. 2018, 76, 204–217. [Google Scholar] [CrossRef] [PubMed]
  232. Head, E. Oxidative damage and cognitive dysfunction: Antioxidant treatments to promote healthy brain aging. Neurochem. Res. 2009, 34, 670–678. [Google Scholar] [CrossRef] [Green Version]
  233. Poddar, J.; Pradhan, M.; Ganguly, G.; Chakrabarti, S. Biochemical deficits and cognitive decline in brain aging: Intervention by dietary supplements. J. Chem. Neuroanat. 2019, 95, 70–80. [Google Scholar] [CrossRef]
  234. Hammett, S.T.; Wall, M.B.; Edwards, T.C.; Smith, A.T. Dietary supplementation of creatine monohydrate reduces the human fMRI BOLD signal. Neurosci. Lett. 2010, 479, 201–205. [Google Scholar] [CrossRef]
  235. Watanabe, A.; Kato, N.; Kato, T. Effects of creatine on mental fatigue and cerebral hemoglobin oxygenation. Neurosci. Res. 2002, 42, 279–285. [Google Scholar] [CrossRef]
  236. McMorris, T.; Harris, R.C.; Howard, A.N.; Langridge, G.; Hall, B.; Corbett, J.; Dicks, M.; Hodgson, C. Creatine supplementation, sleep deprivation, cortisol, melatonin and behavior. Physiol. Behav. 2007, 90, 21–28. [Google Scholar] [CrossRef]
  237. Dworak, M.; Kim, T.; McCarley, R.W.; Basheer, R. Creatine supplementation reduces sleep need and homeostatic sleep pressure in rats. J. Sleep Res. 2017, 26, 377–385. [Google Scholar] [CrossRef] [PubMed]
  238. Gibson, G.E.; Starkov, A.; Blass, J.P.; Ratan, R.R.; Beal, M.F. Cause and consequence: Mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim. Biophys. Acta 2010, 1802, 122–134. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  239. Valenti, D.; De Bari, L.; De Filippis, B.; Henrion-Caude, A.; Vacca, R.A. Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: An overview of Down syndrome, autism, Fragile X and Rett syndrome. Neurosci. Biobehav. Rev. 2014, 46, 202–217. [Google Scholar] [CrossRef] [PubMed]
  240. Adhihetty, P.J.; Beal, M.F. Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. Neuromol. Med. 2008, 10, 275–290. [Google Scholar] [CrossRef] [Green Version]
  241. Kley, R.A.; Tarnopolsky, M.A.; Vorgerd, M. Creatine for treating muscle disorders. Cochrane Database Syst. Rev. 2013, 2013, CD004760. [Google Scholar] [CrossRef]
  242. Shao, A.; Lin, D.; Wang, L.; Tu, S.; Lenahan, C.; Zhang, J. Oxidative Stress at the Crossroads of Aging, Stroke and Depression. Aging Dis. 2020, 11, 1537–1566. [Google Scholar] [CrossRef]
  243. Martin, E.I.; Ressler, K.J.; Binder, E.; Nemeroff, C.B. The Neurobiology of Anxiety Disorders: Brain Imaging, Genetics, and Psychoneuroendocrinology. Psychiatr. Clin. 2009, 32, 549–575. [Google Scholar] [CrossRef] [Green Version]
  244. Yildiz-Yesiloglu, A.; Ankerst, D.P. Review of 1H magnetic resonance spectroscopy findings in major depressive disorder: A meta-analysis. Psychiatry Res. Neuroimag. 2006, 147, 1–25. [Google Scholar] [CrossRef]
  245. Scaglia, F. The role of mitochondrial dysfunction in psychiatric disease. Dev. Disabil. Res. Rev. 2010, 16, 136–143. [Google Scholar] [CrossRef]
  246. Agren, H.; Niklasson, F. Creatinine and creatine in CSF: Indices of brain energy metabolism in depression. Short note. J. Neural. Transm. 1988, 74, 55–59. [Google Scholar] [CrossRef]
  247. Mirza, Y.; O’Neill, J.; Smith, E.A.; Russell, A.; Smith, J.M.; Banerjee, S.P.; Bhandari, R.; Boyd, C.; Rose, M.; Ivey, J.; et al. Increased medial thalamic creatine-phosphocreatine found by proton magnetic resonance spectroscopy in children with obsessive-compulsive disorder versus major depression and healthy controls. J. Child Neurol. 2006, 21, 106–111. [Google Scholar] [CrossRef] [PubMed]
  248. Wood, E.; Hall, K.H.; Tate, W. Role of mitochondria, oxidative stress and the response to antioxidants in myalgic encephalomyelitis/chronic fatigue syndrome: A possible approach to SARS-CoV-2 “long-haulers”? Chronic Dis. Transl. Med. 2021, 7, 14–26. [Google Scholar] [CrossRef] [PubMed]
  249. Frye, M.A.; Watzl, J.; Banakar, S.; O’Neill, J.; Mintz, J.; Davanzo, P.; Fischer, J.; Chirichigno, J.W.; Ventura, J.; Elman, S.; et al. Increased anterior cingulate/medial prefrontal cortical glutamate and creatine in bipolar depression. Neuropsychopharmacology 2007, 32, 2490–2499. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  250. Kondo, D.G.; Sung, Y.-H.; Hellem, T.L.; Fiedler, K.K.; Shi, X.; Jeong, E.-K.; Renshaw, P.F. Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: A 31-phosphorus magnetic resonance spectroscopy study. J. Affect. Disord. 2011, 135, 354–361. [Google Scholar] [CrossRef] [Green Version]
  251. Roitman, S.; Green, T.; Osher, Y.; Karni, N.; Levine, J. Creatine monohydrate in resistant depression: A preliminary study. Bipolar Disord. 2007, 9, 754–758. [Google Scholar] [CrossRef]
  252. Toniolo, R.A.; Silva, M.; Fernandes, F.d.B.F.; Amaral, J.A.d.M.S.; Dias, R.d.S.; Lafer, B. A randomized, double-blind, placebo-controlled, proof-of-concept trial of creatine monohydrate as adjunctive treatment for bipolar depression. J. Neural. Transm. 2018, 125, 247–257. [Google Scholar] [CrossRef] [Green Version]
  253. Kious, B.M.; Kondo, D.G.; Renshaw, P.F. Creatine for the Treatment of Depression. Biomolecules 2019, 9, 406. [Google Scholar] [CrossRef] [Green Version]
  254. Pazini, F.L.; Cunha, M.P.; Rodrigues, A.L.S. The possible beneficial effects of creatine for the management of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 2019, 89, 193–206. [Google Scholar] [CrossRef]
  255. Kondo, D.G.; Forrest, L.N.; Shi, X.; Sung, Y.-H.; Hellem, T.L.; Huber, R.S.; Renshaw, P.F. Creatine target engagement with brain bioenergetics: A dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression. Amino Acids 2016, 48, 1941–1954. [Google Scholar] [CrossRef] [Green Version]
  256. D’Anci, K.E.; Allen, P.J.; Kanarek, R.B. A potential role for creatine in drug abuse? Mol. Neurobiol. 2011, 44, 136–141. [Google Scholar] [CrossRef]
  257. Amital, D.; Vishne, T.; Roitman, S.; Kotler, M.; Levine, J. Open Study of Creatine Monohydrate in Treatment-Resistant Posttraumatic Stress Disorder. J. Clin. Psychiatry 2006, 67, 836–837. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  258. Allen, P.J. Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value? Neurosci. Biobehav. Rev. 2012, 36, 1442–1462. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  259. Rosenthal, T.C.; Majeroni, B.A.; Pretorius, R.; Malik, K. Fatigue: An overview. Am. Fam. Physician 2008, 78, 1173–1179. [Google Scholar]
  260. Jamal, G.A.; Hansen, S. Post-Viral Fatigue Syndrome: Evidence for Underlying Organic Disturbance in the Muscle Fibre. Eur. Neurol. 1989, 29, 273–276. [Google Scholar] [CrossRef] [PubMed]
  261. Edwards, R.H.T.; Newham, D.J.; Peters, T.J. Muscle biochemistry and pathophysiology in postviral fatigue syndrome. Br. Med. Bull. 1991, 47, 826–837. [Google Scholar] [CrossRef] [PubMed]
  262. Lane, R.J.M.; Barrett, M.C.; Taylor, D.J.; Kemp, G.J.; Lodi, R. Heterogeneity in chronic fatigue syndrome: Evidence from magnetic resonance spectroscopy of muscle. Neuromuscul. Disord. 1998, 8, 204–209. [Google Scholar] [CrossRef]
  263. Behan, W.M.H.; More, I.A.R.; Behan, P.O. Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol. 1991, 83, 61–65. [Google Scholar] [CrossRef]
  264. Zhang, C.; Baumer, A.; Mackay, I.R.; Linnane, A.W.; Nagley, P. Unusual pattern of mitochondrial DNA deletions in skeletal muscle of an adult human with chronic fatigue syndrome. Hum. Mol. Genet. 1995, 4, 751–754. [Google Scholar] [CrossRef]
  265. Filler, K.; Lyon, D.; Bennett, J.; McCain, N.; Elswick, R.; Lukkahatai, N.; Saligan, L.N. Association of mitochondrial dysfunction and fatigue: A review of the literature. BBA Clin. 2014, 1, 12–23. [Google Scholar] [CrossRef] [Green Version]
  266. Morris, G.; Maes, M. Mitochondrial dysfunctions in Myalgic Encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab. Brain Dis. 2014, 29, 19–36. [Google Scholar] [CrossRef]
  267. Malatji, B.G.; Meyer, H.; Mason, S.; Engelke, U.F.H.; Wevers, R.A.; Van Reenen, M.; Reinecke, C.J. A diagnostic biomarker profile for fibromyalgia syndrome based on an NMR metabolomics study of selected patients and controls. BMC Neurol. 2017, 17, 88. [Google Scholar] [CrossRef] [PubMed]
  268. Derakhshan, M. Viral infection, a suggestive hypothesis for aetiology of chronic fatigue syndrome. J. Med. Hypotheses Ideas 2008, 2, 10–11. [Google Scholar]
  269. Smith, A.P. Post-viral Fatigue: Implications for Long Covid. Asian J. Res. Infect. Dis. 2021, 17–23. [Google Scholar] [CrossRef]
  270. Carfi, A.; Bernabei, R.; Landi, F. Persistent Symptoms in Patients After Acute COVID-19. JAMA 2020, 324, 603–605. [Google Scholar] [CrossRef]
  271. Doykov, I.; Hällqvist, J.; Gilmour, K.C.; Grandjean, L.; Mills, K.; Heywood, W.E. ‘The long tail of Covid-19’-The detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients. F1000Research 2021, 9, 1349. [Google Scholar] [CrossRef]
  272. Poenaru, S.; Abdallah, S.J.; Corrales-Medina, V.; Cowan, J. COVID-19 and post-infectious myalgic encephalomyelitis/chronic fatigue syndrome: A narrative review. Ther. Adv. Infect. 2021, 8, 20499361211009385. [Google Scholar] [CrossRef]
  273. Ostojic, S.M.; Stojanovic, M.; Drid, P.; Hoffman, J.R.; Sekulic, D.; Zenic, N. Supplementation with Guanidinoacetic Acid in Women with Chronic Fatigue Syndrome. Nutrients 2016, 8, 72. [Google Scholar] [CrossRef]
  274. Ostojic, S.M. Diagnostic and Pharmacological Potency of Creatine in Post-Viral Fatigue Syndrome. Nutrients 2021, 13, 503. [Google Scholar] [CrossRef]
Figure 1. General overview of the metabolic role of creatine in the creatine kinase/phosphocreatine (CK/PCr) system [1]. The diagram depicts connected subcellular energy production and cellular mechanics of creatine metabolism. This chemo-mechanical energy transduction network involves structural and functional coupling of the mitochondrial reticulum (mitochondrial interactosome and oxidative metabolism), phosphagen and glycolytic system (extramitochondrial ATP production), the linker of nucleoskeleton and cytoskeleton complex (nesprins interaction with microtubules, actin polymerization, β-tubulins), motor proteins (e.g., myofibrillar ATPase machinery, vesicles transport), and ion pumps (e.g., SERCA, Na+/K+-ATPase). The cardiolipin-rich domain is represented by parallel black lines. Green sparkled circles represent the subcellular processes where the CK/PCr system is important for functionality. Several proteins of the endoplasmic reticulum–mitochondria organizing network (ERMIONE), the SERCA complex, the TIM/TOM complex, the MICOS complex, the linker of nucleoskeleton and cytoskeleton complex, and the architecture of sarcomere and cytoskeleton are not depicted for readability. ANT: adenine nucleotide translocase; CK: creatine kinase; Cr: creatine; Crn: creatinine; CRT: Na+/Cl-dependent creatine transporter; ERMES: endoplasmic reticulum-mitochondria encounter structure; ETC: electron transport chain; GLUT-4: glucose transporter type 4; HK: hexokinase; mdm10: mitochondrial distribution and morphology protein 10; MICOS: mitochondrial contact site and cristae organizing system; NDPK: nucleoside-diphosphate kinase; NPC: nuclear pore complex; PCr: phosphocreatine; SAM: sorting and assembly machinery; SERCA: Sarco/Endoplasmic Reticulum Ca2+ ATPase; TIM: translocase of the inner membrane complex; TOM: translocase of the outer membrane complex; UCP: uncoupling protein; VDAC: voltage-dependent anion channel. Reprinted with permission. See Bonilla et al. [1] for more details about the metabolic basis of creatine in energy production and disease.
Figure 1. General overview of the metabolic role of creatine in the creatine kinase/phosphocreatine (CK/PCr) system [1]. The diagram depicts connected subcellular energy production and cellular mechanics of creatine metabolism. This chemo-mechanical energy transduction network involves structural and functional coupling of the mitochondrial reticulum (mitochondrial interactosome and oxidative metabolism), phosphagen and glycolytic system (extramitochondrial ATP production), the linker of nucleoskeleton and cytoskeleton complex (nesprins interaction with microtubules, actin polymerization, β-tubulins), motor proteins (e.g., myofibrillar ATPase machinery, vesicles transport), and ion pumps (e.g., SERCA, Na+/K+-ATPase). The cardiolipin-rich domain is represented by parallel black lines. Green sparkled circles represent the subcellular processes where the CK/PCr system is important for functionality. Several proteins of the endoplasmic reticulum–mitochondria organizing network (ERMIONE), the SERCA complex, the TIM/TOM complex, the MICOS complex, the linker of nucleoskeleton and cytoskeleton complex, and the architecture of sarcomere and cytoskeleton are not depicted for readability. ANT: adenine nucleotide translocase; CK: creatine kinase; Cr: creatine; Crn: creatinine; CRT: Na+/Cl-dependent creatine transporter; ERMES: endoplasmic reticulum-mitochondria encounter structure; ETC: electron transport chain; GLUT-4: glucose transporter type 4; HK: hexokinase; mdm10: mitochondrial distribution and morphology protein 10; MICOS: mitochondrial contact site and cristae organizing system; NDPK: nucleoside-diphosphate kinase; NPC: nuclear pore complex; PCr: phosphocreatine; SAM: sorting and assembly machinery; SERCA: Sarco/Endoplasmic Reticulum Ca2+ ATPase; TIM: translocase of the inner membrane complex; TOM: translocase of the outer membrane complex; UCP: uncoupling protein; VDAC: voltage-dependent anion channel. Reprinted with permission. See Bonilla et al. [1] for more details about the metabolic basis of creatine in energy production and disease.
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Figure 2. Panel A: Intracellular cascade after injury, infarction or contusion leads to mitochondrial dysfunction. Panel B: Impact of creatine on mitochondrial dysfunction. Green shows direct increase/stimulation of Cr/PCr, red shows direct decrease/inhibition of Cr/PCr, dotted line represents indirect impact of Cr/PCr on cellular pathways. ATP is adenosine triphosphate; Cr is creatine; PCr is phosphocreatine; ROS is reactive oxygen species; mPTP is mitochondrial permeability transition pore. Adapted from Dean et al. [55].
Figure 2. Panel A: Intracellular cascade after injury, infarction or contusion leads to mitochondrial dysfunction. Panel B: Impact of creatine on mitochondrial dysfunction. Green shows direct increase/stimulation of Cr/PCr, red shows direct decrease/inhibition of Cr/PCr, dotted line represents indirect impact of Cr/PCr on cellular pathways. ATP is adenosine triphosphate; Cr is creatine; PCr is phosphocreatine; ROS is reactive oxygen species; mPTP is mitochondrial permeability transition pore. Adapted from Dean et al. [55].
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Figure 3. Warburg Effect: glycolysis produces 2 ATP instead of 36 ATP, in pathological tissues even despite aerobic conditions. Glc is glucose, Oxy is oxygen, ATP is adenosine triphosphate. Adapted from Vander Heiden et al. [91].
Figure 3. Warburg Effect: glycolysis produces 2 ATP instead of 36 ATP, in pathological tissues even despite aerobic conditions. Glc is glucose, Oxy is oxygen, ATP is adenosine triphosphate. Adapted from Vander Heiden et al. [91].
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Figure 4. Mitochondrial dysfunction and non-communicable diseases. Adapted from Diaz-Vegas et al. [90].
Figure 4. Mitochondrial dysfunction and non-communicable diseases. Adapted from Diaz-Vegas et al. [90].
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Table 1. Level of evidence for creatine supplementation in acute traumatic mitochondrial dysfunction.
Table 1. Level of evidence for creatine supplementation in acute traumatic mitochondrial dysfunction.
StudyDiseaseSubjectTreatmentRandomizedSubjectsEfficacyEffect Role
Sakellaris et al. [71] Traumatic brain injuryHuman0.4 g/kg per day for 6 monthsYes39Improved self-care, cognition, behavior functions and communicationDirect effect on disease
Sakellaris et al. [72] Traumatic brain injuryHuman0.4 g/kg per day for 6 monthsYes39Reduced fatigue, headache and dizzinessDirect effect on disease
Table 2. Level of evidence for creatine supplementation for chronic, atraumatic mitochondrial dysfunction.
Table 2. Level of evidence for creatine supplementation for chronic, atraumatic mitochondrial dysfunction.
StudyDiseaseSubjectTreatmentRandomizedSubjectsEfficacyEffect Role
Guimarães-Ferreira et al. [128] -Animal/vitro5 g/kg per day for 6 days no39Decrease in ROS in muscle tissueAnima model
Kato et al. [124]Bipolar disorderHumansNoneNo25 (disease) vs. 21 (control)Abnormal energy phosphate metabolism in bipolar disorderNo intervention, only descriptive, observational findings
Table 3. Level of evidence of creatine’s role in noncommunicable chronic disease.
Table 3. Level of evidence of creatine’s role in noncommunicable chronic disease.
StudyDiseaseSubjectTreatmentRandomizedSubjectsEfficacyEffect Role
Rider et al. [151] ObesityHumanNoneNone64Deranged cardiac energetics and diastolic dysfunction in obesity groupObservational, disease related changes in metabolism
Scheuermann-Freestone et al. [150]Diabetes Type 2HumanNoneNone36Impaired myocardial and skeletal muscle metabolism (reduced PCR/ATP ratio)Observational disease related changes in metabolism
Lamb et al. [152] HypertensionHumanNoneNone24Altered high-energy phosphate metabolism in hypertension. Cardiac dysfunction correlates with metabolic alterationsObservational, disease related changes in metabolism
Gualano et al. [164]Diabetes Type 2Human5 g creatine for 12 weeks + physical activity programYes25Improved glycemic control in supplementation group (by GLUT-4 recruitment)Direct effect on disease related metabolic effects
Earnest et al. [165]Hyper-cholester-inaemiaHuman4 × 5 g creatine for 5 days and afterwards 2 times per day for 51 days (orally)Yes34Minor reduction of total cholesterol during supplementation. Reduction of triacylglycerol’s and very-low-density-lipoprotein c 4 weeks after finishing supplementation Direct effect of supplementation on metabolism.
Deminice et al. [166]Fatty liverAnimalControl vs. 0.25% choline diet vs. 0.25% choline + 2% creatine dietNone24Prevention of fat liver accumulation and hepatic events in creatine-fed groupAnimal model
Table 4. Level of evidence for creatine supplementation for chronic, atraumatic mitochondrial dysfunction.
Table 4. Level of evidence for creatine supplementation for chronic, atraumatic mitochondrial dysfunction.
StudyDiseaseSubjectTreatmentRandomizedSubjectsEfficacyEffect Role
Elgebaly et al. [187]-Animal/vitro500 mg/kg BWno6Better aortic flow, coronary flow, cardiac output, stroke volume, and stroke workAnimal model
Cisowski et al. [188]Cardiac surgeryHumans6 g 3 days pre-surgery, intra-surgical and two days post- surgery i.v. yes40Reduced arrhythmic events, reduced need of ionotropic medicationDirect effect on surgical procedure
Ruda et al. [189]Ischemic myocardial infarcthuman2 g bolus + 4 g/h over 2 hYes60Reduced arrhythmic eventsDirect effect on short term outcome
Chida et al. [192]Dilated Cardio-myopathyHumanNoneNone13Plasma BNP level was correlated negatively with the myocardial phosphocreatine/adenosine triphosphateObservational finding
Roberts et al. [191].NoneAnimalOral creatine-feedingNoneNot clearHigher cellular ATP during ischemia in creatine-fed rat heartsAnimal model
Table 5. Level of evidence for the role of creatine supplementation in individuals with traumatic and ischemic CNS injuries.
Table 5. Level of evidence for the role of creatine supplementation in individuals with traumatic and ischemic CNS injuries.
StudyDiseaseSubjectTreatmentRandomizedSubjectsEfficacyEffect Role
Zhu et al. [206]None/induced ischemiaAnimal2% creatine-supplemented diet for 4 weeksNone6 per groupReduction in ischemia induced infarct sizeAnimal model
Turner et al. [205]None/induced hypoxiaHuman7-ds oral creatine-supplementationYes15Less decrease in cognitive performance, attentional capacity, corticomotor excitability for creatine-groupHuman brain metabolism
Hausmann et al. [207]None/induced spinal cord injuryAnimal4 weeks oral creatine-supplementationnone20Better locomotor scores after 1 week for creatine-group. Less scar tissue for creatine-group after 2 weeksAnimal model
Sullivan et al. [208]None/induced traumatic brain injuryAnimalMice: 0.1 mL/10 g/BW creatine monohydrate injection for 1, 3 or 5 daysnone40 mice/24 ratsReduction of brain tissue damage size by 36% mice and 50% ratsAnimal model
Rats: 1% creatine diet for 4 weeks.
Prass et al. [209]None/induced experimental strokeAnimalCreatine-rich diet (0%, 0.5%, 1%, 2% for 3 weeksNoneUnclearReduction of infarct size by 40% in 2% creatine-fed groupAnimal model
Table 6. Level of evidence for the role of creatine supplementation in individuals with neurodegenerative disorders.
Table 6. Level of evidence for the role of creatine supplementation in individuals with neurodegenerative disorders.
StudyDiseaseSubjectTreatmentRandomizedSubjectsEfficacyEffect Role
Hammett et al. [234]NoneHuman20 g/d creatine for 5 days + 5 g/d for 2-daysYes22Reduction of stress related blood oxygen level dependent in fMRI in creatine-groupHuman metabolic response
Watanabe et al. [235]NoneHuman8 g/d for 5-daysYes24Reduction of mental fatigue and increased brain oxygen consumption in creatine-groupHuman metabolic response
McMorris et al. [236]NoneHuman4 × 5 g/dyes20Better in central complex executive tasks with creatine while sleep deprivationHuman metabolic response
McMorris et al. [45]NoneHuman4 × 5 g/dYes15random number generation, forward number and spatial recall, and long-term memoryHuman metabolism
Table 7. Level of evidence for the role of creatine supplementation in individuals with psychological disorders.
Table 7. Level of evidence for the role of creatine supplementation in individuals with psychological disorders.
StudyDiseaseSubjectTreatmentRandomizedSubjectsEfficacyEffect Role
Kondo et al. [250]Adolescent major depressive disorderHuman4 g/d creatine for 8 weeksNone15Reduction in children-depression symptom scores. Significant increase in brain phosphocreatine level.Direct effect on disease (no RCT)
Roitman et al. [251]Treatment resistant depressionHuman3–5 g/d creatine for 4 weeksNone8 unipolar depressed patients and two bipolar patientsDevelopment of hypomania/mania in bipolar patients. Improved Hamilton Depression Rating Scale, Hamilton Anxiety Scale, and Clinical Global Impression for 7 of 8 unipolar depressed patientsDirect effect on disease (no RCT)
Toniolo et al. [252]Depressive episode of Bipolar Type 1 and Type 2Human6 g/d creatine for 6 weeksYes35No significant difference in Montgomery-Åsberg Depression Rating Scale by intervention but higher remission rate in creatine supplemented groupDirect effect on disease
Kondo et al. [255]Adolescent with SSRI resistant major depressive disorderHuman0 g vs. 2 g vs. 4 g vs. 10 g creatine supplementation for 8 weeksYes34Clinical depression scores correlated inversely with brain phosphocreatine (PCR) levels. PCR level improved with higher dose.Potential direct effect on disease
Table 8. Summary of literature on the effects of creatine precursors on chronic fatigue and Post-COVID syndrome.
Table 8. Summary of literature on the effects of creatine precursors on chronic fatigue and Post-COVID syndrome.
StudyDiseaseSubjectTreatmentRandomizedSubjectsEfficacyEffect Role
Ostojic et al. [264]Chronic Fatigue syndromeHuman2 g, 4 g oral Guanidinoacetic Acid for 3 months vs. placeboYes21Higher muscle creatine-phosphate level and better oxidative capacity. However, no significant improvement of fatigue symptomsDirect effect on disease related metabolism
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Marshall, R.P.; Droste, J.-N.; Giessing, J.; Kreider, R.B. Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review. Nutrients 2022, 14, 529. https://doi.org/10.3390/nu14030529

AMA Style

Marshall RP, Droste J-N, Giessing J, Kreider RB. Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review. Nutrients. 2022; 14(3):529. https://doi.org/10.3390/nu14030529

Chicago/Turabian Style

Marshall, Robert Percy, Jan-Niklas Droste, Jürgen Giessing, and Richard B. Kreider. 2022. "Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review" Nutrients 14, no. 3: 529. https://doi.org/10.3390/nu14030529

APA Style

Marshall, R. P., Droste, J. -N., Giessing, J., & Kreider, R. B. (2022). Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review. Nutrients, 14(3), 529. https://doi.org/10.3390/nu14030529

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