Coenzyme Q10 Supplementation in Athletes: A Systematic Review

Background: To summarize available evidence in the literature on the impacts of CoQ10 supplementation on metabolic, biochemical, and performance outcomes in athletes. Methods: Six databases, Cochrane Library (33 articles), PubMed (90 articles), Scopus (55 articles), Embase (60 articles), SPORTDiscus (1056 articles), and Science Direct (165 articles), were researched. After applying the eligibility criteria, articles were selected for peer review independently as they were identified by June 2022. The protocol for this systematic review was registered on PROSPERO (CRD42022357750). Results: Of the 1409 articles found, 16 were selected for this systematic review. After CoQ10 supplementation, a decrease in oxidative stress markers was observed, followed by higher antioxidant activity. On the other hand, lower levels of liver damage markers (ALT); Aspartate aminotransferase (AST); and Gamma-glutamyl transpeptidase (γGT) were identified. Finally, we found a reduction in fatigue indicators such as Creatine Kinase (CK) and an increase in anaerobic performance. Conclusions: This systematic review concludes that supplementation with orally administered CoQ10 (30–300 mg) was able to potentiate plasma antioxidant activity and anaerobic performance, reducing markers linked to oxidative stress and liver damage in athletes from different modalities aged 17 years old and older.


Introduction
The evidence demonstrates numerous benefits in human health promoted by the practice of Physical Activity (PA) and Physical Exercise (PE), including the reduction in the risk of chronic and cardiometabolic diseases and the risk of early mortality [1,2].On the other hand, strenuous PE, which is generally associated with a great demand for physical effort, intensity, and duration, enhances the development of physical abilities and high performance, demanding a great energy demand from its practitioners [3].These exhaustive practices can establish large proportions of damage to organ systems, resulting in inflammatory processes, chronic muscle injuries, pain, and proteolysis that can lead to cell apoptosis [4,5].The safe use of supplements becomes necessary, as it is a viable and reliable way to meet high nutritional demands that cannot only be obtained from your daily diet and improve athletic performance [6,7].
Nutrients 2023, 15, 3990 2 of 14 The use of nutritional supplements serves different purposes around the world, but only 5% are intended for high-performance athletes to supplement food and improve metabolic function and performance [8,9].In eukaryotic cells, Coenzyme Q10 (CoQ 10 ) is present in three oxidation states: ubiquinol (Q10 H 2 ), ubisemiquinone, and ubiquinone in its full oxidation state.It participates in aerobic processes to produce Adenosine Triphosphate (ATP), acting directly as an electron carrier in oxidative phosphorylation that occurs in mitochondria, as well as assisting in the maintenance of the redox cycle by assisting in the antioxidant response [10][11][12][13].Its biosynthesis pathway occurs via the side chain of the polyisoprenoid CoQ, starting from acetyl-CoA and passing through mevalonate and isopentenyl pyrophosphate, the same as cholesterol.Studies show that CoQ 10 supplementation promotes an increase in the levels of this substance, mainly in the mitochondrial region of various tissues such as the brain, heart, and kidneys [14,15].
In addition, they can act to combat the excess production of Reactive Oxygen Species (ROS), which are part of the pathophysiology of numerous chronic diseases, including cardiometabolic and neurodegenerative diseases [16,17].It is known that athletes of different levels (amateur to elite) modalities can produce high levels of ROS associated with reduced antioxidant defenses, causing Oxidative Stress (OS) [18].Some systematic reviews have demonstrated the benefits of CoQ 10 supplementation in health and disease conditions [19][20][21].Furthermore, Drobnic et al. (2022) observed an increase in plasma levels of CoQ 10 after its supplementation, promoting benefits in performance indicators and recovery in athletes of different sports [22].However, different from previous findings, in this review, we sought to identify the impacts of CoQ 10 supplementation on outcomes related to body composition, biochemistry, and performance parameters since they are not entirely clear in athletes of different levels and modalities.Therefore, this systematic review aims to summarize available evidence in the literature on the impacts of CoQ 10 supplementation on body composition, biochemical, and performance outcomes in athletes.

Methods
The present systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and was previously registered on PROSPERO (CRD42022357750).

Eligibility Criteria
Eligibility criteria were previously selected to minimize the risk of bias.The inclusion and exclusion criteria followed the PICOS (Population/Intervention/Control/Outcomes/ Study) (Table 1).There were no restrictions on language or publication date.Studies that did not meet the eligibility criteria, review publications, letters, duplicates, and the presence of data used in different studies were excluded.

Selection and Data Collection Process
The screening was performed by reading the title, abstract, and full text.The selection of studies was performed by two independent researchers (MSSF and GCJS).Data was extracted via two independent researchers.Discrepancies were resolved by a third rater (DEdSF) (Figure 1).

Data Items
Data were extracted about the study (Author and year); sample characteristics (age, sex, sample size); information about the type of athletes or category of athletes (amateurs, professionals, or elite); modality or type of sport practiced; and protocol CoQ 10 supplementation (route and dose of administration).In the absence of information, data were not considered.Data were collected as follows: (1) Body composition outcomes such as Body Mass Index; Fat percentage (%); and Body mass or Weight (kg).( 2

Methodological Quality Assessment
The "Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Analytical Randomized Controlled Trial and Non-Randomized Experimental Studies" [21] was used to verify the methodological quality of the articles included.The JBI consists of eight questions that assess the methodological quality of the articles based on the following criteria: selection of participants, confounding variables, validity, and reliability of the results.The questions were answered with "Yes", "No", or "Undefined".When the answer was "yes", a score was given; when the answer was "no" or "undefined", no score was given.The score for each article was calculated as a percentage and the quality of each study was rated as high (80-100%), fair (50-79%), or low (50%).All studies were independently reviewed by two reviewers.Discrepancies between raters were resolved by consensus.

Selection and Data Collection Process
The screening was performed by reading the title, abstract, and full tex of studies was performed by two independent researchers (MSSF and G extracted via two independent researchers.Discrepancies were resolved b (DEdSF) (Figure 1).

Body Composition and Biochemical Outcomes
Body composition is described using the body mass index (BMI), body fat (%, kg), and body mass (kg) (Table 4).All protocols showed no changes in BMI, fat mass, and body mass.However, studies by Mohammadi et al., 2020 [36] and Holloway et al., 2014 [34] showed a reduction in BMI and body fat, respectively.The biochemical parameters (REDOX balance, lipid and glucose profile, kidney/liver damage markers, and bioenergetic outcomes) are shown in Figure 2. REDOX balance outcomes are evaluated by pro and antioxidant markers.CoQ 10 supplementation causes an increase in indicators of antioxidant activity such as CAT, TAC, and TAS.Changes were not observed in the GPx.Regarding the pro-oxidant markers, there was either a reduction (Basal and induced membrane hydroperoxides, 8-OHdG, LPO, Carbonyls, MPO, XO, and Cytosolic ROS) or no change (H 2 O 2 , scavenging activity against superoxide anion, oxidative DNA damage, and hypoxanthine) of the markers.CoQ 10 supplementation did not promote changes in FFA, NEFA, phospholipids, triglycerides, total cholesterol, and glucose levels.Only HDL levels were reduced Holloway et al., 2014 [34].There were no changes in renal function markers (creatinine, uric acid, and blood urea nitrogen).However, liver function markers such as bilirubin, AST, ALT, and γGT decreased (Castro et al., 2012 [33]; Emani et al., 2018 [25]; Suzuki et al., 2020 [28]).

Fatigue Markers
Regarding fatigue markers (Table 4), no differences were observed in max lactate, submax lactate, the workload at the lactate threshold, time to exhaustion, and RPE.However, in the protocol by Mohammadi et al., 2020 [36], an increase in the fatigue index was observed, Snider et al., 1992 [39].On the other hand, the percentage of fatigue was lower in the protocol used by Suzuki et al., 2020 [39].Six studies evaluated CK levels after supplementation where five showed a reduction, while for CPK levels, no differences were observed [30].Three studies showed no difference in lactate levels after supplementation [30] (Holloway et al., 2014 [34]; Snider et al., 1992 [39]).Only one study demonstrated a reduction after CoQ 10 ingestion (Emani et al., 2018 [25]).Likewise, there was a reduction in myoglobin and enzyme levels of NADPH oxidase and LDH in all protocols.

Performance Outcomes
Evaluated performance outcomes via respiratory, hemodynamic, neuromuscular, and bioenergetic parameters (Table 5).No differences were observed in VO 2 max and peak levels in five studies.Only in the study by Yikioski et al., 1997 [37] was there an increase in VO 2 max associated with the AET and ANT increase.Additionally, only Deichmann et al. 2012 observed an increase in the time to anaerobic threshold after CoQ 10 supplementation, with no differences observed in hemodynamic outcomes.Six studies included in the present review evaluated different neuromuscular variables.The supplementation protocol was able to increase the total work (W) [29], muscle strength [30], aerobic power (W), average power (W), maximum power (W), and minimum power (W), respectively [36].However, only one study showed a significant reduction in the average of mean power output; power output (W•kg•bw); 10 × 10 s test (W•kg•bw); 15 × 10 s (W•kg•bw), [31].Four studies did not show significant changes in neuromuscular variables [25,31,32,36].

Methodological Quality Assessment
All studies demonstrated fair quality (75%).The identification and control of confounders were not evaluated in all studies.However, the inclusion criteria, description of context participants, reliable and valid measurements, and adequate statistical analysis were considered (Table 6).
Notes: Y-YES, N-No.Q1: Was the inclusion criteria well defined?Q2: Have participants and context been described in detail?Q3: Were the measurements collected in a valid and reliable way?Q4: Were standardized and objective inclusion criteria used?Q5 Were any confounding variables found?Q6: Were strategies used to deal with confounding variables?Q7: Were the results measured validly and reliably?Q8: Was the statistical analysis used adequate?

Discussion
This systematic review aimed to summarize the findings in the literature about the impacts of coenzyme Q10 supplementation on body composition, and biochemical and performance markers in athletes of different modalities.Within the main results, we found that the protocol did not promote changes in body composition, kidney function, and aerobic performance.However, after CoQ 10 supplementation, there was a decrease in oxidative stress indicators, followed by an increase in antioxidant capacity.Additionally, improvement in liver function and fatigue markers was also observed, with a consequent increase in the anaerobic performance assessed by neuromuscular variables, including average of mean power; power output, power at least (W), 10 × 10 s test, 15 × 10 s, total work, muscle strength, and bioenergetic outcomes such as the time to anaerobic threshold.
Corroborating our results, Ghavami et al., 2020 [40], when performing a systematic review with meta-analysis using twenty randomized clinical trials, did not observe significant differences in anthropometric markers including weight, BMI, and waist circumference in non-athlete adults after CoQ 10 supplementation [40].It is understood that changes in body measurements and composition may affect the functioning of mitochondria, which play a crucial role in producing energy via cellular signaling pathways that rely on the oxidation of carbohydrates and fatty acids [41,42].Fatty acids are transported to the interior of the mitochondria via transport proteins located in its outer membrane known as Carnitine PalmitoylTransferase I (CPT-I) and II (CPT-II), starting several reactions linked to mitochondrial b-oxidation [43].These reactions effectively contribute to the control of lipid metabolism, preventing its accumulation, which is directly linked to metabolic disorders including overweight and obesity [44].
We observed that the CoQ 10 supplementation increased antioxidant activity and was associated with lower levels of OS markers in athletes.Ho et al. demonstrated that 12 weeks of supplementation with 300 mg of CoQ 10 increased the TAC of Taekwondo and soccer athletes [45].In this sense, the use of antioxidant supplements in sports is recommended since athletes are exposed to sports with high demands of physical effort contained in training and competitions [46,47].This scenario promotes deleterious metabolic effects including excessive production of Reactive Oxygen Species (ROS) associated with low activity of antioxidant defenses, promoting OS, and inflammation impacting health and athletic performance [48,49].
The results showed no changes in lipid profile (FFA, HDL, NEFA, phospholipids, triglycerides, and total cholesterol), glucose, and markers of kidney damage after supplementation with CoQ 10 supplementation in athletes.Studies with this population are scarce and need to establish reliable conclusions.However, the efficiency of CoQ 10 supplementation in non-athlete subjects and those affected by different pathologies including type 2 diabetes (T2DM) are consolidated [50].
Zahedi et al. used 150 mg of CoQ 10 in 20 patients with T2DM for 12 weeks; after the protocol, there was a significant reduction in fasting plasma glucose, insulin, and hemoglobin A1C was identified.Furthermore, these findings suggest that the use of CoQ 10 plays an important role in the control of carbohydrate metabolism [51].The participation of this macronutrient is essential to produce ATP, which occurs mainly via aerobic reactions including oxidative phosphorylation, which has the help of CoQ 10 in the connectivity of complexes I, II, and III of the electron transport chain [52].Moreover, bioenergetic disturbances that result in a decrease in ATP intake are linked to a drop in athletic performance [53,54].
The data showed a decrease in liver damage markers after the use of CoQ 10 .Evidence in non-athletes and athletes points to impacts on liver function.Farsi et al. performed 100 mg of CoQ 10 supplementation for 12 weeks in 41 patients with Non-Alcoholic Fatty Liver Disease (NAFLD); their results showed a decrease in AST and γGT, as well as lower levels of inflammation and degree of steatosis, which were positive changes in the prognosis clinic of these patients [55].On the other hand, Liao et al. found no significant differences in hepatic mitochondrial functionality in adolescent Chinese athletes [56].This systematic review concludes that CoQ 10 supplementation can effectively reduce fatigue markers and improve anaerobic performance in athletes.However, there is no significant effect on aerobic capacity.It is important to note that voluntary muscle fatigue is influenced by various factors and is regulated by both central and peripheral mechanisms [57].Elevated levels of fatigue are identified via biochemical markers in the blood that can effectively alter athletic performance [58].Therefore, sports supplementation strategies should be indicated to contain the deleterious effects on the athletes.Drobnic et al. summarized evidence systematically and pointed out that CoQ 10 supplementation can decrease muscular fatigue by promoting low levels of inflammatory response and muscle damage markers including creatine kinase and myoglobin [22].Unlike our work, the authors included studies with non-athletes and athletes.
In aerobic capacity indicators, we did not observe improvements after CoQ 10 supplementation, according to the body of evidence available in the present systematic review.Similarly, Liao demonstrated that 100 mg of CoQ 10 supplementation for 28 days was not able to improve the VO 2 Max of adolescent swimmers [56].However, we observed significant changes in components of anaerobic performance including anaerobic threshold, muscle strength (number of repetitions), muscle power, and total work measured in Watts after CoQ 10 supplementation.High levels of these anaerobic performance variables are essential for sports performance and obtaining results in different modalities [59].Recent findings indicate that these advantages could lead to (1) reduced OS production by boosting antioxidant capacity; (2) decreased production of cellular indicators of inflammation and muscle exhaustion; and (3) enhanced muscular endurance and a combination of aerobic and anaerobic metabolic pathways that work together to generate more energy availability needed for high-intensity and short-duration physical activities [60].

Limitations and Strengths
This report acknowledges some limitations in the studies included.Firstly, the amount of CoQ 10 supplementation and duration varied among athletes, making it challenging to determine the necessary dose for optimal health and performance benefits.Secondly, different sports have varying physical, technical, and bioenergetic characteristics, so studies stratified by sport would provide more insights into the mechanisms of CoQ 10 supplementation.Lastly, there was heterogeneity in the participants.Despite these limitations, this report is the first to examine the effects of CoQ 10 supplementation on athletes' body composition, REDOX balance, lipid and glycemic profiles, and markers of kidney and liver damage.The findings on fatigue markers and athletic performance were displayed in an easy-to-understand format, making it useful for future studies and prescribing to various populations of athletes and non-athletes.

Future Directions and Perspectives
The purpose of the present work was to systematically demonstrate that CoQ 10 supplementation performed is capable of exerting biological benefits at the molecular and cellular levels via the promotion of control in the oxidative balance since oxidative stress is part of the pathophysiology of several diseases, which can affect athletes exposed to high demands of physical and mental effort.At the clinical level, reducing liver damage markers, which, when deregulated, point to a possible state of aggression to the liver due to multiple pathological conditions.In addition, we observed significant improvements in anaerobic performance and fatigue indicators.Finally, the use of CoQ 10 or any supplement must respect the biological individuality of each athlete and the specificity of their modality, as well as be prescribed responsibly by a legally qualified professional.We recommend that further studies indicate that safe CoQ 10 supplementation can be used to promote a high level of athletic performance in various modalities.In addition, they demonstrate their relevance for maintaining health and, mainly, as an adjunct aid to the treatment and rehabilitation of chronic degenerative diseases, including cardiovascular, metabolic, and aging-related diseases.

Conclusions
This systematic review concludes that supplementation with CoQ 10 (30-300 mg) orally administered was able to potentiate antioxidant activity and anaerobic performance, reducing markers linked to oxidative stress and liver damage in athletes from different modalities aged 17 years old and older.

Figure 1 .
Figure 1.PRISMA 2020 flow diagram for new systematic reviews, which included searches of databases and registers only.Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). ** If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Figure 2 .
Figure 2. Impacts of Coenzyme Q10 supplementation on body composition, biochemical and performance outcomes of athletes from different modalities.BMI: Body Mass Index; mg: milligrams.Figure 2. Impacts of Coenzyme Q10 supplementation on body composition, biochemical and performance outcomes of athletes from different modalities.BMI: Body Mass Index; mg: milligrams.

Figure 2 .
Figure 2. Impacts of Coenzyme Q10 supplementation on body composition, biochemical and performance outcomes of athletes from different modalities.BMI: Body Mass Index; mg: milligrams.Figure 2. Impacts of Coenzyme Q10 supplementation on body composition, biochemical and performance outcomes of athletes from different modalities.BMI: Body Mass Index; mg: milligrams.
; Case reports; Letters to editors; comments, etc.

Table 3 .
Sample, sports modalities, and protocol of CoQ 10 supplementation characteristics.

Table 4 .
Body composition and biochemical outcomes of athletes after CoQ 10 supplementation.

Table 5 .
Performance outcomes of athletes after CoQ 10 supplementation.

Table 6 .
Study quality assessment-Joanna Briggs Institute.