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Int. J. Mol. Sci. 2016, 17(10), 1771; https://doi.org/10.3390/ijms17101771

Review
Melatonin as a Potential Agent in the Treatment of Sarcopenia
1
Department of Morphology and Cellular Biology, Medicine Faculty, University of Oviedo, Julian Claveria, s/n, Oviedo 33006, Spain
2
Department of Cellular and Structural Biology, UTHSCSA, San Antonio, TX 78229, USA
3
Service of Microbiology, Hospital Universitario Central de Asturias, Avenida de Roma, s/n, Oviedo 33011, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Charles J. Malemud
Received: 15 September 2016 / Accepted: 17 October 2016 / Published: 24 October 2016

Abstract

:
Considering the increased speed at which the world population is aging, sarcopenia could become an epidemic in this century. This condition currently has no means of prevention or treatment. Melatonin is a highly effective and ubiquitously acting antioxidant and free radical scavenger that is normally produced in all organisms. This molecule has been implicated in a huge number of biological processes, from anticonvulsant properties in children to protective effects on the lung in chronic obstructive pulmonary disease. In this review, we summarize the data which suggest that melatonin may be beneficial in attenuating, reducing or preventing each of the symptoms that characterize sarcopenia. The findings are not limited to sarcopenia, but also apply to osteoporosis-related sarcopenia and to age-related neuromuscular junction dysfunction. Since melatonin has a high safety profile and is drastically reduced in advanced age, its potential utility in the treatment of sarcopenic patients and related dysfunctions should be considered.
Keywords:
melatonin; sarcopenia; frailty; skeletal muscle; aging

1. Introduction

Worldwide estimates predict 2 billion people will be over 65 years old by 2050 [1]. Thus, an increasingly significant percentage of the population demands remedies and treatments for the deleterious processes that age induces. The scientific community is currently at a loss when it comes to meeting these requirements. Aging is a multifactorial process that provokes slow and persistent functional decline. This gradual physiological deterioration becomes disabling for a high percentage of the elderly population, where it impairs quality of life and increases the demands on primary caregivers and healthcare providers. Of all the degenerative processes, the development of limitations in mobility is one of the most common, leading to a reduced capacity for daily living activities, disability and loss of independence. Slow walking speed, together with unintentional weight loss, self-reported exhaustion, weakness (grip strength) and low physical activity, are the criteria that characterize frailty status. This aging phenotype has been described in detail by Fried et al. [2]. This state of frailty also is characterized by a reduced capacity to respond to demands caused by diminishing functional reserve; this puts the individual in a special risk category when facing minor stressors and is associated with poor outcomes (disability, hospitalization and death) [3,4].
In older adults, mobility limitations have been defined as the self-reported inability to walk a mile, climb stairs or perform heavy housework [5]. This impaired mobility is very often associated with a well-established factor of age-related decline in muscle mass designated as sarcopenia [6]. Sarcopenia, however, not only refers to muscle mass deterioration; numerous other factors are involved in the reduction in muscle quality associated with aging. These include derangement of skeletal myocytes, vascular dysfunction, reduced aerobic capacity, fat infiltration and a decline in bone mineral density [6,7].
The high number of individuals affected by this syndrome or at least by some sarcopenia-related features has caused sarcopenia to reach epidemic proportions. Moreover, there is no effective cure currently available for this condition and likewise no known treatments, even palliative, are available. The need to develop interventions to prevent or treat sarcopenia has been repeatedly claimed in the literature [8,9,10]. In the current brief review, we summarize previous data suggesting that melatonin mayto limit the development of several of the derangements associated with sarcopenia. Melatonin has a variety of beneficial effects that may slow the development or reduce the severity of the deleterious processes which inevitably lead to sarcopenia in aging population. To date, the evidence for melatonin’s efficacy relative to reducing sarcopenia has not been systematically summarized.

2. Sarcopenia Syndrome

Sarcopenia is a term derived from the Greek words sarx (flesh) and penia (loss) that was introduced by Rosenberg [11] and was used to classically describe the decline in muscle mass among older people [7,12]. Currently, sarcopenia is a well-documented condition associated with the impaired mobility that occurs with aging [13]. There is increasingly evidence, however, that not only the decline in muscle mass is responsible for sarcopenia, but also a failure in muscle strength or power (referred to as dynapenia) is commonly associated with sarcopenia [6,14,15]. Both sarcopenia and dynapenia typically increase with advancing age, but there are individuals in whom there is a discrepancy between changes in muscle mass and muscle strength, mainly related to occupational physical activity in their midlife [6]. Such activity appears to delay sarcopenia development, while dynapenia is a more constant factor that compromises wellbeing at old ages [15]. To take into account this discrepancy, a new term (i.e., muscle quality) is being increasingly used, referring to the force generating capacity per unit cross-sectional area [6,16,17]. Muscle quality is negatively affected by several processes.
Sarcopenia and energetic imbalance are characteristics of the physiological framework that explain frailty and its consequences [18]. Walston and Fried suggest that there is some feedback between these components, the so-called frailty cycle. This cycle stems from the physiological changes associated with aging, which results in an imbalance between anabolism and catabolism. This state embraces multiple systems and cellular pathways implicated in age-dependent muscle degeneration (reviewed by [7,14]). Thus, sarcopenic muscle exhibits several cellular dysfunctions which result from oxidative stress, mainly due to mitochondrial dysfunction and a reduction of radical scavenging capability. Also included is a reduction in cellular turnover with a significant decrease in the number of satellite cells, alterations in proteolytic activities including those of the proteasome, autophagic dysregulation and even changes in apoptosis. These cellular derangements are associated or are even part of the more general perturbations also involved in sarcopenia development. These include a decrease in sex hormones [19] and an elevated pro-inflammatory state [20]. Eventually, sarcopenia is related to adipocyte infiltration with increases in both intra- and inter-muscular adipose tissue which significantly contributes to the decline in muscle quality [21]. Additional contributing factors include osteoporosis due to close relationship between muscle and bone, which are a single functional unit [7] and a decline in neurophysiological activity. This relates to the fact that age-related changes in the neuromuscular junction (NMJ) play a key role in musculoskeletal impairment, preceding or following the decline in muscle mass [22].
Collectively, the described alterations are embodied in the term sarcopenia and all are well-established risk factors for the major negative health-related conditions and events that characterize aging, including frailty, disability, institutionalization and mortality [23]. The development of preventive and therapeutic strategies against sarcopenia is considered an urgent need by health professionals. Based on what is known about the actions of melatonin, we propose that this molecule may have the potential to counteract sarcopenic damage or, moreover, may prevent some of the alterations associated with muscle quality loss. Additionally, we cited the published literature that shows the efficacious and beneficial effects of melatonin against the features which constitute the multi-pathology called sarcopenia.

3. Why Melatonin?

Melatonin, also known as N-acetyl-5-methoxytryptamine, is a derivative of tryptophan, an essential amino acid [24]. It is produced by the pineal gland in a circadian manner with maximal production during the night. It is involved in synchronization of circadian rhythms in physiological functions including sleep timing, blood pressure, seasonal reproduction and many others [25,26,27,28,29]. There is also evidence that all other cells produce melatonin [30,31], continually throughout the day, mainly as an antioxidant and free radical scavenger [32,33,34,35]. Melatonin is present in all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk [36,37]; and perhaps in mitochondria and chloroplasts where it may have the capacity to synthesize and metabolize melatonin itself [31,38]. This molecule has important protective capabilities, mainly based on its high potency as a free radical scavenger, low toxicity and solubility in both aqueous and organic media [30,39].
Pineal production and plasma melatonin levels progressively drop during aging [40,41,42] to the extent that in advanced age its levels are almost null. The loss of melatonin during aging may have great importance in the general deterioration that the elderly experience. Several investigations have reported a general improvement in life quality due to melatonin supplementation in older adults [43,44,45]. Moreover, numerous articles relate the age-associated decline in melatonin levels with the development of several diseases [46,47,48].
Melatonin is undoubtedly more than a zeitgeber and an antioxidant molecule since it seems to be essential at the cellular level as a physiological regulator of homeostasis. Its therapeutic applications are numerous, from pediatric [49,50,51] to geriatric diseases [52,53,54]; this includes cancer [55,56], sleep disturbances [57,58] and neurodegenerative diseases [59,60].
Several clinical trials with melatonin supplementation as a treatment have been successfully performed [61]. These melatonin treatments have often had positive outcomes in different pathologies: reducing cardiac morbidity [62], controlling adverse effects of chemotherapy [63] and alleviating bipolar disorders [64] among others. Also, melatonin has been used as a treatment with significant success in Duchenne muscular dystrophy [65] where it reduced the muscle degenerative process. Based on previous knowledge about the role of melatonin and sarcopenia (as summarized below), it is likely that melatonin may be effective in treating this condition.

4. Cellular Impact of Sarcopenia

Sarcopenia is a highly burdensome geriatric syndrome. The heterogeneity of its clinical correlates and the complexity of its pathogenesis make the development of effective preventive and therapeutic measures difficult. In this section we describe the numerous changes that occur at the cellular level in sarcopenic muscle [66].

4.1. Increase in Oxidative Stress and Mitochondrial Alterations

Aging is characterized by an increase in oxidative stress which is exacerbated during sarcopenia development. The relationship of oxidative stress to sarcopenia has been experimentally defined [67,68]. Considering this, theoretically at least, the addition of an antioxidant should produce beneficial effects in this condition. However, not all reactive species are harmful. Certainly, it is well-established that some reactive oxygen species (ROS), reactive nitrogen species (RNS), and a basal level of oxidative stress are essential for cell survival [69]. Oxidant generation, within a hormetic range, is essential for intracellular signaling [70] and optimal force production [71]. Thus, very highly efficient antioxidants may paradoxically be harmful unless their effects on the redox balance are closely titrated [72]. However, melatonin seems not to be a typical radical scavenger and many publications show that melatonin also regulates cellular homeostasis [37] and could even promote the generation of free radicals when necessary [34]. For example, we have shown that when high oxidative stress is necessary for adequate organ development, daily melatonin injections initially induce a reduction of oxidative stress but, subsequently, when the melatonin injections are continued, free radical generation is restored [73]. The collective findings indicate that melatonin is able to reduce free radical concentrations but maintain them inside homeostatic limits and, moreover, melatonin’s action as a free radical scavenger and as antioxidant are context specific as described by Proietti and colleagues [74].
The rise in oxidative stress in sarcopenia is mainly a result of mitochondrial dysfunction. Any derangements in skeletal myocyte mitochondrial function are recognized as major factors that contribute to age-dependent muscle degeneration [67]. In this regard, it is noteworthy that slow walking speed has been adopted as a criterion for defining sarcopenia [75]; this is likely due to a mitochondrial bioenergetic decline during muscle aging [76]. Melatonin and its metabolites are powerful antioxidants protecting the electron transport chain and mitochondrial DNA from oxidative damage more efficiently than other conventional antioxidants [77]. This protection of the respiratory chain allows melatonin to increase ATP production in mitochondria [78].

4.2. Cellular Vacuolization: Alterations in Autophagy

The process of vacuolization is currently poorly understood. According to Henics and Wheatley [79], vacuolization is simply the state of being with vacuoles; this implies a continual process of becoming progressively more vacuolated. This occurs in most cell types spontaneously or via a wide range of inductive stimuli. Vacuoles can be formed from several organelle types of the endosomal/lysosomal compartment and is generally considered a degenerative process. The involvement of autophagosomes in vacuole formation is widely accepted [80]. Also, some agents impair autophagy, inducing blockage, which results in vacuole accumulation [81]. Strongly supporting this hypothesis, several articles show functional defects in autophagy as a characteristic of sarcopenic muscle [7,82]; this has been occasionally accompanied by perinuclear accumulation of autophagic vacuoles [83].
Melatonin, in its role as a homeostasis stabilizer, has been shown to induce [84] or reduce [85] autophagy. In relation to muscle, melatonin is highly versatile molecule and either induces autophagy [86] or inhibits it [87], depending on pathological processes involved, since oxidative stress has a close relationship with autophagy. For example, melatonin induces autophagy in myoblast cells collaborating in myogenic differentiation (MyoD) degradation [88] but it inhibits autophagy in muscles from carbon tetrachloride-treated mice by reducing oxidative stress-induced damage [89].

4.3. Protein Degradation Deterioration

Sarcopenia is a syndrome where the cell’s catabolic machinery has collapsed or has become misregulated [90]. The accumulation of lipofuscin granules in an increasing number of lysosomes of sarcopenic muscles is an example of impaired lysosomal degradative capacity [91]. In this process, only a small amount of lysosomal enzymes remains available for degradative pathways [67]; this significantly contributes to the reduction in the degenerative capacity of these organelles. On the other hand, higher levels of myostatin, a transforming growth factor-β (TGF-β) family member, induce muscle wasting by activating proteasomal-mediated catabolism of intracellular proteins [92]. In addition, defects in protein synthesis has been detected in muscles of sarcopenic patients [93]
Melatonin reduces endoplasmic reticulum stress in skeletal muscle by increasing the expression of several proteins as well as mRNA levels [89]; this improves protein synthesis. Likewise, melatonin is an important regulator of proteasome [94] and lysosomal mechanisms [88], thereby enhancing cell quality.

4.4. Decrease in Satellite Cells and Increase in Apoptosis

Satellite cells in skeletal muscle are quiescent mono-nucleated myogenic cells, located between the sarcolemma and basement membrane of terminally-differentiated muscle fibres [95]. The life-long maintenance of muscle tissue involves satellite cells, since under homeostatic conditions satellite cells are activated by stimuli such as physical trauma or growth signals [96]. Sarcopenia increases the susceptibility to muscle injury [97] and the reduced muscle mass contributes to falls [98]; in these situations satellite cell activation would be essential for improving regeneration of these old muscles. However, satellite cells are drastically reduced in sarcopenia increasing the negative consequences of sarcopenic muscle [99] and/or its funcionality [100]. Unfortunately, these changes are sarcopenic characteristics [7].
Melatonin also increases satellite cells following muscle injury in rats [101] by reducing the apoptotic processes via modulation of signaling pathways which causes significant muscle regeneration in these animals. Antiapoptotic actions of melatonin have been described in many tissues and in a variety of normal cell types [102,103]. However, melatonin’s role in apoptosis can differ among normal and cancer cells, since several publications have shown melatonin’s capability to destroy cancer cells by triggering apoptosis [104,105,106]. In contrast, in normal skeletal muscle, some authors have described in detail how melatonin prevents apoptosis and limits the oxidative stress that causes mitochondria permeability transition and subsequent death [107]. Melatonin, for example, attenuates apoptotic processes during ischemia/reperfusion in skeletal muscle [108]. Considering these findings, melatonin has been proven to significantly reduce or, even, counteract several pathophysiological processes specifically associated with sarcopenia [7].

4.5. Chronic Low Inflammation

There are other processes, some of them being a result of the changes described above, which are common to different pathologies and are part of the sarcopenic complex. Melatonin may also counteract or reduce those pathologies. One example is the systemic subacute inflammation which is a predominant characteristic of the aging process [109]. This low grade inflammation has been implicated in the development of a number of chronic diseases [110] and is associated with sarcopenia development as well [67,111]. The damaging agents in this process are notably interleukin 6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor α (TNF-α) [112,113]. Recent evidence has documented a role for melatonin in reducing inflammation in muscle cells, acting specifically against these cytokines in rats [114] and also in humans [115]. The anti-inflammatory actions of melatonin are well-documented in numerous organs [116].

4.6. Endocrine Signaling

Studies on the nature and magnitude of age-related perturbations in circulating hormones as well as the responsiveness of target tissues are major features of sarcopenia research [82]. A number of hormone levels change during sarcopenia, including myokines and adipokines, due to the crosstalk between muscle and adipose tissue [117,118]. Also, alterations in the renin–angiotensin system promote muscular inflammation, mitochondrial dysfunction, and apoptosis [119]; insulin resistance leads to perturbed metabolism and misrouted signaling [120]. Also, reductions in testosterone and dehydroepiandrosterone contribute to muscle loss or weakness [121], while growth hormone (GH) and insulin-like growth factor 1 (IGF-1) decrease, which is deleterious to the physical function of skeletal muscle with age [122].
Hormonal supplementation in the older adults has been used to restore endocrine signaling. This procedure is controversial and disappointing results in sarcopenic individuals have been obtained [67]. As a result, great disparities between recommendations from scientific societies related to aging and elderly patients in general have been mentioned [121]. Consequently, hormonal supplementation seems not to be a desirable option. As an example, special attention should be paid regarding GH where long-time supplementation as an anti-aging strategy has caused a number of severe side effects associated with this treatment, and the Growth Hormone Research Society has warned against the use of GH or its secretagogues [123].
With regard to supplementation with melatonin, firstly, no significant adverse effects have been reported with its use at any concentration or at any treatment time. Also, melatonin, as an effective testosterone substitute, has been shown to prevent muscular atrophy in rats induced by castration through the IGF-1 axis [124]. Moreover, melatonin reduces adipogenesis in obese mice [85], collaborates in insulin resistance attenuation in Caenorhabditis elegans [125] and has a regulatory role in autocrine and paracrine responses in muscle and adipose tissue [126]. Additionally, melatonin has been shown to be more effective than GH in recovering physiological functions in smooth muscle from old rats [127].

4.7. Vascular Aging

Aging of the vascular system significantly hinders the uptake of oxygen and nutrients by muscle cells; this is closely related to sarcopenia development. Thus, aged skeletal muscle shows reduced blood flow capacity [128] together with extensive damage to endothelium-dependent vasodilation. Both processes promote mitochondrial destruction in muscle cells due to a reduction in microvascular oxygenation [129]; this in turn, induces ATP failure, increases ROS generation that also affects blood vessel integrity. Thus, a vicious cycle involving oxidant production and vascular and muscular damage ensues [67].
In contrast, a long-term treatment with melatonin has vasculoprotective properties [130]; for example, it restores vascular dysfunction in a model of accelerated aging (i.e., the senescence accelerated mouse-prone 8 (SAMP8)). Moreover, melatonin improves endothelial damage and causes important improvements in vessel cytoarchitecture in aged animals [131]. Finally, benefits in delaying age-related cellular damage in the cardiovascular system have been observed in aged rats supplemented with caffeic acid phenethyl ester and melatonin [132].
Age-related damage of skeletal muscle cannot be studied as an isolated entity because to its close relation with bone and the involvement of neuromuscular junctions. Unrepaired damage to one of these two systems renders treatments for improving sarcopenia useless. It is essential that melatonin’s capability of restoring the integrity of the musculoskeletal system and neuromuscular junctions also be considered in any attempts to reduce sarcopenia.

5. Sarcopenia and Osteoporosis

As mentioned above, bone and muscle are closely interrelated. Thus, when aging affects one of these two tissues, the functionality of the other is likewise compromised [66]. Thus, as muscle quality deteriorates during aging, also bone becomes weakened when it develops osteoporosis.
Osteoporosis literally means “porous bone”. It is a consequence of a reduction in bone mineral density which significantly increases fracture risk, which is the most serious complication of osteoporosis [133]. Muscle force has an important influence on essential bone properties such as mass, size, shape, and, even, architecture [134]. Thus, in elderly sarcopenic patients when the muscle strain falls below a given threshold, bone remodeling activates a so-called disuse mode, which results in less bone formation and greater bone resorption [66]. The reliance of muscle health on bone and vice versa is so interrelated that several researchers consider it one syndrome, with terms including sarco-osteopenia, sarco-osteoporosis, or dysmobility syndrome to distinguish disorders which are prone to a high risk of fractures [66,135,136].
Oxidative stress and autophagic alterations have been implicated in the development of osteoporosis [137], which could account for the beneficial effects of melatonin in this disease [138]. A recent published clinical trial has provided evidence related to the ability of melatonin to improve bone mineral density in humans [139], thereby protecting them against fractures. The ability of melatonin to protect against osteroporosis would also provide benefits in terms of limiting sarcopenia, since elevated bone strength is usually associated with greater muscular tone.

6. Neuromuscular Junction

The NMJ is the site at which efferent neurons communicate with muscle fibers. They function in the transmission of signals from the motor neuron to the skeletal muscle fibers to ensure precise control of skeletal muscle contraction and therefore voluntary movement. When the function of the motor neuron terminal is lost, the muscular fiber innervated by this neuron loses its contact to the nervous system and becomes incapable of generating volitional muscle contractions [22]. Although aging is usually associated with a reduction in NMJ function, the mechanisms involved are not well understood. Some lines of evidence point to the changes being causally related to the decline in muscle mass and function as observed in sarcopenia; however, which occurs first, sarcopenia or a reduction in the function of the NMJ, remains unknown [22].
Once again, oxidative stress seems to be implicated in NMJ impairment together with mitochondrial dysfunction and inflammation being prominent features [140]. Thus, melatonin, due to its potent antioxidant activities could be a key player in resolving or preventing this deregulation. In fact, published reports using different animals show that melatonin reverses age-related neuromuscular transmission dysfunction [141] and improves, at the same time, muscle physiology [142].
While still limited, the scientific evidence is consistent in terms of suggesting that melatonin significantly improves aged muscle as well as other cellular alterations characteristic of sarcopenia. Melatonin’s action also applies to the pathophysiological processes associated to sarcopenia including muscle dysfunction that is closely interlinked to sarcopenia. Finally, it is necessary to remember that melatonin levels are gradually lost throughout life [41], being almost undetectable in the elderly; this could easily facilitate sarcopenia development. In light of these findings, it is reasonable to assume that maintaining normal endogenous levels of melatonin or administering it as an exogenous supplement may alleviate age-related muscular decline and the development of sarcopenia.

7. Conclusions

Sarcopenia is a highly burdensome geriatric syndrome. It is commonly associated with osteroporosis and neuromuscular dysfunction. Currently, no effective treatment for this degenerative process has been identified. Melatonin has a high safety profile and no serious toxicity related to melatonin usage has been reported. Here, we summarized the scientific evidence that melatonin prevents and counteracts mitochondrial impairments, reduces oxidative stress and autophagic alterations in muscle cells, increases the number of satellite cells and limits sarcopenic changes in skeletal muscle. Likewise, melatonin lowers chronic low inflammation levels and reduces vascular aging, all of which are usually present in sarcopenic muscle. Similarly, melatonin improves the endocrine signaling which deteriorates in aged individuals. As a consequence, melatonin may be useful to prevent or treat sarcopenia-associated diseases including osteoporosis and neuromuscular dysfunction (Figure 1). Collectively, the published data suggest that melatonin may be a useful aid in slowing age-related muscle deterioration (i.e., sarcopenia as well as its associated conditions). If so, stronger muscles could translate into fewer falls and bone fractures in the older population, which are factors that normally seriously compromise aged individuals’ health.

Acknowledgments

Ana Coto-Montes and Jose A. Boga are members of the INPROTEOLYS and INEUROPA network. Ana Coto-Montes and Jose A. Boga are team-leaders from the cellular Response to Oxidative Stress (cROS) research group within the Campus of International Excellence (University of Oviedo). This study and stays of Ana Coto-Montes and Jose A. Boga were supported by the “Salvador de Madariaga” Programme from the Ministerio de Educacion, Cultura y Deportes, FISS-13-RD12/0043/0030, FISS-11-01381 and FISS-14-PI13/02741 (Instituto de Salud Carlos III), GRUPIN14-071 (Plan de Ciencia, Tecnología e Innovación (PCTI) del Principado de Asturias), and Fondo Europeo de Desarrollo Regional (FEDER) funds.

Author Contributions

All authors have equally contributed to the development of this review.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. United Nations, Department of Economic and Social Affairs, Population Division. World Population Ageing; United Nations: New York, NY, USA, 2015; ST/ESA/SER.A/390. [Google Scholar]
  2. Fried, L.P.; Tangen, C.M.; Walston, J.; Newman, A.B.; Hirsch, C.; Gottdiener, J.; Seeman, T.; Tracy, R.; Kop, W.J.; Burke, G.; et al. Frailty in older adults: Evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 2001, 56, M146–M156. [Google Scholar] [CrossRef] [PubMed]
  3. Campbell, A.J.; Buchner, D.M. Unstable disability and the fluctuations of frailty. Age Ageing 1997, 26, 315–318. [Google Scholar] [CrossRef] [PubMed]
  4. Rockwood, K.; Hogan, D.B.; MacKnight, C. Conceptualisation and measurement of frailty in elderly people. Drugs Aging 2000, 17, 295–302. [Google Scholar] [CrossRef] [PubMed]
  5. Dufour, A.B.; Hannan, M.T.; Murabito, J.M.; Kiel, D.P.; McLean, R.R. Sarcopenia definitions considering body size and fat mass are associated with mobility limitations: The Framingham Study. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68, 168–174. [Google Scholar] [CrossRef] [PubMed]
  6. McGregor, R.A.; Cameron-Smith, D.; Poppitt, S.D. It is not just muscle mass: A review of muscle quality, composition and metabolism during ageing as determinants of muscle function and mobility in later life. Longev. Healthspan 2014, 3, 9. [Google Scholar] [CrossRef] [PubMed]
  7. Tarantino, U.; Piccirilli, E.; Fantini, M.; Baldi, J.; Gasbarra, E.; Bei, R. Sarcopenia and fragility fractures: Molecular and clinical evidence of the bone-muscle interaction. J. Bone Jt. Surg. Am. 2015, 97, 429–437. [Google Scholar] [CrossRef] [PubMed]
  8. Brass, E.P.; Sietsema, K.E. Considerations in the development of drugs to treat sarcopenia. J. Am. Geriatr. Soc. 2011, 59, 530–535. [Google Scholar] [CrossRef] [PubMed]
  9. Chumlea, W.C.; Cesari, M.; Evans, W.J.; Ferrucci, L.; Fielding, R.A.; Pahor, M.; Studenski, S.; Vellas, B.; International Working Group on Sarcopenia Task Force Members. Sarcopenia: Designing phase IIB trials. J. Nutr. Health Aging 2011, 15, 450–455. [Google Scholar] [CrossRef] [PubMed]
  10. Matthews, G.D.; Huang, C.L.; Sun, L.; Zaidi, M. Translational musculoskeletal science: Is sarcopenia the next clinical target after osteoporosis? Ann. N. Y. Acad. Sci. 2011, 1237, 95–105. [Google Scholar] [CrossRef] [PubMed]
  11. Rosenberg, I.H. Summary comments: Epidemiological and methodological problems in determining nutritional status of older persons. Ann. Intern. Med. 1989, 50, 1231–1233. [Google Scholar]
  12. Rosenberg, I.H. Sarcopenia: Origins and clinical relevance. J. Nutr. 1997, 127, 990S–991S. [Google Scholar] [CrossRef] [PubMed]
  13. Nair, K.S. Aging muscle. Am. J. Clin. Nutr. 2005, 81, 953–963. [Google Scholar] [PubMed]
  14. Kalinkovich, A.; Livshits, G. Sarcopenia: The search for emerging biomarkers. Ageing Res. Rev. 2015, 22, 58–71. [Google Scholar] [CrossRef] [PubMed]
  15. Mitchell, W.K.; Williams, J.; Atherton, P.; Larvin, M.; Lund, J.; Narici, M. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front. Physiol. 2012, 3, 260. [Google Scholar] [CrossRef] [PubMed]
  16. Barbat-Artigas, S.; Rolland, Y.; Zamboni, M.; Aubertin-Leheudre, M. How to assess functional status: A new muscle quality index. J. Nutr. Health Aging 2012, 16, 67–77. [Google Scholar] [CrossRef] [PubMed]
  17. Beavers, K.M.; Beavers, D.P.; Houston, D.K.; Harris, T.B.; Hue, T.F.; Koster, A.; Newman, A.B.; Simonsick, E.M.; Studenski, S.A.; Nicklas, B.J.; et al. Associations between body composition and gait-speed decline: Results from the Health, Aging, and Body Composition Study. Am. J. Clin. Nutr. 2013, 97, 552–560. [Google Scholar] [CrossRef] [PubMed]
  18. Walston, J.; Fried, L.P. Frailty and the older man. Med. Clin. N. Am. 1999, 83, 1173–1194. [Google Scholar] [CrossRef]
  19. Iannuzzi-Sucich, M.; Prestwood, K.M.; Kenny, A.M. Prevalence of sarcopenia and predictors of skeletal muscle mass in healthy, older men and women. J. Gerontol. A Biol. Sci. Med. Sci. 2002, 57, M772–M777. [Google Scholar] [CrossRef] [PubMed]
  20. Leng, Y.; Ahmadi-Abhari, S.; Wainwright, N.W.; Cappuccio, F.P.; Surtees, P.G.; Luben, R.; Brayne, C.; Khaw, K.T. Daytime napping, sleep duration and serum C reactive protein: A population-based cohort study. BMJ Open 2014, 11, e006071. [Google Scholar] [CrossRef] [PubMed]
  21. Miljkovic, N.; Lim, J.-Y.; Miljkovic, I.; Frontera, W.-R. Aging of skeletal muscle fibers. Ann. Rehabil. Med. 2015, 39, 155–162. [Google Scholar] [CrossRef] [PubMed]
  22. Gonzalez-Freire, M.; de Cabo, R.; Studenski, S.A.; Ferrucci, L. The neuromuscular junction: Aging at the crossroad between nerves and muscle. Front. Aging Neurosci. 2014, 6, 208. [Google Scholar] [CrossRef] [PubMed]
  23. Visser, M.; Schaap, L.A. Consequences of sarcopenia. Clin. Geriatr. Med. 2011, 27, 387–399. [Google Scholar] [CrossRef] [PubMed]
  24. Stehle, J.; Reuss, S.; Riemann, R.; Seidel, A.; Vollrath, L. The role of arginine-vasopressin for pineal melatonin synthesis in the rat: Involvement of vasopressinergic receptors. Neurosci. Lett. 1991, 123, 131–134. [Google Scholar] [CrossRef]
  25. Dawson, D.; Encel, N. Melatonin and sleep in humans. J. Pineal Res. 1993, 15, 1–12. [Google Scholar] [CrossRef] [PubMed]
  26. Reiter, R.J.; Tan, D.X.; Korkmaz, A. The circadian melatonin rhythm and its modulation: Possible impact on hypertension. J. Hypertens. Suppl. 2009, 27, S17–S20. [Google Scholar] [CrossRef] [PubMed]
  27. Calvo, J.R.; González-Yanes, C.; Maldonado, M.D. The role of melatonin in the cells of the innate immunity: A review. J. Pineal Res. 2013, 55, 103–120. [Google Scholar] [CrossRef] [PubMed]
  28. Reiter, R.J.; Tamura, H.; Tan, D.X.; Xu, X.Y. Melatonin and the circadian system: Contributions to successful female reproduction. Fertil. Steril. 2014, 102, 321–328. [Google Scholar] [CrossRef] [PubMed]
  29. Pechanova, O.; Paulis, L.; Simko, F. Peripheral and central effects of melatonin on blood pressure regulation. Int. J. Mol. Sci. 2014, 15, 17920–17937. [Google Scholar] [CrossRef] [PubMed]
  30. Venegas, C.; García, J.A.; Escames, G.; Ortiz, F.; López, A.; Doerrier, C.; García-Corzo, L.; López, L.C.; Reiter, R.J.; Acuña-Castroviejo, D. Extrapineal melatonin: Analysis of its subcellular distribution and daily fluctuations. J. Pineal Res. 2012, 52, 217–227. [Google Scholar] [CrossRef] [PubMed]
  31. Tan, D.X. Mitochondria and chloroplasts as the original sites of melatonin synthesis: A hypothesis related to melatonin’s primary function and evolution in eukaryotes. J. Pineal Res. 2013, 54, 127–138. [Google Scholar] [CrossRef] [PubMed]
  32. Hardeland, R.; Tan, D.X.; Reiter, R.J. Kynuramine, metabolites of melatonin and other indoles: The resurrection of an almost forgotten class of biogenic amines. J. Pineal Res. 2009, 47, 109–126. [Google Scholar] [CrossRef] [PubMed]
  33. Tan, D.X.; Manchester, L.C.; Terron, M.P.; Flores, L.J.; Reiter, R.J. One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? J. Pineal Res. 2007, 42, 28–42. [Google Scholar] [CrossRef] [PubMed]
  34. Zhang, H.M.; Zhang, Y. Melatonin: A well-documented antioxidant with conditional pro-oxidant actions. J. Pineal Res. 2014, 57, 131–146. [Google Scholar] [CrossRef] [PubMed]
  35. Galano, A.; Medina, M.E.; Tan, D.X.; Reiter, R.J. Melatonin and its metabolites as copper chelating agents and their role in inhibiting oxidative stress: A physicochemical analysis. J. Pineal Res. 2015, 58, 107–116. [Google Scholar] [CrossRef] [PubMed]
  36. Reiter, R.J.; Tan, D.X.; Rosales-Corral, S.; Manchester, L.C. The universal nature, unequal distribution and antioxidant functions of melatonin and its derivatives. Mini Rev. Med. Chem. 2013, 13, 373–384. [Google Scholar] [CrossRef] [PubMed]
  37. Acuña-Castroviejo, D.; Escames, G.; Venegas, C.; Díaz-Casado, M.E.; Lima-Cabello, E.; López, L.C.; Rosales-Corral, S.; Tan, D.X.; Reiter, R.J. Extrapineal melatonin: Sources, regulation, and potential functions. Cell. Mol. Life Sci. 2014, 71, 2997–3025. [Google Scholar] [CrossRef] [PubMed]
  38. Manchester, L.C.; Coto-Montes, A.; Boga, J.A.; Andersen, L.P.H.; Zhou, Z.; Galano, A.; Vriend, J.; Tan, D.X.; Reiter, R.J. An ancient molecule that makes oxygen metabolically tolerable. J. Pineal Res. 2015, 59, 403–419. [Google Scholar] [CrossRef] [PubMed]
  39. Tan, D.X.; Korkmaz, A.; Reiter, R.J.; Manchester, L.C. Ebola virus disease: Potential use of melatonin as a treatment. J. Pineal Res. 2014, 57, 381–384. [Google Scholar] [CrossRef] [PubMed]
  40. Reiter, R.J.; Richardson, B.A.; Johnson, L.Y.; Ferguson, B.N.; Dinh, D.T. Pineal melatonin rhythm: Reduction in aging Syrian hamsters. Science 1980, 210, 1372–1373. [Google Scholar] [CrossRef] [PubMed]
  41. Reiter, R.J.; Craft, C.M.; Johnson, J.E., Jr.; King, T.S.; Richardson, B.A.; Vaughan, G.M.; Vaughan, M.K. Age-associated reduction in nocturnal pineal melatonin levels in female rats. Endocrinology 1981, 109, 1295–1297. [Google Scholar] [CrossRef] [PubMed]
  42. Iguichi, H.; Kato, K.I.; Ibayashi, H. Age-dependent reduction in serum melatonin concentrations in healthy human subjects. J. Clin. Endocrinol. Metab. 1982, 55, 27–29. [Google Scholar] [CrossRef] [PubMed]
  43. Caballero, B.; Vega-Naredo, I.; Sierra, V.; Huidobro-Fernández, C.; Soria-Valles, C.; de Gonzalo-Calvo, D.; Tolivia, D.; Gutierrez-Cuesta, J.; Pallas, M.; Camins, A.; et al. Favorable effects of a prolonged treatment with melatonin on the level of oxidative damage and neurodegeneration in senescence-accelerated mice. J. Pineal Res. 2008, 45, 302–311. [Google Scholar] [CrossRef] [PubMed]
  44. García-Macia, M.; Vega-Naredo, I.; de Gonzalo-Calvo, D.; Rodríguez-González, S.M.; Camello, P.J.; Camello-Almaraz, C.; Martín-Cano, F.E.; Rodríguez-Colunga, M.J.; Pozo, M.J.; Coto-Montes, A.M. Melatonin induces neural SOD2 expression independent of the NF-kappaB pathway and improves the mitochondrial population and function in old mice. J. Pineal Res. 2011, 50, 54–63. [Google Scholar] [CrossRef] [PubMed]
  45. Rosales-Corral, S.A.; Lopez-Armas, G.; Cruz-Ramos, J.; Melnikov, V.G.; Tan, D.X.; Manchester, L.C.; Munoz, R.; Reiter, R.J. Alterations in lipid levels of mitochondrial membranes induced by Amyloid-β: A protective role of melatonin. Int. J. Alzheimer’s Dis. 2012, 2012, 459806. [Google Scholar] [CrossRef] [PubMed]
  46. Bubenik, G.A.; Konturek, S.J. Melatonin and aging: Prospects for human treatment. J. Physiol. Pharmacol. 2011, 62, 13–19. [Google Scholar] [PubMed]
  47. Ito, K.; Colley, T.; Mercado, N. Geroprotectors as a novel therapeutic strategy for COPD, an accelerating aging disease. Int. J. Chronic Obstr. Pulm. Dis. 2012, 7, 641–652. [Google Scholar] [CrossRef] [PubMed]
  48. Hill, S.M.; Cheng, C.; Yuan, L.; Mao, L.; Jockers, R.; Dauchy, B.; Blask, D.E. Age-related decline in melatonin and its MT1 receptor are associated with decreased sensitivity to melatonin and enhanced mammary tumor growth. Curr. Aging Sci. 2013, 6, 125–133. [Google Scholar] [CrossRef] [PubMed]
  49. Gitto, E.; Pellegrino, S.; Gitto, P.; Barberi, I.; Reiter, R.J. Oxidative stress of the newborn in the pre- and postnatal period and the clinical utility of melatonin. J. Pineal Res. 2009, 46, 128–139. [Google Scholar] [CrossRef] [PubMed]
  50. Marseglia, L.; Aversa, S.; Barberi, I.; Salpietro, C.D.; Cusumano, E.; Speciale, A.; Saija, A.; Romeo, C.; Trimarchi, G.; Reiter, R.J.; et al. High endogenous melatonin levels in critically ill children: A pilot study. J. Pediatr. 2013, 162, 357–360. [Google Scholar] [CrossRef] [PubMed]
  51. Schwichtenberg, A.J.; Malow, B.A. Melatonin Treatment in Children with Developmental Disabilities. Sleep Med. Clin. 2015, 10, 181–187. [Google Scholar] [CrossRef] [PubMed]
  52. Cardinali, D.P.; Vigo, D.E.; Olivar, N.; Vidal, M.F.; Furio, A.M.; Brusco, L.I. Therapeutic application of melatonin in mild cognitive impairment. Am. J. Neurodegener. Dis. 2012, 1, 280–291. [Google Scholar] [PubMed]
  53. Gallucci, M.; Flores-Obando, R.; Mazzuco, S.; Ongaro, F.; di Giorgi, E.; Boldrini, P.; Durante, E.; Frigato, A.; Albani, D.; Forloni, G.; et al. Melatonin and the Charlson Comorbidity Index (CCI): The Treviso Longeva (Trelong) study. Int. J. Biol. Markers 2014, 29, e253–e260. [Google Scholar] [CrossRef] [PubMed]
  54. Boga, J.A.; Coto-Montes, A.; Rosales-Corral, S.A.; Tan, D.X.; Reiter, R.J. Beneficial actions of melatonin in the management of viral infections: A new use for this “molecular handyman”? Rev. Med. Virol. 2012, 22, 323–338. [Google Scholar] [CrossRef] [PubMed]
  55. Hill, S.M.; Belancio, V.P.; Dauchy, R.T.; Xiang, S.; Brimer, S.; Mao, L.; Hauch, A.; Lundberg, P.W.; Summers, W.; Yuan, L.; et al. Melatonin: An inhibitor of breast cancer. Endocr. Relat. Cancer 2015, 22, R183–R204. [Google Scholar] [CrossRef] [PubMed]
  56. Xin, Z.; Jiang, S.; Jiang, P.; Yan, X.; Fan, C.; Di, S.; Wu, G.; Yang, Y.; Reiter, R.J.; Ji, G. Melatonin as a treatment for gastrointestinal cancer: A review. J. Pineal Res. 2015, 58, 375–387. [Google Scholar] [CrossRef] [PubMed]
  57. Song, Y.; Dowling, G.A.; Wallhagen, M.I.; Lee, K.A.; Strawbridge, W.J. Sleep in older adults with Alzheimer’s disease. J. Neurosci. Nurs. 2010, 42, 190–198. [Google Scholar] [CrossRef] [PubMed]
  58. Golombek, D.A.; Pandi-Perumal, S.R.; Brown, G.M.; Cardinali, D.P. Some implications of melatonin use in chronopharmacology of insomnia. Eur. J. Pharmacol. 2015, 762, 42–48. [Google Scholar] [CrossRef] [PubMed]
  59. Rosales-Corral, S.A.; Acuña-Castroviejo, D.; Coto-Montes, A.; Boga, J.A.; Manchester, L.C.; Fuentes-Broto, L.; Korkmaz, A.; Ma, S.; Tan, D.X.; Reiter, R.J. Alzheimer’s disease: Pathological mechanisms and the beneficial role of melatonin. J. Pineal Res. 2012, 52, 167–202. [Google Scholar] [CrossRef] [PubMed]
  60. Miller, E.; Morel, A.; Saso, L.; Saluk, J. Melatonin redox activity. Its potential clinical applications in neurodegenerative disorders. Curr. Top. Med. Chem. 2015, 15, 163–169. [Google Scholar] [CrossRef] [PubMed]
  61. Sánchez-Barceló, E.J.; Mediavilla, M.D.; Tan, D.X.; Reiter, R.J. Clinical uses of melatonin: Evaluation of human trials. Curr. Med. Chem. 2010, 17, 2070–2095. [Google Scholar] [CrossRef] [PubMed]
  62. Gögenur, I.; Kücükakin, B.; Panduro Jensen, L.; Reiter, R.J.; Rosenberg, J. Melatonin reduces cardiac morbidity and markers of myocardial ischemia after elective abdominal aortic aneurysm repair: A randomized, placebo-controlled, clinical trial. J. Pineal Res. 2014, 57, 10–15. [Google Scholar] [CrossRef] [PubMed]
  63. Sookprasert, A.; Johns, N.P.; Phunmanee, A.; Pongthai, P.; Cheawchanwattana, A.; Johns, J.; Konsil, J.; Plaimee, P.; Porasuphatana, S.; Jitpimolmard, S. Melatonin in patients with cancer receiving chemotherapy: A randomized, double-blind, placebo-controlled trial. Anticancer Res. 2014, 34, 7327–7337. [Google Scholar] [PubMed]
  64. Mostafavi, A.; Solhi, M.; Mohammadi, M.R.; Hamedi, M.; Keshavarzi, M.; Akhondzadeh, S. Melatonin decreases olanzapine induced metabolic side-effects in adolescents with bipolar disorder: A randomized double-blind placebo-controlled trial. Acta Med. Iran. 2014, 52, 734–739. [Google Scholar] [PubMed]
  65. Chahbouni, M.; Escames, G.; Venegas, C.; Sevilla, B.; García, J.A.; López, L.C.; Muñoz-Hoyos, A.; Molina-Carballo, A.; Acuña-Castroviejo, D. Melatonin treatment normalizes plasma pro-inflammatory cytokines and nitrosative/oxidative stress in patients suffering from Duchenne muscular dystrophy. J. Pineal Res. 2010, 48, 282–289. [Google Scholar] [CrossRef] [PubMed]
  66. Tarantino, U.; Baldi, J.; Celi, M.; Rao, C.; Liuni, F.M.; Iundusi, R.; Gasbarra, E. Osteoporosis and sarcopenia: The connections. Aging Clin. Exp. Res. 2013, 25, S93–S95. [Google Scholar] [CrossRef] [PubMed]
  67. Marzetti, E.; Calvani, R.; Cesari, M.; Buford, T.W.; Lorenzi, M.; Behnke, B.J.; Leeuwenburgh, C. Mitochondrial dysfunction and sarcopenia of aging: From signaling pathways to clinical trials. Int. J. Biochem. Cell Biol. 2013, 45, 2288–2301. [Google Scholar] [CrossRef] [PubMed]
  68. Hepple, R.T. Mitochondrial involvement and impact in aging skeletal muscle. Front. Aging Neurosci. 2014, 6, 211. [Google Scholar] [CrossRef] [PubMed]
  69. Yan, L.J. Positive oxidative stress in aging and aging-related disease tolerance. Redox Biol. 2014, 2, 165–169. [Google Scholar] [CrossRef] [PubMed]
  70. Handy, D.E.; Loscalzo, J. Redox regulation of mitochondrial function. Antioxid. Redox Signal. 2012, 16, 1323–1367. [Google Scholar] [CrossRef] [PubMed]
  71. Reid, M.B.; Khawli, F.A.; Moody, M.R. Reactive oxygen in skeletal muscle. III. Contractility of unfatigued muscle. J. Appl. Physiol. 1993, 75, 1081–1087. [Google Scholar] [PubMed]
  72. Cerullo, F.; Gambassi, G.; Cesari, M. Rationale for antioxidant supplementation in sarcopenia. J. Aging Res. 2012, 2012, 316943. [Google Scholar] [CrossRef] [PubMed]
  73. Vega-Naredo, I.; Caballero, B.; Sierra, V.; García-Macia, M.; de Gonzalo-Calvo, D.; Oliveira, P.J.; Rodríguez-Colunga, M.J.; Coto-Montes, A. Melatonin modulates autophagy through a redox-mediated action in female Syrian hamster Harderian gland controlling cell type and gland activity. J. Pineal Res. 2012, 52, 80–92. [Google Scholar] [CrossRef] [PubMed]
  74. Proietti, S.; Cucina, A.; Dobrowolny, G.; D’Anselmi, F.; Dinicola, S.; Masiello, M.G.; Pasqualato, A.; Palombo, A.; Morini, V.; Reiter, R.J.; et al. Melatonin down-regulates MDM2 gene expression and enhances p53 acetylation in MCF-7 cells. J. Pineal Res. 2014, 57, 120–129. [Google Scholar] [CrossRef] [PubMed]
  75. Cruz-Jentoft, A.J.; Baeyens, J.P.; Bauer, J.M.; Boirie, Y.; Cederholm, T.; Landi, F.; Martin, F.C.; Michel, J.P.; Rolland, Y.; Schneider, S.M.; et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing 2010, 39, 412–423. [Google Scholar] [CrossRef] [PubMed]
  76. Coen, P.M.; Jubrias, S.A.; Distefano, G.; Amati, F.; Mackey, D.C.; Glynn, N.W.; Manini, T.M.; Wohlgemuth, S.E.; Leeuwenburgh, C.; Cummings, S.R.; et al. Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults. J. Gerontol. A Biol. Sci. Med. Sci. 2013, 68, 447–455. [Google Scholar] [CrossRef] [PubMed]
  77. Ramis, M.R.; Esteban, S.; Miralles, A.; Tan, D.X.; Reiter, R.J. Protective effects of melatonin and mitochondria-targeted antioxidants against oxidative stress: A review. Curr. Med. Chem. 2015, 22, 2690–2711. [Google Scholar] [CrossRef] [PubMed]
  78. Agil, A.; El-Hammadi, M.; Jiménez-Aranda, A.; Tassi, M.; Abdo, W.; Fernández-Vázquez, G.; Reiter, R.J. Melatonin reduces hepatic mitochondrial dysfunction in diabetic obese rats. J. Pineal Res. 2015, 59, 70–79. [Google Scholar] [CrossRef] [PubMed]
  79. Henics, T.; Wheatley, D.N. Cytoplasmic vacuolation, adaptation and cell death: A view on new perspectives and features. Biol. Cell 1999, 91, 485–498. [Google Scholar] [CrossRef]
  80. Shubin, A.V.; Demidyuk, I.V.; Lunina, N.A.; Komissarov, A.A.; Roschina, M.P.; Leonova, O.G.; Kostrov, S.V. Protease 3C of hepatitis A virus induces vacuolization of lysosomal/endosomal organelles and caspase-independent cell death. BMC Cell Biol. 2015, 16, 4. [Google Scholar] [CrossRef] [PubMed]
  81. Vega-Naredo, I.; Caballero, B.; Sierra, V.; Huidobro-Fernández, C.; de Gonzalo-Calvo, D.; García-Macia, M.; Tolivia, D.; Rodríguez-Colunga, M.J.; Coto-Montes, A. Sexual dimorphism of autophagy in Syrian hamster Harderian gland culminates in a holocrine secretion in female glands. Autophagy 2009, 5, 1004–1017. [Google Scholar] [CrossRef] [PubMed]
  82. Sakuma, K.; Yamaguchi, A. Sarcopenia and age-related endocrine function. Int. J. Endocrinol. 2012, 2012, 127362. [Google Scholar] [CrossRef] [PubMed]
  83. Sabatelli, P.; Castagnaro, S.; Tagliavini, F.; Chrisam, M.; Sardone, F.; Demay, L.; Richard, P.; Santi, S.; Maraldi, N.M.; Merlini, L.; et al. Aggresome-autophagy involvement in a sarcopenic patient with rigid spine syndrome and a p.C150R Mutation in FHL1 gene. Front. Aging Neurosci. 2014, 6, 215. [Google Scholar] [CrossRef] [PubMed]
  84. Coto-Montes, A.; Boga, J.A.; Rosales-Corral, S.; Fuentes-Broto, L.; Tan, D.X.; Reiter, R.J. Role of melatonin in the regulation of autophagy and mitophagy: A review. Mol. Cell. Endocrinol. 2012, 361, 12–23. [Google Scholar] [CrossRef] [PubMed]
  85. De Luxán-Delgado, B.; Caballero, B.; Potes, Y.; Rubio-González, A.; Rodríguez, I.; Gutiérrez-Rodríguez, J.; Solano, J.J.; Coto-Montes, A. Melatonin administration decreases adipogenesis in the liver of ob/ob mice through autophagy modulation. J. Pineal Res. 2014, 56, 126–133. [Google Scholar] [CrossRef] [PubMed]
  86. Hong, Y.; Won, J.; Lee, Y.; Lee, S.; Park, K.; Chang, K.T.; Hong, Y. Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells. J. Pineal Res. 2014, 56, 264–274. [Google Scholar] [CrossRef] [PubMed]
  87. Hong, Y.; Kim, J.H.; Jin, Y.; Lee, S.; Park, K.; Lee, Y.; Chang, K.T.; Hong, Y. Melatonin treatment combined with treadmill exercise accelerates muscular adaptation through early inhibition of CHOP-mediated autophagy in the gastrocnemius of rats with intra-articular collagenase-induced knee laxity. J. Pineal Res. 2014, 56, 175–188. [Google Scholar] [CrossRef] [PubMed]
  88. Kim, C.H.; Kim, K.H.; Yoo, Y.M. Melatonin-induced autophagy is associated with degradation of MyoD protein in C2C12 myoblast cells. J. Pineal Res. 2012, 53, 289–297. [Google Scholar] [CrossRef] [PubMed]
  89. San-Miguel, B.; Crespo, I.; Sánchez, D.I.; González-Fernández, B.; Ortiz de Urbina, J.J.; Tuñón, M.J.; González-Gallego, J. Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis. J. Pineal Res. 2015, 59, 151–162. [Google Scholar] [CrossRef] [PubMed]
  90. Brunk, U.T.; Terman, A. The mitochondrial-lysosomal axis theory of aging: Accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur. J. Biochem. 2002, 269, 1996–2002. [Google Scholar] [CrossRef] [PubMed]
  91. Terman, A.; Kurz, T.; Navratil, M.; Arriaga, E.A.; Brunk, U.T. Mitochondrial turnover and aging of longlived postmitotic cells: The mitochondrial-lysosomal axis theory of aging. Antioxid. Redox Signal. 2010, 12, 503–535. [Google Scholar] [CrossRef] [PubMed]
  92. Sriram, S.; Subramanian, S.; Sathiakumar, D.; Venkatesh, R.; Salerno, M.S.; McFarlane, C.D.; Kambadur, R.; Sharma, M. Modulation of reactive oxygen species in skeletal muscle by myostatin is mediated through NF-κB. Aging Cell 2011, 10, 931–948. [Google Scholar] [CrossRef] [PubMed]
  93. Sakuma, K.; Aoi, W.; Yamaguchi, A. Current understanding of sarcopenia: Possible candidates modulating muscle mass. Pflug. Arch. 2015, 467, 213–229. [Google Scholar] [CrossRef] [PubMed]
  94. Vriend, J.; Reiter, R.J. Melatonin as a proteasome inhibitor. Is there any clinical evidence? Life Sci. 2014, 115, 8–14. [Google Scholar] [CrossRef] [PubMed]
  95. Morgan, J.E.; Partridge, T.A. Muscle satellite cells. Int. J. Biochem. Cell Biol. 2003, 35, 1151–1156. [Google Scholar] [CrossRef]
  96. Dumont, N.A.; Bentzinger, C.F.; Sincennes, M.C.; Rudnicki, M.A. Satellite cells and skeletal muscle regeneration. Compr. Physiol. 2015, 5, 1027–1059. [Google Scholar] [PubMed]
  97. Faulkner, J.A.; Brooks, S.V.; Zerba, E. Muscle atrophy and weakness with aging: Contraction-induced injury as an underlying mechanism. J. Gerontol. A Biol. Sci. Med. Sci. 1995, 50, 124–129. [Google Scholar] [PubMed]
  98. Tinetti, M.E. Where is the vision for fall prevention? J. Am. Geriatr. Soc. 2001, 49, 676–677. [Google Scholar] [CrossRef] [PubMed]
  99. Alway, S.E.; Myers, M.J.; Mohamed, J.S. Regulation of satellite cell function in sarcopenia. Front. Aging Neurosci. 2014, 6, 246. [Google Scholar] [CrossRef] [PubMed]
  100. Van der Meer, S.F.; Jaspers, R.T.; Jones, D.A.; Degens, H. Time-course of changes in the myonuclear domain during denervation in young-adult and old rat gastrocnemius muscle. Muscle Nerve 2011, 43, 212–222. [Google Scholar] [CrossRef] [PubMed][Green Version]
  101. Stratos, I.; Richter, N.; Rotter, R.; Li, Z.; Zechner, D.; Mittlmeier, T.; Vollmar, B. Melatonin restores muscle regeneration and enhances muscle function after crush injury in rats. J. Pineal Res. 2012, 52, 62–70. [Google Scholar] [CrossRef] [PubMed]
  102. Li, Z.; Nickkholgh, A.; Yi, X.; Bruns, H.; Gross, M.L.; Hoffmann, K.; Mohr, E.; Zorn, M.; Büchler, M.W.; Schemmer, P. Melatonin protects kidney grafts from ischemia/reperfusion injury through inhibition of NF-kB and apoptosis after experimental kidney transplantation. J. Pineal Res. 2009, 46, 365–372. [Google Scholar] [CrossRef] [PubMed]
  103. Jou, M.J.; Peng, T.I.; Hsu, L.F.; Jou, S.B.; Reiter, R.J.; Yang, C.M.; Chiao, C.C.; Lin, Y.F.; Chen, C.C. Visualization of melatonin multiple mitochondria levels of protection against mitochondrial Ca(2+) mediated permeability transition and beyond in rat brain astrocytes. J. Pineal Res. 2010, 48, 20–38. [Google Scholar] [CrossRef] [PubMed]
  104. Tanaka, T.; Yasui, Y.; Tanaka, M.; Tanaka, T.; Oyama, T.; Rahman, K.M. Melatonin suppresses AOM/DSS-induced large bowel oncogenesis in rats. Chem. Biol. Interact. 2009, 177, 128–136. [Google Scholar] [CrossRef] [PubMed]
  105. Leja-Szpak, A.; Jaworek, J.; Pierzchalski, P.; Reiter, R.J. Melatonin induces pro-apoptotic signaling pathway in human pancreatic carcinoma cells (PANC-1). J. Pineal Res. 2010, 49, 248–255. [Google Scholar] [CrossRef] [PubMed]
  106. Mao, L.; Cheng, Q.; Guardiola-Lemaître, B.; Schuster-Klein, C.; Dong, C.; Lai, L.; Hill, SM. In vitro and in vivo antitumor activity of melatonin receptor agonists. J. Pineal Res. 2010, 49, 210–221. [Google Scholar] [CrossRef] [PubMed]
  107. Hibaoui, Y.; Roulet, E.; Ruegg, U.T. Melatonin prevents oxidative stress-mediated mitochondrial permeability transition and death in skeletal muscle cells. J. Pineal Res. 2009, 47, 238–252. [Google Scholar] [CrossRef] [PubMed]
  108. Wang, W.Z. Melatonin reduces ischemia/reperfusion-induced superoxide generation in arterial wall and cell death in skeletal muscle. J. Pineal Res. 2006, 41, 255–260. [Google Scholar] [CrossRef] [PubMed]
  109. De Gonzalo-Calvo, D.; Fernández-García, B.; de Luxán-Delgado, B.; Rodríguez-González, S.; García-Macia, M.; Suárez, F.M.; Solano, J.J.; Rodríguez-Colunga, M.J.; Coto-Montes, A. Long-term training induces a healthy inflammatory and endocrine emergent biomarker profile in elderly men. Age (Dordr) 2012, 34, 761–771. [Google Scholar] [CrossRef] [PubMed]
  110. De Gonzalo-Calvo, D.; Neitzert, K.; Fernández, M.; Vega-Naredo, I.; Caballero, B.; García-Macía, M.; Suárez, F.M.; Rodríguez-Colunga, M.J.; Solano, J.J.; Coto-Montes, A. Differential inflammatory responses in aging and disease: TNF-alpha and IL-6 as possible biomarkers. Free Radic. Biol Med. 2010, 49, 733–737. [Google Scholar] [CrossRef] [PubMed]
  111. Cesari, M.; Kritchevsky, S.B.; Baumgartner, R.N.; Atkinson, H.H.; Penninx, B.W.; Lenchik, L.; Palla, S.L.; Ambrosius, W.T.; Tracy, R.P.; Pahor, M. Sarcopenia, obesity, and inflammation results from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors study. Am. J. Clin. Nutr. 2005, 82, 428–434. [Google Scholar] [PubMed]
  112. Ferrucci, L.; Penninx, B.W.; Volpato, S.; Harris, T.B.; Bandeen-Roche, K.; Balfour, J.; Leveille, S.G.; Fried, L.P.; Md, J.M. Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels. J. Am. Geriatr. Soc. 2002, 50, 1947–1954. [Google Scholar] [CrossRef] [PubMed]
  113. Michaud, M.; Balardy, L.; Moulis, G.; Gaudin, C.; Peyrot, C.; Vellas, B.; Cesari, M.; Nourhashemi, F. Proinflammatory cytokines, aging, and age-related diseases. J. Am. Med. Dir. Assoc. 2013, 14, 877–882. [Google Scholar] [CrossRef] [PubMed]
  114. Borges, L.S.; Dermargos, A.; da Silva Junior, E.P.; Weimann, E.; Lambertucci, R.H.; Hatanaka, E. Melatonin decreases muscular oxidative stress and inflammation induced by strenuous exercise and stimulates growth factor synthesis. J. Pineal Res. 2015, 58, 166–172. [Google Scholar] [CrossRef] [PubMed]
  115. Ochoa, J.J.; Díaz-Castro, J.; Kajarabille, N.; García, C.; Guisado, I.M.; de Teresa, C.; Guisado, R. Melatonin supplementation ameliorates oxidative stress and inflammatory signaling induced by strenuous exercise in adult human males. J. Pineal Res. 2011, 51, 373–380. [Google Scholar] [CrossRef] [PubMed]
  116. Mauriz, J.L.; Collado, P.S.; Veneroso, C.; Reiter, R.J.; González-Gallego, J. A review of the molecular aspects of melatonin’s anti-inflammatory actions: Recent insights and new perspectives. J. Pineal Res. 2013, 54, 1–14. [Google Scholar] [CrossRef] [PubMed]
  117. Iwabu, M.; Yamauchi, T.; Okada-Iwabu, M.; Sato, K.; Nakagawa, T.; Funata, M.; Yamaguchi, M.; Namiki, S.; Nakayama, R.; Tabata, M.; et al. Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca2+ and AMPK/SIRT1. Nature 2010, 464, 1313–1319. [Google Scholar] [CrossRef] [PubMed]
  118. Li, L.; Pan, R.; Li, R.; Niemann, B.; Aurich, A.C.; Chen, Y.; Rohrbach, S. Mitochondrial biogenesis and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation by physical activity: Intact adipocytokine signaling is required. Diabetes 2011, 60, 157–167. [Google Scholar] [CrossRef] [PubMed]
  119. Carter, C.S.; Onder, G.; Kritchevsky, S.B.; Pahor, M. Angiotensin-converting enzyme inhibition intervention in elderly persons: Effects on body composition and physical performance. J. Gerontol. A Biol. Sci. Med. Sci. 2005, 60, 1437–1446. [Google Scholar] [CrossRef] [PubMed]
  120. Kob, R.; Bollheimer, L.C.; Bertsch, T.; Fellner, C.; Djukic, M.; Sieber, C.C.; Fischer, B.E. Sarcopenic obesity: Molecular clues to a better understanding of its pathogenesis? Biogerontology 2015, 6, 15–29. [Google Scholar] [CrossRef] [PubMed]
  121. Samaras, N.; Papadopoulou, M.A.; Samaras, D.; Ongaro, F. Off-label use of hormones as an antiaging strategy: A review. Clin. Interv. Aging 2014, 9, 1175–1186. [Google Scholar] [CrossRef] [PubMed]
  122. Giovannini, S.; Marzetti, E.; Borst, S.E.; Leeuwenburgh, C. Modulation of GH/IGF-1 axis: Potential strategies to counteract sarcopenia in older adults. Mech. Ageing Dev. 2008, 129, 593–601. [Google Scholar] [CrossRef] [PubMed]
  123. Thorner, M.O. Statement by the Growth Hormone Research Society on the GH/IGF-I axis in extending health span. J. Gerontol. A Biol. Sci. Med. Sci. 2009, 64, 1039–1044. [Google Scholar] [CrossRef] [PubMed]
  124. Oner, J.; Oner, H.; Sahin, Z.; Demir, R.; Ustünel, I. Melatonin is as effective as testosterone in the prevention of soleus muscle atrophy induced by castration in rats. Anat. Rec. (Hoboken) 2008, 291, 448–455. [Google Scholar] [CrossRef] [PubMed]
  125. Das, U.N. A defect in the activity of Delta6 and Delta5 desaturases may be a factor predisposing to the development of insulin resistance syndrome. Prostaglandins Leukot. Essent. Fat. Acids 2005, 72, 343–350. [Google Scholar] [CrossRef] [PubMed]
  126. Luchetti, F.; Canonico, B.; Bartolini, D.; Arcangeletti, M.; Ciffolilli, S.; Murdolo, G.; Piroddi, M.; Papa, S.; Reiter, R.J.; Galli, F. Melatonin regulates mesenchymal stem cell differentiation: A review. J. Pineal Res. 2014, 56, 382–397. [Google Scholar] [CrossRef] [PubMed]
  127. Pascua, P.; Camello-Almaraz, C.; Camello, P.J.; Martin-Cano, F.E.; Vara, E.; Fernandez-Tresguerres, J.A.; Pozo, M.J. Melatonin, and to a lesser extent growth hormone, restores colonic smooth muscle physiology in old rats. J. Pineal Res. 2011, 51, 405–415. [Google Scholar] [CrossRef] [PubMed]
  128. De Van, A.E.; Eskurza, I.; Pierce, G.L.; Walker, A.E.; Jablonski, K.L.; Kaplon, R.E.; Seals, D.R. Regular aerobic exercise protects against impaired fasting plasma glucose-associated vascular endothelial dysfunction with aging. Clin. Sci. (Lond.) 2013, 124, 325–331. [Google Scholar] [CrossRef] [PubMed]
  129. Behnke, B.J.; Padilla, D.J.; Ferreira, L.F.; Delp, M.D.; Musch, T.I.; Poole, D.C. Effects of arterial hypotension on microvascular oxygen exchange in contracting skeletal muscle. J. Appl. Physiol. 1985, 100, 1019–1026. [Google Scholar] [CrossRef] [PubMed]
  130. Rosei, C.A.; de Ciuceis, C.; Rossini, C.; Porteri, E.; Rezzani, R.; Rodella, L.; Favero, G.; Sarkar, A.; Rosei, E.A.; Rizzoni, D. 7D.10: Effects of melatonin on contractile responses in small arteries of ageing mice. J. Hypertens. 2015, 33 (Suppl. S1), e103. [Google Scholar] [CrossRef] [PubMed]
  131. Rodella, L.F.; Favero, G.; Rossini, C.; Foglio, E.; Bonomini, F.; Reiter, R.J.; Rezzani, R. Aging and vascular dysfunction: Beneficial melatonin effects. Age (Dordr) 2013, 35, 103–115. [Google Scholar] [CrossRef] [PubMed]
  132. Eşrefoğlu, M.; Gül, M.; Ateş, B.; Erdoğan, A. The effects of caffeic acid phenethyl ester and melatonin on age-related vascular remodeling and cardiac damage. Fundam. Clin. Pharmacol. 2011, 25, 580–590. [Google Scholar] [CrossRef] [PubMed]
  133. Cummings, S.R.; Melton, L.J. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002, 359, 1761–1767. [Google Scholar] [CrossRef]
  134. Frost, H.M. Muscle, bone, and the Utah paradigm: A 1999 overview. Med. Sci. Sports Exerc. 2000, 32, 911–917. [Google Scholar] [CrossRef] [PubMed]
  135. Binkley, N.; Buehring, B. Beyond FRAX: It’s time to consider “sarco-osteopenia”. J. Clin. Densitom. 2009, 12, 413–416. [Google Scholar] [CrossRef] [PubMed]
  136. Binkley, N.; Krueger, D.; Buehring, B. What’s in a name revisited: Should osteoporosis and sarcopenia be considered components of “dysmobility syndrome?”. Osteoporos. Int. 2013, 24, 2955–2959. [Google Scholar] [CrossRef] [PubMed]
  137. Yang, Y.H.; Li, B.; Zheng, X.F.; Chen, J.W.; Chen, K.; Jiang, S.D.; Jiang, L.S. Oxidative damage to osteoblasts can be alleviated by early autophagy through the endoplasmic reticulum stress pathway-implications for the treatment of osteoporosis. Free Radic. Biol. Med. 2014, 77, 10–20. [Google Scholar] [CrossRef] [PubMed]
  138. Maria, S.; Witt-Enderby, P.A. Melatonin effects on bone: Potential use for the prevention and treatment for osteopenia, osteoporosis, and periodontal disease and for use in bone-grafting procedures. J. Pineal Res. 2014, 56, 115–125. [Google Scholar] [CrossRef] [PubMed]
  139. Amstrup, A.K.; Sikjaer, T.; Heickendorff, L.; Mosekilde, L.; Rejnmark, L. Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: A randomized controlled trial. J. Pineal Res. 2015, 59, 221–229. [Google Scholar] [CrossRef] [PubMed]
  140. Peterson, C.M.; Johannsen, D.L.; Ravussin, E. Skeletal muscle mitochondria and aging: A review. J. Aging Res. 2012, 2012, 194821. [Google Scholar] [CrossRef] [PubMed]
  141. Gomez-Pinilla, P.J.; Camello, P.J.; Pozo, M.J. Melatonin treatment reverts age-related changes in guinea pig gallbladder neuromuscular transmission and contractility. J. Pharmacol. Exp. Ther. 2006, 319, 847–856. [Google Scholar] [CrossRef] [PubMed]
  142. Gomez-Pinilla, P.J.; Camello, P.J.; Pozo, M.J. Effects of melatonin on gallbladder neuromuscular function in acute cholecystitis. J. Pharmacol. Exp. Ther. 2007, 323, 138–146. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Schematic overview of the potential beneficial effects of melatonin in osteoporosis, sarcopenia and disruption of the neuromuscular junction.
Figure 1. Schematic overview of the potential beneficial effects of melatonin in osteoporosis, sarcopenia and disruption of the neuromuscular junction.
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