Review articlesSatellite cells in ageing: use it or lose it
Abstract
Individuals that maintain healthy skeletal tissue tend to live healthier, happier lives as proper muscle function enables maintenance of independence and actuation of autonomy. The onset of skeletal muscle decline begins around the age of 30, and muscle atrophy is associated with a number of serious morbidities and mortalities. Satellite cells are responsible for regeneration of skeletal muscle and enter a reversible non-dividing state of quiescence under homeostatic conditions. In response to injury, satellite cells are able to activate and re-enter the cell cycle, creating new cells to repair and create nascent muscle fibres while preserving a small population that can return to quiescence for future regenerative demands. However, in aged muscle, satellite cells that experience prolonged quiescence will undergo programmed cellular senescence, an irreversible non-dividing state that handicaps the regenerative capabilities of muscle. This review examines how periodic activation and cycling of satellite cells through exercise can mitigate senescence acquisition and myogenic decline.
1. Introduction
Skeletal muscle accounts for approximately 40% of the human body weight and its functions include maintaining posture, mobility, regulating body temperature, energy storage and soft tissue support. Given its many important functions, it is unsurprising that muscle strength is positively correlated with better quality of life and negatively correlated with all-cause mortality [1–4].
The relationship between muscle strength and morbidity is more apparent in geriatric populations where sarcopaenia, age-related muscle atrophy, can lead to falls, disability and mortality. For example, the majority of hip fractures occur within individuals over 65 years of age [5]. Atrophy of stabilizer muscles can lead to loss of balance, important in preventing falls. Diminishing grip strength reduces one's ability to catch oneself in the event of a fall, and in the event of an accident, there is less muscle mass to cushion upon impact. Together, the greater risk of falls combined with sarcopaenia and osteoporosis are why the elderly are at a heightened risk of hip fractures, one of the highest predictors of morbidity and mortality in geriatric populations, with 1 year mortalities ranging from 14% to 58% [5,6]. Overall muscle decline begins around the age of 30, with an average annual muscle mass loss of 3–5%, with a total loss of up to 30% within an individual's lifetime [7–9].
Fortunately, skeletal muscle has remarkable regenerative capabilities, and age-related muscle loss can be drastically attenuated with exercise. On a physiological level, regular exercise has been shown to increase vascularization and perfusion, important for waste removal; muscle efficiency and greater recruitment of myofibres; flexibility and muscle tension; and bone strength and density, required to support muscles [10–12].
On the cellular level, exercise has been shown to increase mitochondrial numbers and quality, enhance innervation by neuromuscular junctions, stimulate supporting cells in the interstitial area of muscle (i.e. fibroapidogenic progenitors, FAPs), and stimulate satellite cells to activate for muscle repair and growth [13–16].
In this review, we address the role of quiescence in muscle regeneration, the mechanisms that prevent senescence in quiescent muscle stem cells, and how exercise contributes to long-term satellite cell viability at a cellular and molecular level.
2. Muscle regeneration and the satellite cell niche
Molecular and genetic studies in mice have greatly elucidated our understanding of the mechanisms that govern satellite cell function during the growth and regeneration of skeletal muscle [17–20]. Satellite cells, named after their satellite position on the myofibre, are a heterogeneous population of stem cells and committed cells that are required for muscle repair. Satellite cells highly express the transcription factor Pax7 and sequentially express myogenic regulatory factors (MRFs) (Myf5, MyoD, MyoG, Mrf4) as they proliferate and then differentiate [21–24]. Pax7+ satellite stem cells mark their commitment to the myogenic lineage as committed myogenic cells by upregulating Myf5. The onset of Myf5 and MyoD protein expression marks the transition into myoblasts. Myogenin induction marks the entry of myoblasts into the terminal differentiation programme and subsequent fusion with other differentiating cells or with existing myofibres (figure 1) [25–27].
Figure 1. Satellite cell quiescence versus activation. Satellite stem (Pax7+:Myf5−) and committed cells (Pax7+:Myf5+) are able to exit the cell cycle and arrest in a reversible quiescent G0 state. Satellite stem and committed cells are primed for rapid cell cycle reentry by transitioning to a second reversible quiescent state called GAlert. Committed satellite cells in GAlert begin transcribing downstream MRFs Myf5 and MyoD. Satellite cells in GAlert are primed to quickly respond to regenerative demands by entering the cell cycle faster than G0 quiescent satellite cells. Active progenitor cells initiate the terminal differentiation programme to upregulate MyoG and Mrf4 in myoblasts and myocytes before fusion into myotubes.
Approximately 10% of the satellite cell population appear to be a long-term self-renewing stem cell population expressing Pax7 but not Myf5. The remaining 90% of the satellite cell population are committed cells that have expressed Myf5 and appear to form a short-term self-renewing population. Transplantation and serial injury experiments have demonstrated the satellite stem cell population to be capable of replenishing the stem cell population in addition to re-establishing the pool of committed satellite cells [22].
Central to a satellite cell's behaviour is the immediate microenvironment that envelops the cell with structural proteins, and the various signalling factors from other nearby cell types. The nearest structures in proximity to a quiescent satellite cell include matrices of the fibrous sheath of basal lamina closest to the apical side of the satellite cell, and the plasma membrane of the myofibre at the basal side of the satellite cell. Satellite cells are often closely associated with capillary endothelial cells, as muscle tends to be a highly vascularized tissue [28]. Other cell types of the local milieu including fibrocyte/adipocyte progenitors (FAPS), pericytes and motor neurons can be found in the muscle interstitium [17]. Under homeostatic conditions, the satellite cell niche provides cues to actively maintain quiescence signalling pathways while suppressing activation pathways [29,30]. Upon injury, these cues activate satellite cells to prepare for the anticipated demands of regeneration [31]. Inflammatory cytokines are also released to provide chemotaxic cues for leucocytes, such as the macrophages required to clear debris and remove toxic waste [32–36]. Preservation of the stem cell pool is critical for maintaining regeneration potential, and thus the niche also provides cues for satellite cells to return to quiescence when regeneration is complete.
While the young niche favours stem cell quiescence, the aged niche provides cues that promote activation and differentiation [17,29,37–47]. Importantly, aged satellite cells demonstrate intrinsic defects that exposure to young niche environments cannot overcome, favouring differentiation and senescence rather than quiescence [38,48–52]. The aged niche and age-related stem cell defects lead to the typical fibro-adipogenic phenotype seen in aged and dystrophic muscle. These findings suggest that prolonged, chronic activation leads to stem cell exhaustion, and that maintenance of stem cell quiescence is paramount to maintaining a healthy stem cell population throughout the ageing process.
3. Satellite cells prefer quiescence
Homeostatic quiescence and activation is critical for establishing short- and long-term regenerative potential of the muscle by activating satellite cells and creating new progenitors for muscle repair, while preserving a small population of stem and committed satellite cells that can enter quiescence for the future regenerative demands.
In response to injury or inflammation, satellite cells will activate and enter the cell cycle to begin dividing and creating new cells for regeneration. Depending on the degree of regeneration required, satellite stem cells (Pax7+/Myf5−) will change their preference for asymmetric self-renewal or symmetric expansion of the stem cell pool. Under normal homeostatic turnover or minor damage, satellite cells preferentially undergo asymmetric division that will produce one stem cell (Pax7+/Myf5−) and one committed cell (Pax7+/Myf5+), which can then become a progenitor and undergo successive rounds of division [17,22,53]. Conversely, under more severe circumstances where damage is greater and demand for regenerative cells higher, satellite stem cells initially undergo symmetric division in order to rapidly expand the stem cell pool to facilitate large-scale generation of progenitors through asymmetric divisions [18,22,53,54].
Under homeostatic conditions, or following injury when active muscle repair is no longer required, satellite cells must be able to exit the cell cycle and enter a reversible state of quiescence to preserve and maintain long-term regeneration potential of its resident muscle [55,56]. Multiple studies have demonstrated that the loss of quiescence and the ability to exit and re-enter quiescence leads to a loss of ‘stemness’, homeostatic decline of the satellite cell population, and eventual inability to regenerate damaged muscle [57–59].
Transcriptomics and proteomic analysis of quiescent satellite cells have revealed a number of transmembrane receptors that are highly expressed within this population, including M-/N- cadherin junctions, Sprouty1, integrinβ1, frizzled receptors, OSMβ, CalcR and Notch receptors [60,61]. These receptors are part of a number of pleiotropic signalling cascades involved in actively maintaining quiescence by preserving cell/niche polarity, inhibition of cell motility and migration, regulating cytoskeletal organization, inhibiting gene of transcription/translation, inhibition of cell proliferation, and repression of activation-driving signalling axes such as ERK and hippo pathways [57,62–71]. Quiescent cells also maintain their G0 state by regulating chromatin compaction and slowing protein synthesis [72,73].
In response to inflammation and injury, satellite cells can enter a second reversible quiescent state before activation called GAlert [74]. Committed satellite cells in GAlert are primed to express downstream targets of the myogenic lineage and withhold protein expression through post-transcriptional and post-translational modifications [75,76]. Satellite cells in GAlert enter the cell cycle at least twice as fast as satellite cells in G0, facilitating a rapid response to injury. These findings suggest a hierarchical cascade model of quiescence and satellite cell recruitment during regeneration wherein quiescent G0 and GAlert populations are present at each stage of the myogenic lineage (figure 1).
Unlike the serious injury models and techniques (i.e. cardiotoxin, BaCl2, freeze and crush injuries) routinely performed on animal models to investigate muscle regeneration [77], humans do not typically experience such traumatic injuries during their lifetime. Thus, the real-world demand on quiescent satellite cells to activate and regenerate is comparatively lower, involving mainly homeostatic turnover and the response to exercise.
Given the impressive regenerative properties of skeletal muscle and lower demands of the modern day lifestyle, the reasons behind early adult onset of muscle decline remain elusive [7,8]. Recent findings on satellite cell quiescence and exercise in ageing populations provide a new paradigm on how to prevent age-related muscle regenerative decline.
4. Quiescence is a double-edged sword
Reversible quiescence is necessary in maintaining long-term regenerative potential, as a subset of regenerative stem cells and progenitors need to be preserved to adequately respond to future demands. However, periods of prolonged satellite cell quiescence may negatively impact long-term viability, leading to impaired regenerative potential (figure 2a). Despite lower protein synthesis, metabolism and general cellular activity, quiescent satellite cells still require cellular processes to actively maintain quiescence. These processes generate cellular waste, organelle damage and mitochondrial ROS from energy production (figure 2b) [72–74,78]. Accumulation of these waste products can harm the long-term viability of quiescent satellite cells. Fortunately, quiescent satellite cells have a number of protective mechanisms to prevent a build-up of cell waste products, DNA damage and transition to senescence [51,79–83].
Figure 2. Healthy quiescence requires periodic activation. (a) Prolonged quiescence is met with detrimental effects, including high proteotoxicity, mitochondrial dysfunction, genomic instability and impaired regeneration. As satellite cells age, they are prone to prolonged states of quiescence during times of inactivity. (b) Quiescent satellite cells accumulate defects in the form of misfolded proteins, mitochondrial damage, reactive oxygen species (ROS) and DNA damage, and begin to express senescence markers. (c) Activation and mitosis of satellite cells induced through exercise or injury upregulates several processes that actively clear cellular waste, including the ubiquitin/proteasome pathway (UPP), autophagy/mitophagy and the DNA damage response (DDR). Passive dilution of cellular waste is also achieved through increased cytoplasm during mitosis. (d) During the return to homeostasis, satellite cells re-enter quiescence, exhibiting lower levels of proteotoxicity, healthy mitochondria, intact genomic integrity and a high regenerative potential.
Quiescent satellite cells under prolonged periods of quiescence are at risk of proteotoxicity (figure 2b). During deep quiescence, accumulation of dysfunctional proteins and organelles that would otherwise be diluted through rounds of cell division can increase cytotoxicity leading to senescence and apoptosis [84–86]. To combat proteotoxicity, systems for cell product turnover are important for maintaining cell viability.
The ubiquitin–proteasome system is one of the primary systems involved in pruning the proteomic landscape. This system is critical for maintaining cell identity. For example, Pax7 expression is regulated by Nedd4, a ubiquitin-ligase that is expressed during both quiescence and activation [87]. Satellite cell-specific knockout studies of the proteasomal subunit Rpt3 demonstrate the importance of the ubiquitin–proteasome system in maintaining quiescence [83]. Disruption of the proteasome through deletion of Rpt3 significantly depletes the quiescent satellite cell population in resting muscle. Moreover, post-injury muscle regeneration is disrupted under Rpt3 knockout conditions, with a significant decline in Pax7-expressing quiescent satellite cell numbers at both 5 and 15 days post injury.
Autophagy also plays a pivotal role in the cell's capacity to maintain cellular integrity through recycling of intracellular components, such as defective or surplus proteins and organelles [85,88]. For the purpose of this review, autophagy will be used in reference to macroautophagy, one of the main forms of autophagy that occur [89]. Autophagy is a critical cellular process in maintaining cell viability, and its disruption in satellite cells promotes muscle atrophy and mitochondrial dysfunction [90–93]. Proper autophagy function is required throughout the cell cycle, including active cycling and quiescence [51,94].
Pharmacological inhibition of autophagy and satellite cell-specific ablation of Atg7, an essential component of macroautophagy, demonstrate the requirement for a basal level of homeostatic autophagy in preventing quiescent satellite cells from transitioning into senescence [51]. Indeed, disrupted autophagy results in increased p62 and ubiquitin-positive aggregates, which mark damaged organelles and substrates for degradation respectively. Conversely, increased autophagy by Atg7 overexpression is able to rescue the proliferative defect and reduce numbers of senescent satellite cells in geriatric mice [51].
All cells accumulate DNA damage from several intrinsic and extrinsic sources during ageing [95]. Satellite cells actively employ DNA damage responses (DDRs) as they activate and progress through the cell cycle towards differentiation [81,96]. Relatively little is known specifically concerning DDRs and satellite cell function. However, quiescent haematopoietic stem cells activate DDRs upon entry into the cell cycle to combat age-related DNA damage [97]. Presumably satellite cells upregulate DDRs in a similar fashion upon exiting quiescence and entering the cell cycle. The importance of a robust DDR in satellite cells can easily be expected, as this stem cell population must maintain in-tact genetic integrity to seed a lifetime of regeneration.
Quiescent satellite cells in G0 display a detectable low level of energy metabolism and predominantly derive their energy needs from glycolysis, unlike most G1-arrested cells that rely on oxidative phosphorylation [98–100]. Despite a preference for glycolysis in quiescent satellite cells, which does not rely on mitochondrial function [101], the ability to remove damaged mitochondria remains integral to maintaining cell viability. Mitophagy impairment results in increased reactive oxygen species (ROS), DNA damage and senescence markers that can be attenuated using pharmacological ROS inhibition [51]. Recent reports have shed light on this paradox and have demonstrated that fatty acid metabolism is also required to maintain an in-tact quiescent state [102,103], and peroxisome-targeted inhibition of fatty acid oxidation lead to premature differentiation of myoblasts in vitro [103]. As satellite cells exit quiescence and enter the cell cycle, a metabolic switch to oxidative phosphorylation occurs, with an expected increase in mitochondrial density and recycling [99].
Unfortunately, these protective mechanisms in place are not enough to maintain long-term satellite cell viability and regenerative capabilities of muscle over the lifetime of an individual. Quiescent geriatric satellite cells eventually enter a pre-senescent state by de-repression of p16INK4a (Cdkn2α), which inhibits multiple quiescence-inducing pathways and increases DNA damage through a ROS-positive feedback loop [50,104]. Geriatric muscle satellite cells are not as capable and efficient in transitioning from G0 quiescence to activation required for creating new progenitors and consequently are unable to keep up with muscle degradation. Indeed, muscle cross-sections of adult and geriatric mice compared to young mice exhibit signs of muscle decline: fibre atrophy, loss of innervation, and re-expression of embryonic myosin heavy chain and central nucleation [50,51,80,105–107].
It appears the autophagy and mitophagy pathways active during prolonged quiescence are not sufficient to prevent satellite cells from transitioning into senescence [82]. What, then, can we do to prevent this seemingly inevitable decline in homeostatic satellite cell regenerative function? We postulate that periodic activation and cycling of satellite cells is required to remove proteotoxic waste through cytoplasmic dilution and upregulation of autophagy to maintain long-term cell viability (figure 2c,d).
5. Exercise activates satellite cells
Exercise bestows several benefits to overall health, including improved bone strength, offset obesity [12], and improved cardiovascular [108], cognitive [109], and immune system functions [110]. One of the most apparent outcomes of exercise is improved function and health of skeletal muscle [11,111,112]. Here we will discuss the effect of exercise on the satellite cell population within skeletal muscle.
The muscle regeneration field has been focused on muscle formation during embryogenesis and regeneration following severe injury and disease progression. Less clear are the mechanisms regulating satellite cell activity during homeostasis, response to eccentric exercise and ageing. The satellite cell population maintains a level of functional heterogeneity, with subpopulations of satellite cells mounting differential responses depending on environmental stimuli [113,114]. Satellite cell lineage tracing experiments using multi-colour Pax7CreERTM:R26RBrainbow2.1 mice reveal that clonal complexity is maintained during homeostatic ageing and undergoes clonal selection during severe muscle injury [54]. This suggests that the satellite cell response differs depending on different thresholds of stress. However, it is not clear as to what type and to what degree of response is potentiated following stress caused by various types of exercise.
Eccentric exercise enhances myofibre hypertrophy, and stimulates satellite cell activation and proliferation [115]. Aerobic endurance training stimulates satellite cell activation, and human strength training studies with both single and long-term training sessions result in a marked induction of satellite cell proliferation [116–126]. Proper satellite cell function is indeed responsible for exercise-induced muscle mass gain, as satellite cell depletion by irradiation results in the loss of expected hypertrophy following weight bearing exercises [127,128]. Indeed, satellite cell activation and fusion into existing myofibres are an integral part of myofibre growth and accumulation of myonuclei following exercise [129–131]. It is possible that impairment of satellite cell activation partly contributes to muscle atrophy observed in sedentary lifestyles [132–134] and during space flight [135] due to a loss of force-induced activation.
Paradoxically, activation of satellite cells through exercise enhances muscle function, yet the age-related dysfunction of satellite cells arises due to their heightened propensity to activate and differentiate. As discussed earlier, this is in part due to age-related changes intrinsic to satellite cells [38,48–52], and to the aged stem cell niche [17,29,37–47]. However, it appears that in contrast to the exhaustive chronic satellite cell activation associated with age, acute activation of satellite cells following exercise leads to a regenerative response that is met with a subsequent return to quiescence. Supporting this notion are studies demonstrating the benefits to overall muscle health in elderly people who perform resistance training, which stimulates satellite cell activation [115,136–142]. As such, exercise may drive significantly different satellite cell activation signalling compared to the response observed due to age-related defects. Besides signalling differences within the satellite cells, systemic factors may also be at play. For example, factors associated with exercise such as increased vascularization [143] may reduce chronic inflammation, allow for more efficient removal of cellular debris and waste build-up in the niche, and promote satellite cell function.
Current understanding of the factors that activate satellite cells during eccentric exercise is limited as most molecular studies describe satellite cells either in the non-stressed or severely injured state. It appears that satellite cell activation during exercise is mediated by elements released from the myofibre and interstitial cell populations. Signalling cascades that appear to be responsible for driving satellite cell activation in response to exercise induced muscle stress include IGF1, IL-6/JAK/STAT3, hippo and SIRT1 pathways [79,144–147].
IGF-1 is released from muscle fibres following mechanical strain and exercise, driving muscle hypertrophy [144,148]. Barton-Davis et al. observed that the hypertrophic effect of IGF1 was approximately halved in the absence of satellite cells in irradiation experiments [149]. Supporting these findings, other transient IGF1 overexpression studies in muscle report the accumulation of myonuclei, an event mediated by satellite cell fusion to existing myofibres [150]. Interestingly, a splice variant of IGF1 (IGF-1Eb), termed mechano-growth factor, is produced and released from muscle following weight-bearing exercise, and is thought to drive satellite cell proliferation [151]. However, this effect is contested with in vitro studies on C2C12 and human primary myoblast cultures failing to demonstrate any significant increase in proliferation following treatment with this IGF1 splice variant [152,153].
Interleukin 6 (IL-6) is a pro-inflammatory cytokine that is released from growing muscle [154]. IL-6 has been shown to be released following resistance training exercise, with concomitant satellite cell proliferation and STAT3 signalling activation [145]. STAT3 signalling is implicated in satellite cell progression through the myogenic lineage [145,155–157]. However, it should be noted that age-related chronic STAT3 activity inhibits satellite cell expansion and has been implicated in age-related satellite cell exhaustion [48,158].
Non-myogenic cells that reside within the interstitial spaces of muscle appear to also play a role in the IL-6 signalling axis post-exercise, namely FAPs and infiltrating eosinophils. FAPs provide functional support for satellite cells and influence their activation [155,159–163]. Following muscle injury, eosinophils infiltrate the interstitial space in close proximity to FAPs and satellite cells, and release interleukin 4 (IL-4) [160]. IL-4 release from eosinophils stimulates FAPs, which secrete IL-6 when activated, providing an additional source of this cytokine within a regenerating muscle [160,162,164]. Interestingly, eosinophils have been shown to secrete IL-4 when activated by Meteorin-like (Metrnl), a myokine that is secreted following exercise [165]. These findings demonstrate that satellite cell activation post-exercise is a multi-faceted phenomenon, with several cell types and factors working in concert to mediate a regenerative environment, similar to the response following severe injury.
Hippo signalling through YAP and Taz has been demonstrated to play a role in satellite cell activation and proliferation [166–168]. Interestingly, it is becoming more evident that mechanotransduction is a primary activator of the hippo pathway [169,170]. This is in line with a recent findings by Eliazer et al. that demonstrate Rho-dependent mechano-signalling to repress YAP during quiescence to prevent satellite cell activation [146]. These findings give rise to the idea that exercise-induced mechanotransduction may activate satellite cells through involvement of the hippo pathway. Additionally, physical activation by massage has been reported to activate and increase satellite cell numbers, suggesting that a sensitive mechano-sensing mechanism is involved in satellite cell activation under healthy conditions, which could potentially involve hippo signalling [171].
Lastly, SIRT1 is another signalling effector that has been implicated in satellite cell activation and is upregulated in muscle following exercise [147,172]. SIRT1 is among the family of sirtuin deacetylase proteins, which exert NAD+-dependent activities and act as metabolic sensors [173]. SIRT1 is thought to upregulate autophagy as the cell exits quiescence to provide additional energy for activation and proliferation [79]. Deletion of SIRT1 leads to a delay in satellite cell activation [79]. Indeed, satellite cell-specific SIRT1 knockout prevents muscle regeneration, and its overexpression improves muscle regeneration in older mice [174]. Since SIRT1 influences satellite cells through regulation of autophagy, it would be interesting to determine whether an age-related loss of SIRT1 expression is involved in the decline of satellite cell function linked to age-related autophagy dysfunction. Perhaps exercised-induced expression/activity of SIRT1 is capable of ameliorating dysfunctional autophagy in satellite cells.
Despite the well-established beneficial effect of resistance training, exercise alone does not prevent all age-related defects in skeletal muscle. Concomitant with sarcopaenia is a change in muscle composition within geriatric muscle: a shift of type 2 towards type 1 myofibres [175,176]. Even in cases of lifelong exercise, the shift from type 2 to type 1 myofibres persists [177] and the satellite cell population still diminishes to some degree over age [39,178–181]. Exercise-induced satellite cell activation also experiences some degree of impairment during ageing, as demonstrated by expression of myostatin within satellite cells, an inhibitor of satellite cell activation and self-renewal [178,181,182]. Regardless, lifelong resistance exercise should be pursued as the effects of sarcopaenia are greatly diminished when compared with sedentary lifestyles. As demonstrated in this review, the beneficial effects of exercise to muscle are derived from not only direct stimulation of muscle fibres, but also simultaneous activation of the muscle stem cell pool.
6. Concluding remarks
Higher quality of life and happiness is strongly associated with an individual's ability to exercise self-agency, and maintaining locomotion is a key aspect of this pursuit. Skeletal muscle health and exercise deserve greater attention in today's world, where a sedentary lifestyle is the norm, while obesity and cardiovascular disease are the leading causes of death. Although age-related muscle atrophy is the focus of many geriatric studies, it is clear that the decline in satellite cell number and function coincides with the gradual muscle loss that begins much earlier, at approximately 30 years of age.
Many additional mechanisms behind satellite cell function decline in ageing remain to be discovered. However, it appears to be multi-factorial and involve defects and misregulation of cell maintenance, quiescence and activation pathways that prevent cell damage. It is evident that satellite cells are activated through various signalling pathways following exercise. Of particular relevance, cellular processes involved in the upkeep of cellular integrity (proteasome-mediated protein degradation, autophagy and DDRs) are upregulated during activation and proliferation. Moreover, satellite cells increase their cytoplasm during rounds of proliferation, which dilutes cellular waste and dysfunctional organelles between daughter cells. It is evident that waste and DNA damage accrued within periods of satellite cell quiescence are most effectively managed during periods of activation. Frequent activation of muscle satellite cells through exercise is a key process required to offset age-related waste/damage accumulation that leads to senescence. Physical inactivity becomes more detrimental with age as satellite cells accumulate higher levels of cellular waste and DNA damage during longer periods of deep quiescence.
Currently, our understanding of satellite cell behaviour in response to exercise is relatively limited compared with more severe models of injury. Future work in this field is needed to decipher the clonal dynamics of satellite cells following exercise. For example, is satellite cell replacement through asymmetric division sufficient to respond to exercise-induced stress, or is pre-expansion of the satellite cell pool required to mount a more robust response? Moreover, what is the threshold and range of exercise-induced mechanical stress that drives satellite cell activation, and perhaps different clonal dynamics? Are certain subpopulations of satellite cells more sensitive to mechanical stress within the normal range of exercise? Elucidating these mechanisms will reveal important information relevant to combating age-related muscle decline, as well as designing therapeutics to offset muscle atrophy that arises from sedentary lifestyle, space flight and disease.
Data accessibility
This article has no additional data.
Authors' contributions
W.C., D.D. and M.A.R. wrote the paper.
Competing interests
We declare we have no competing interests.
Funding
The studies from the laboratory of M.A.R. were carried out with support of grants from the Canadian Institutes for Health Research (FDN-148387), US National Institutes for Health (R01AR044031), Muscular Dystrophy Association, the Ontario Institute for Regenerative Medicine and the Stem Cell Network. M.A.R. holds the Canada Research Chair in Molecular Genetics. W.C. holds a University of Ottawa Brain and Mind Research Institute Éric Poulin Centre for Neuromuscular Disease Scholarship in Translation Research Award. D.D. holds a Frederick Banting and Charles Best Canada Graduate Scholarships–Doctoral Award (CGS-D).
References
- 1.
Mishra SI, Scherer RW, Snyder C, Geigle PM, Berlanstein DR, Topaloglu O . 2012 Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Database Syst. Rev. CD008465. (doi:10.1002/14651858.CD008465.pub2) PubMed, Web of Science, Google Scholar - 2.
Haraldstad K, Rohde G, Stea TH, Lohne-Seiler H, Hetlelid K, Paulsen G, Berntsen S . 2017 Changes in health-related quality of life in elderly men after 12 weeks of strength training. Eur. Rev. Aging Phys. Act. 14, 8. (doi:10.1186/s11556-017-0177-3) Crossref, PubMed, Web of Science, Google Scholar - 3.
Garcia-Hermoso A, Cavero-Redondo I, Ramirez-Velez R, Ruiz JR, Ortega FB, Lee DC, Martinez-Vizcaino V . 2018 Muscular strength as a predictor of all-cause mortality in an apparently healthy population: a systematic review and meta-analysis of data from approximately 2 million men and women. Arch. Phys. Med. Rehabil. 99, 2100-2113.e2105. (doi:10.1016/j.apmr.2018.01.008) Crossref, PubMed, Web of Science, Google Scholar - 4.
Hart PD, Buck DJ . 2019 The effect of resistance training on health-related quality of life in older adults: systematic review and meta-analysis. Health Promot. Perspect. 9, 1-12. (doi:10.15171/hpp.2019.01) Crossref, PubMed, Web of Science, Google Scholar - 5.
Schnell S, Friedman SM, Mendelson DA, Bingham KW, Kates SL . 2010 The 1-year mortality of patients treated in a hip fracture program for elders. Geriatr. Orthop. Surg. Rehabil. 1, 6-14. (doi:10.1177/2151458510378105) Crossref, PubMed, Google Scholar - 6.
Marquis K, Debigare R, Lacasse Y, LeBlanc P, Jobin J, Carrier G, Maltais F . 2002 Midthigh muscle cross-sectional area is a better predictor of mortality than body mass index in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 166, 809-813. (doi:10.1164/rccm.2107031) Crossref, PubMed, Web of Science, Google Scholar - 7.
Goodpaster BH 2006 The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J. Gerontol. A Biol. Sci. Med. Sci. 61, 1059-1064. (doi:10.1093/gerona/61.10.1059) Crossref, PubMed, Web of Science, Google Scholar - 8.
Keller K, Engelhardt M . 2013 Strength and muscle mass loss with aging process: age and strength loss. Muscles Ligaments Tendons J. 3, 346-350. Crossref, PubMed, Google Scholar - 9.
Carraro U 2017 Recovery from muscle weakness by exercise and FES: lessons from Masters, active or sedentary seniors and SCI patients. Aging Clin. Exp. Res. 29, 579-590. (doi:10.1007/s40520-016-0619-1) Crossref, PubMed, Web of Science, Google Scholar - 10.
Warburton DER, Nicol CW, Bredin SSD . 2006 Health benefits of physical activity: the evidence. CMAJ 174, 801-809. (doi:10.1503/cmaj.051351) Crossref, PubMed, Web of Science, Google Scholar - 11.
Cartee GD, Hepple RT, Bamman MM, Zierath JR . 2016 Exercise promotes healthy aging of skeletal muscle. Cell Metab. 23, 1034-1047. (doi:10.1016/j.cmet.2016.05.007) Crossref, PubMed, Web of Science, Google Scholar - 12.
Pagnotti GM, Styner M, Uzer G, Patel VS, Wright LE, Ness KK, Guise TA, Rubin J, Rubin CT . 2019 Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity. Nat. Rev. Endocrinol. 15, 339-355. (doi:10.1038/s41574-019-0170-1) Crossref, PubMed, Web of Science, Google Scholar - 13.
Hood DA, Memme JM, Oliveira AN, Triolo M . 2019 Maintenance of skeletal muscle mitochondria in health, exercise, and aging. Annu. Rev. Physiol. 81, 19-41. (doi:10.1146/annurev-physiol-020518-114310) Crossref, PubMed, Web of Science, Google Scholar - 14.
Krause Neto W, Ciena AP, Anaruma CA, de Souza RR, Gama EF . 2015 Effects of exercise on neuromuscular junction components across age: systematic review of animal experimental studies. BMC Res. Notes 8, 713. (doi:10.1186/s13104-015-1644-4) Crossref, PubMed, Google Scholar - 15.
Collao N, Farup J, De Lisio M . 2020 Role of metabolic stress and exercise in regulating fibro/adipogenic progenitors. Front. Cell Dev. Biol. 8, 9. (doi:10.3389/fcell.2020.00009) Crossref, PubMed, Web of Science, Google Scholar - 16.
Snijders T, Nederveen JP, McKay BR, Joanisse S, Verdijk LB, van Loon LJC, Parise G . 2015 Satellite cells in human skeletal muscle plasticity. Front. Physiol. 6, 283. (doi:10.3389/fphys.2015.00283) Crossref, PubMed, Web of Science, Google Scholar - 17.
Yin H, Price F, Rudnicki MA . 2013 Satellite cells and the muscle stem cell niche. Physiol. Rev. 93, 23-67. (doi:10.1152/physrev.00043.2011) Crossref, PubMed, Web of Science, Google Scholar - 18.
Feige P, Brun CE, Ritso M, Rudnicki MA . 2018 Orienting muscle stem cells for regeneration in homeostasis, aging, and disease. Cell Stem Cell 23, 653-664. (doi:10.1016/j.stem.2018.10.006) Crossref, PubMed, Web of Science, Google Scholar - 19.
Wang YX, Rudnicki MA . 2011 Satellite cells, the engines of muscle repair. Nat. Rev. Mol. Cell Biol. 13, 127-133. (doi:10.1038/nrm3265) Crossref, PubMed, Web of Science, Google Scholar - 20.
Chang NC, Rudnicki MA . 2014 Satellite cells: the architects of skeletal muscle. Curr. Top. Dev. Biol. 107, 161-181. (doi:10.1016/b978-0-12-416022-4.00006-8) Crossref, PubMed, Web of Science, Google Scholar - 21.
Seale P, Sabourin LA, Girgis-Gabardo A, Mansouri A, Gruss P, Rudnicki MA . 2000 Pax7 is required for the specification of myogenic satellite cells. Cell 102, 777-786. (doi:10.1016/S0092-8674(00)00066-0) Crossref, PubMed, Web of Science, Google Scholar - 22.
Kuang S, Kuroda K, Le Grand F, Rudnicki MA . 2007 Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129, 999-1010. (doi:10.1016/j.cell.2007.03.044) Crossref, PubMed, Web of Science, Google Scholar - 23.
Bentzinger CF, Wang YX, Rudnicki MA . 2012 Building muscle: molecular regulation of myogenesis. Cold Spring Harb. Perspect. Biol. 4, a008342. (doi:10.1101/cshperspect.a008342) Crossref, PubMed, Web of Science, Google Scholar - 24.
Dumont NA, Bentzinger CF, Sincennes MC, Rudnicki MA . 2015 Satellite cells and skeletal muscle regeneration. Compr. Physiol. 5, 1027-1059. (doi:10.1002/cphy.c140068) Crossref, PubMed, Web of Science, Google Scholar - 25.
Hollenberg SM, Cheng PF, Weintraub H . 1993 Use of a conditional MyoD transcription factor in studies of MyoD trans-activation and muscle determination. Proc. Natl Acad. Sci. USA 90, 8028-8032. (doi:10.1073/pnas.90.17.8028) Crossref, PubMed, Web of Science, Google Scholar - 26.
Rudnicki MA, Schnegelsberg PN, Stead RH, Braun T, Arnold HH, Jaenisch R . 1993 MyoD or Myf-5 is required for the formation of skeletal muscle. Cell 75, 1351-1359. (doi:10.1016/0092-8674(93)90621-v) Crossref, PubMed, Web of Science, Google Scholar - 27.
Megeney LA, Kablar B, Garrett K, Anderson JE, Rudnicki MA . 1996 MyoD is required for myogenic stem cell function in adult skeletal muscle. Genes Dev. 10, 1173-1183. Crossref, PubMed, Web of Science, Google Scholar - 28.
Christov C 2007 Muscle satellite cells and endothelial cells: close neighbors and privileged partners. Mol. Biol. Cell 18, 1397-1409. (doi:10.1091/mbc.e06-08-0693) Crossref, PubMed, Web of Science, Google Scholar - 29.
Baghdadi MB, Castel D, Machado L, Fukada SI, Birk DE, Relaix F, Tajbakhsh S, Mourikis P . 2018 Reciprocal signalling by Notch-Collagen V-CALCR retains muscle stem cells in their niche. Nature 557, 714-718. (doi:10.1038/s41586-018-0144-9) Crossref, PubMed, Web of Science, Google Scholar - 30.
Zhang L 2019 The CalcR-PKA-Yap1 axis is critical for maintaining quiescence in muscle stem cells. Cell Rep. 29, 2154-2163.e2155. (doi:10.1016/j.celrep.2019.10.057) Crossref, PubMed, Web of Science, Google Scholar - 31.
Rodgers JT, Schroeder MD, Ma C, Rando TA . 2017 HGFA is an injury-regulated systemic factor that induces the transition of stem cells into GAlert. Cell Rep. 19, 479-486. (doi:10.1016/j.celrep.2017.03.066) Crossref, PubMed, Web of Science, Google Scholar - 32.
Grounds MD . 1998 Age-associated changes in the response of skeletal muscle cells to exercise and regeneration. Ann. N. Y. Acad. Sci. 854, 78-91. (doi:10.1111/j.1749-6632.1998.tb09894.x) Crossref, PubMed, Web of Science, Google Scholar - 33.
Tidball JG . 2005 Inflammatory processes in muscle injury and repair. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R345-R353. (doi:10.1152/ajpregu.00454.2004) Crossref, PubMed, Web of Science, Google Scholar - 34.
Robertson TA, Maley MA, Grounds MD, Papadimitriou JM . 1993 The role of macrophages in skeletal muscle regeneration with particular reference to chemotaxis. Exp. Cell Res. 207, 321-331. (doi:10.1006/excr.1993.1199) Crossref, PubMed, Web of Science, Google Scholar - 35.
McLennan IS . 1996 Degenerating and regenerating skeletal muscles contain several subpopulations of macrophages with distinct spatial and temporal distributions. J. Anat. 188(Pt 1), 17-28. PubMed, Web of Science, Google Scholar - 36.
Bischoff R . 1997 Chemotaxis of skeletal muscle satellite cells. Dev. Dyn. 208, 505-515. (doi:10.1002/(sici)1097-0177(199704)208:4%3C505::aid-aja6%3E3.0.co;2-m) Crossref, PubMed, Web of Science, Google Scholar - 37.
Eisner C, Cummings M, Johnston G, Tung LW, Groppa E, Chang C, Rossi FM . 2020 Murine tissue-resident PDGFRα+ fibro-adipogenic progenitors spontaneously acquire osteogenic phenotype in an altered inflammatory environment. J. Bone Miner. Res. (doi:10.1002/jbmr.4020) Crossref, PubMed, Web of Science, Google Scholar - 38.
Rebo J, Mehdipour M, Gathwala R, Causey K, Liu Y, Conboy MJ, Conboy IM . 2016 A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nat. Commun. 7, 13363. (doi:10.1038/ncomms13363) Crossref, PubMed, Web of Science, Google Scholar - 39.
Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA . 2005 Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760-764. (doi:10.1038/nature03260) Crossref, PubMed, Web of Science, Google Scholar - 40.
Tang H 2019 mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism. Aging Cell 18, e12943. (doi:10.1111/acel.12943) Crossref, PubMed, Web of Science, Google Scholar - 41.
Baghdadi MB, Firmino J, Soni K, Evano B, Di Girolamo D, Mourikis P, Castel D, Tajbakhsh S . 2018 Notch-induced miR-708 antagonizes satellite cell migration and maintains quiescence. Cell Stem Cell 23, 859-868.e855. (doi:10.1016/j.stem.2018.09.017) Crossref, PubMed, Web of Science, Google Scholar - 42.
Brandes RP, Fleming I, Busse R . 2005 Endothelial aging. Cardiovasc. Res. 66, 286-294. (doi:10.1016/j.cardiores.2004.12.027) Crossref, PubMed, Web of Science, Google Scholar - 43.
Yildiz O . 2007 Vascular smooth muscle and endothelial functions in aging. Ann. N. Y. Acad. Sci. 1100, 353-360. (doi:10.1196/annals.1395.038) Crossref, PubMed, Web of Science, Google Scholar - 44.
Richmonds CR, Boonyapisit K, Kusner LL, Kaminski HJ . 1999 Nitric oxide synthase in aging rat skeletal muscle. Mech. Ageing Dev. 109, 177-189. (doi:10.1016/s0047-6374(99)00035-4) Crossref, PubMed, Web of Science, Google Scholar - 45.
Anderson JE . 2000 A role for nitric oxide in muscle repair: nitric oxide-mediated activation of muscle satellite cells. Mol. Biol. Cell 11, 1859-1874. (doi:10.1091/mbc.11.5.1859) Crossref, PubMed, Web of Science, Google Scholar - 46.
Wagatsuma A . 2006 Effect of aging on expression of angiogenesis-related factors in mouse skeletal muscle. Exp. Gerontol. 41, 49-54. (doi:10.1016/j.exger.2005.10.003) Crossref, PubMed, Web of Science, Google Scholar - 47.
Ryan NA, Zwetsloot KA, Westerkamp LM, Hickner RC, Pofahl WE, Gavin TP . 2006 Lower skeletal muscle capillarization and VEGF expression in aged vs. young men. J. Appl. Physiol. 100, 178-185. (doi:10.1152/japplphysiol.00827.2005) Crossref, PubMed, Web of Science, Google Scholar - 48.
Price FD, von Maltzahn J, Bentzinger CF, Dumont NA, Yin H, Chang NC, Wilson DH, Frenette J, Rudnicki MA . 2014 Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat. Med. 20, 1174-1181. (doi:10.1038/nm.3655) Crossref, PubMed, Web of Science, Google Scholar - 49.
Liu L, Charville GW, Cheung TH, Yoo B, Santos PJ, Schroeder M, Rando TA . 2018 Impaired Notch signaling leads to a decrease in p53 activity and mitotic catastrophe in aged muscle stem cells. Cell Stem Cell 23, 544-556.e544. (doi:10.1016/j.stem.2018.08.019) Crossref, PubMed, Web of Science, Google Scholar - 50.
Sousa-Victor P 2014 Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316-321. (doi:10.1038/nature13013) Crossref, PubMed, Web of Science, Google Scholar - 51.
García-Prat L, Muñoz-Cánoves P, Martinez-Vicente M . 2016 Dysfunctional autophagy is a driver of muscle stem cell functional decline with aging. Autophagy 12, 612-613. (doi:10.1080/15548627.2016.1143211) Crossref, PubMed, Web of Science, Google Scholar - 52.
Brunet A, Rando TA . 2017 Interaction between epigenetic and metabolism in aging stem cells. Curr. Opin Cell Biol. 45, 1-7. (doi:10.1016/j.ceb.2016.12.009) Crossref, PubMed, Web of Science, Google Scholar - 53.
Le Grand F, Jones AE, Seale V, Scime A, Rudnicki MA . 2009 Wnt7a activates the planar cell polarity pathway to drive the symmetric expansion of satellite stem cells. Cell Stem Cell 4, 535-547. (doi:10.1016/j.stem.2009.03.013) Crossref, PubMed, Web of Science, Google Scholar - 54.
Tierney MT, Stec MJ, Rulands S, Simons BD, Sacco A . 2018 Muscle stem cells exhibit distinct clonal dynamics in response to tissue repair and homeostatic aging. Cell Stem Cell 22, 119-127.e113. (doi:10.1016/j.stem.2017.11.009) Crossref, PubMed, Web of Science, Google Scholar - 55.
Hartwell LH, Culotti J, Pringle JR, Reid BJ . 1974 Genetic control of the cell division cycle in yeast. Science 183, 46-51. (doi:10.1126/science.183.4120.46) Crossref, PubMed, Web of Science, Google Scholar - 56.
Mendelsohn ML . 1962 Chronic infusion of tritiated thymidine into mice with tumors. Science 135, 213-215. (doi:10.1126/science.135.3499.213) Crossref, PubMed, Web of Science, Google Scholar - 57.
Shea KL, Xiang W, LaPorta VS, Licht JD, Keller C, Basson MA, Brack AS . 2010 Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration. Cell Stem Cell 6, 117-129. (doi:10.1016/j.stem.2009.12.015) Crossref, PubMed, Web of Science, Google Scholar - 58.
Bigot A 2015 Age-associated methylation suppresses SPRY1, leading to a failure of re-quiescence and loss of the reserve stem cell pool in elderly muscle. Cell Rep. 13, 1172-1182. (doi:10.1016/j.celrep.2015.09.067) Crossref, PubMed, Web of Science, Google Scholar - 59.
Chakkalakal JV, Christensen J, Xiang W, Tierney MT, Boscolo FS, Sacco A, Brack AS . 2014 Early forming label-retaining muscle stem cells require p27kip1 for maintenance of the primitive state. Development 141, 1649-1659. (doi:10.1242/dev.100842) Crossref, PubMed, Web of Science, Google Scholar - 60.
van Velthoven CTJ, de Morree A, Egner IM, Brett JO, Rando TA . 2017 Transcriptional profiling of quiescent muscle stem cells in vivo. Cell Rep. 21, 1994-2004. (doi:10.1016/j.celrep.2017.10.037) Crossref, PubMed, Web of Science, Google Scholar - 61.
Machado L 2017 In situ fixation redefines quiescence and early activation of skeletal muscle stem cells. Cell Rep. 21, 1982-1993. (doi:10.1016/j.celrep.2017.10.080) Crossref, PubMed, Web of Science, Google Scholar - 62.
Rozo M, Li L, Fan CM . 2016 Targeting β1-integrin signaling enhances regeneration in aged and dystrophic muscle in mice. Nat. Med. 22, 889-896. (doi:10.1038/nm.4116) Crossref, PubMed, Web of Science, Google Scholar - 63.
Goel AJ, Rieder MK, Arnold HH, Radice GL, Krauss RS . 2017 Niche cadherins control the quiescence-to-activation transition in muscle stem cells. Cell Rep. 21, 2236-2250. (doi:10.1016/j.celrep.2017.10.102) Crossref, PubMed, Web of Science, Google Scholar - 64.
Eliazer S, Brack AS . 2016 Lost in translation: preserving satellite cell function with global translational control. Cell Stem Cell 18, 5-7. (doi:10.1016/j.stem.2015.12.006) Crossref, PubMed, Web of Science, Google Scholar - 65.
Fukada S, Uezumi A, Ikemoto M, Masuda S, Segawa M, Tanimura N, Yamamoto H, Miyagoe-Suzuki Y, Takeda S . 2007 Molecular signature of quiescent satellite cells in adult skeletal muscle. Stem Cells 25, 2448-2459. (doi:10.1634/stemcells.2007-0019) Crossref, PubMed, Web of Science, Google Scholar - 66.
Sampath SC, Sampath SC, Ho ATV, Corbel SY, Millstone JD . 2018 Induction of muscle stem cell quiescence by the secreted niche factor Oncostatin M. Nat. Commun. 9, 1-9. (doi:10.1038/s41467-018-03876-8) Crossref, PubMed, Web of Science, Google Scholar - 67.
Bjornson CR, Cheung TH, Liu L, Tripathi PV, Steeper KM, Rando TA . 2012 Notch signaling is necessary to maintain quiescence in adult muscle stem cells. Stem Cells 30, 232-242. (doi:10.1002/stem.773) Crossref, PubMed, Web of Science, Google Scholar - 68.
Mourikis P, Sambasivan R, Castel D, Rocheteau P, Bizzarro V, Tajbakhsh S . 2012 A critical requirement for notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells 30, 243-252. (doi:10.1002/stem.775) Crossref, PubMed, Web of Science, Google Scholar - 69.
Verma M, Asakura Y, Murakonda BSR, Pengo T, Latroche C, Chazaud B, McLoon LK, Asakura A . 2018 Muscle satellite cell cross-talk with a vascular niche maintains quiescence via VEGF and Notch signaling. Cell Stem Cell 23, 530-543. (doi:10.1016/j.stem.2018.09.007) Crossref, PubMed, Web of Science, Google Scholar - 70.
Cheung TH, Quach NL, Charville GW, Liu L, Park L, Edalati A, Yoo B, Hoang P, Rando TA . 2012 Maintenance of muscle stem-cell quiescence by microRNA-489. Nature 482, 524-528. (doi:10.1038/nature10834) Crossref, PubMed, Web of Science, Google Scholar - 71.
Kim JH 2016 Sex hormones establish a reserve pool of adult muscle stem cells. Nat. Cell Biol. 18, 930-940. (doi:10.1038/ncb3401) Crossref, PubMed, Web of Science, Google Scholar - 72.
Machado L, Relaix F . 2016 Heterochromatin compaction is regulated by Suv4-20h1 to maintains skeletal muscle stem cells quiescence. Stem Cell Investig. 3, 23. (doi:10.21037/sci.2016.06.04) Crossref, PubMed, Google Scholar - 73.
Zismanov V, Chichkov V, Colangelo V, Jamet S, Wang S, Syme A, Koromilas AE, Crist C . 2016 Phosphorylation of eIF2α is a translational control mechanism regulating muscle stem cell quiescence and self-renewal. Cell Stem Cell 18, 79-90. (doi:10.1016/j.stem.2015.09.020) Crossref, PubMed, Web of Science, Google Scholar - 74.
Rodgers JT 2014 mTORC1 controls the adaptive transition of quiescent stem cells from G0 to GAlert. Nature 510, 393-396. (doi:10.1038/nature13255) Crossref, PubMed, Web of Science, Google Scholar - 75.
Crist CG, Montarras D, Buckingham M . 2012 Muscle satellite cells are primed for myogenesis but maintain quiescence with sequestration of Myf5 mRNA targeted by microRNA-31 in mRNP granules. Cell Stem Cell 11, 118-126. (doi:10.1016/j.stem.2012.03.011) Crossref, PubMed, Web of Science, Google Scholar - 76.
de Morree A, van Velthoven CTJ, Gan Q, Salvi JS, Klein JDD, Akimenko I, Quarta M, Biressi S, Rando TA . 2017 Staufen1 inhibits MyoD translation to actively maintain muscle stem cell quiescence. Proc. Natl Acad. Sci. USA 114, E8996-E9005. (doi:10.1073/pnas.1708725114) Crossref, PubMed, Web of Science, Google Scholar - 77.
Hardy D 2016 Comparative study of injury models for studying muscle regeneration in mice. PLoS ONE 11, e0147198. (doi:10.1371/journal.pone.0147198) Crossref, PubMed, Web of Science, Google Scholar - 78.
van Velthoven CTJ, Rando TA . 2019 Stem cell quiescence: dynamism, restraint, and cellular idling. Cell Stem Cell 24, 213-225. (doi:10.1016/j.stem.2019.01.001) Crossref, PubMed, Web of Science, Google Scholar - 79.
Tang AH, Rando TA . 2014 Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. EMBO J. 33, 2782-2797. (doi:10.15252/embj.201488278) Crossref, PubMed, Web of Science, Google Scholar - 80.
Garcia-Prat L, Sousa-Victor P, Munoz-Canoves P . 2013 Functional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells. FEBS J. 280, 4051-4062. (doi:10.1111/febs.12221) Crossref, PubMed, Web of Science, Google Scholar - 81.
Latella L, Dall'Agnese A, Boscolo FS, Nardoni C, Cosentino M, Lahm A, Sacco A, Puri PL . 2017 DNA damage signaling mediates the functional antagonism between replicative senescence and terminal muscle differentiation. Genes Dev. 31, 648-659. (doi:10.1101/gad.293266.116) Crossref, PubMed, Web of Science, Google Scholar - 82.
Wen X, Klionsky DJ . 2016 Autophagy is a key factor in maintaining the regenerative capacity of muscle stem cells by promoting quiescence and preventing senescence. Autophagy 12, 617-618. (doi:10.1080/15548627.2016.1158373) Crossref, PubMed, Web of Science, Google Scholar - 83.
Kitajima Y 2018 The ubiquitin-proteasome system is indispensable for the maintenance of muscle stem cells. Stem Cell Reports 11, 1523-1538. (doi:10.1016/j.stemcr.2018.10.009) Crossref, PubMed, Web of Science, Google Scholar - 84.
Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y . 2004 In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101-1111. (doi:10.1091/mbc.e03-09-0704) Crossref, PubMed, Web of Science, Google Scholar - 85.
Mizushima N, Levine B, Cuervo AM, Klionsky DJ . 2008 Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075. (doi:10.1038/nature06639) Crossref, PubMed, Web of Science, Google Scholar - 86.
Rubinsztein DC, Marino G, Kroemer G . 2011 Autophagy and aging. Cell 146, 682-695. (doi:10.1016/j.cell.2011.07.030) Crossref, PubMed, Web of Science, Google Scholar - 87.
Bustos F, de la Vega E, Cabezas F, Thompson J, Cornelison DD, Olwin BB, Yates JR, Olguin HC . 2015 NEDD4 regulates PAX7 levels promoting activation of the differentiation program in skeletal muscle precursors. Stem Cells 33, 3138-3151. (doi:10.1002/stem.2125) Crossref, PubMed, Web of Science, Google Scholar - 88.
Levine B, Kroemer G . 2008 Autophagy in the pathogenesis of disease. Cell 132, 27-42. (doi:10.1016/j.cell.2007.12.018) Crossref, PubMed, Web of Science, Google Scholar - 89.
Dikic I, Elazar Z . 2018 Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349-364. (doi:10.1038/s41580-018-0003-4) Crossref, PubMed, Web of Science, Google Scholar - 90.
Marzetti E, Hwang JC, Lees HA, Wohlgemuth SE, Dupont-Versteegden EE, Carter CS, Bernabei R, Leeuwenburgh C . 2010 Mitochondrial death effectors: relevance to sarcopenia and disuse muscle atrophy. Biochim. Biophys. Acta 1800, 235-244. (doi:10.1016/j.bbagen.2009.05.007) Crossref, PubMed, Web of Science, Google Scholar - 91.
Powers SK, Smuder AJ, Judge AR . 2012 Oxidative stress and disuse muscle atrophy: cause or consequence? Curr. Opin. Clin. Nutr. Metab. Care 15, 240-245. (doi:10.1097/MCO.0b013e328352b4c2) Crossref, PubMed, Web of Science, Google Scholar - 92.
Masiero E 2009 Autophagy is required to maintain muscle mass. Cell Metab. 10, 507-515. (doi:10.1016/j.cmet.2009.10.008) Crossref, PubMed, Web of Science, Google Scholar - 93.
Segales J, Perdiguero E 2020 Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals. Nat. Commun. 11, 189. (doi:10.1038/s41467-019-13832-9) Crossref, PubMed, Web of Science, Google Scholar - 94.
Fiacco E 2016 Autophagy regulates satellite cell ability to regenerate normal and dystrophic muscles. Cell Death Differ. 23, 1839-1849. (doi:10.1038/cdd.2016.70) Crossref, PubMed, Web of Science, Google Scholar - 95.
da Silva PFL, Schumacher B . 2019 DNA damage responses in ageing. Open Biol. 9, 190168. (doi:10.1098/rsob.190168) Link, Web of Science, Google Scholar - 96.
Simonatto M, Marullo F, Chiacchiera F, Musaro A, Wang JY 2013 DNA damage-activated ABL-MyoD signaling contributes to DNA repair in skeletal myoblasts. Cell Death Differ. 20, 1664-1674. (doi:10.1038/cdd.2013.118) Crossref, PubMed, Web of Science, Google Scholar - 97.
Beerman I, Seita J, Inlay MA, Weissman IL, Rossi DJ . 2014 Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 15, 37-50. (doi:10.1016/j.stem.2014.04.016) Crossref, PubMed, Web of Science, Google Scholar - 98.
Wust S 2018 Metabolic maturation during muscle stem cell differentiation is achieved by miR-1/133a-mediated inhibition of the Dlk1-Dio3 mega gene cluster. Cell Metab. 27, 1026-1039.e1026. (doi:10.1016/j.cmet.2018.02.022) Crossref, PubMed, Web of Science, Google Scholar - 99.
L'Honore A, Commere PH, Ouimette JF, Montarras D, Drouin J, Buckingham M . 2016 Redox regulation by Pitx2 and Pitx3 is critical for fetal myogenesis. Dev. Cell 39, 756. (doi:10.1016/j.devcel.2016.12.011) Crossref, PubMed, Web of Science, Google Scholar - 100.
Relaix F, Machado L . 2018 Waking up muscle stem cells: PI3 K signalling is ringing. EMBO J. 37, e99297. (doi:10.15252/embj.201899297) Crossref, PubMed, Web of Science, Google Scholar - 101.
Ryall JG . 2017 Simultaneous measurement of mitochondrial and glycolytic activity in quiescent muscle stem cells. Methods Mol. Biol. 1556, 245-253. (doi:10.1007/978-1-4939-6771-1_13) Crossref, PubMed, Google Scholar - 102.
Shyh-Chang N, Ng HH . 2017 The metabolic programming of stem cells. Genes Dev. 31, 336-346. (doi:10.1101/gad.293167.116) Crossref, PubMed, Web of Science, Google Scholar - 103.
Pala F, Di Girolamo D, Mella S, Yennek S, Chatre L, Ricchetti M, Tajbakhsh S . 2018 Distinct metabolic states govern skeletal muscle stem cell fates during prenatal and postnatal myogenesis. J. Cell Sci. 131, jcs212977. (doi:10.1242/jcs.212977) Crossref, PubMed, Web of Science, Google Scholar - 104.
Takahashi K, Yamanaka S . 2006 Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676. (doi:10.1016/j.cell.2006.07.024) Crossref, PubMed, Web of Science, Google Scholar - 105.
McPhee JS, Cameron J, Maden-Wilkinson T, Piasecki M, Yap MH, Jones DA, Degens H . 2018 The contributions of fiber atrophy, fiber loss, in situ specific force, and voluntary activation to weakness in sarcopenia. J. Gerontol. A 73, 1287-1294. (doi:10.1093/gerona/gly040) Crossref, Google Scholar - 106.
Valdez G, Tapia JC, Kang H, Clemenson GD, Gage FH, Lichtman JW, Sanes JR . 2010 Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise. Proc. Natl Acad. Sci. USA 107, 14 863-14 868. (doi:10.1073/pnas.1002220107) Crossref, Web of Science, Google Scholar - 107.
Monemi M, Eriksson PO, Dubail I, Butler-Browne GS, Thornell LE . 1996 Fetal myosin heavy chain increases in human masseter muscle during aging. FEBS Lett. 386, 87-90. (doi:10.1016/0014-5793(96)00402-4) Crossref, PubMed, Web of Science, Google Scholar - 108.
Coats AJS, Forman DE, Haykowsky M, Kitzman DW, McNeil A, Campbell TS, Arena R . 2017 Physical function and exercise training in older patients with heart failure. Nat. Rev. Cardiol. 14, 550-559. (doi:10.1038/nrcardio.2017.70) Crossref, PubMed, Web of Science, Google Scholar - 109.
Gomez-Pinilla F, Hillman C . 2013 The influence of exercise on cognitive abilities. Compr. Physiol. 3, 403-428. (doi:10.1002/cphy.c110063) Crossref, PubMed, Web of Science, Google Scholar - 110.
Sellami M, Gasmi M, Denham J, Hayes LD, Stratton D, Padulo J, Bragazzi N . 2018 Effects of acute and chronic exercise on immunological parameters in the elderly aged: can physical activity counteract the effects of aging? Front. Immunol. 9, 2187. (doi:10.3389/fimmu.2018.02187) Crossref, PubMed, Web of Science, Google Scholar - 111.
Egan B, Zierath JR . 2013 Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 17, 162-184. (doi:10.1016/j.cmet.2012.12.012) Crossref, PubMed, Web of Science, Google Scholar - 112.
Bamman MM, Roberts BM, Adams GR . 2018 Molecular regulation of exercise-induced muscle fiber hypertrophy. Cold Spring Harb. Perspect. Med. 8, a029751. (doi:10.1101/cshperspect.a029751) Crossref, PubMed, Web of Science, Google Scholar - 113.
Tierney MT, Sacco A . 2016 Satellite cell heterogeneity in skeletal muscle homeostasis. Trends Cell Biol. 26, 434-444. (doi:10.1016/j.tcb.2016.02.004) Crossref, PubMed, Web of Science, Google Scholar - 114.
Evano B, Tajbakhsh S . 2018 Skeletal muscle stem cells in comfort and stress. NPJ Regen. Med. 3, 24. (doi:10.1038/s41536-018-0062-3) Crossref, PubMed, Web of Science, Google Scholar - 115.
Darr KC, Schultz E . 1987 Exercise-induced satellite cell activation in growing and mature skeletal muscle. J. Appl. Physiol. 63, 1816-1821. (doi:10.1152/jappl.1987.63.5.1816) Crossref, PubMed, Web of Science, Google Scholar - 116.
Kadi F, Schjerling P, Andersen LL, Charifi N, Madsen JL, Christensen LR, Andersen JL . 2004 The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles. J. Physiol. 558, 1005-1012. (doi:10.1113/jphysiol.2004.065904) Crossref, PubMed, Web of Science, Google Scholar - 117.
Olsen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olesen JL, Suetta C, Kjaer M . 2006 Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J. Physiol. 573, 525-534. (doi:10.1113/jphysiol.2006.107359) Crossref, PubMed, Web of Science, Google Scholar - 118.
Mackey AL, Esmarck B, Kadi F, Koskinen SO, Kongsgaard M, Sylvestersen A, Hansen JJ, Larsen G, Kjaer M . 2007 Enhanced satellite cell proliferation with resistance training in elderly men and women. Scand. J. Med. Sci. Sports 17, 34-42. (doi:10.1111/j.1600-0838.2006.00534.x) PubMed, Web of Science, Google Scholar - 119.
Petrella JK, Kim JS, Mayhew DL, Cross JM, Bamman MM . 2008 Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis. J. Appl. Physiol. 104, 1736-1742. (doi:10.1152/japplphysiol.01215.2007) Crossref, PubMed, Web of Science, Google Scholar - 120.
Mikkelsen UR, Langberg H, Helmark IC, Skovgaard D, Andersen LL, Kjaer M, Mackey AL . 2009 Local NSAID infusion inhibits satellite cell proliferation in human skeletal muscle after eccentric exercise. J. Appl. Physiol. 107, 1600-1611. (doi:10.1152/japplphysiol.00707.2009) Crossref, PubMed, Web of Science, Google Scholar - 121.
Mackey AL, Holm L, Reitelseder S, Pedersen TG, Doessing S, Kadi F, Kjaer M . 2011 Myogenic response of human skeletal muscle to 12 weeks of resistance training at light loading intensity. Scand. J. Med. Sci. Sports 21, 773-782. (doi:10.1111/j.1600-0838.2010.01178.x) Crossref, PubMed, Web of Science, Google Scholar - 122.
Mackey AL, Andersen LL, Frandsen U, Sjogaard G . 2011 Strength training increases the size of the satellite cell pool in type I and II fibres of chronically painful trapezius muscle in females. J. Physiol. 589, 5503-5515. (doi:10.1113/jphysiol.2011.217885) Crossref, PubMed, Web of Science, Google Scholar - 123.
Farup J, Rahbek SK, Riis S, Vendelbo MH, Paoli F, Vissing K . 2014 Influence of exercise contraction mode and protein supplementation on human skeletal muscle satellite cell content and muscle fiber growth. J. Appl. Physiol. 117, 898-909. (doi:10.1152/japplphysiol.00261.2014) Crossref, PubMed, Web of Science, Google Scholar - 124.
Farup J, Rahbek SK, Knudsen IS, de Paoli F, Mackey AL, Vissing K . 2014 Whey protein supplementation accelerates satellite cell proliferation during recovery from eccentric exercise. Amino Acids 46, 2503-2516. (doi:10.1007/s00726-014-1810-3) Crossref, PubMed, Web of Science, Google Scholar - 125.
Joanisse S, Gillen JB, Bellamy LM, McKay BR, Tarnopolsky MA, Gibala MJ, Parise G . 2013 Evidence for the contribution of muscle stem cells to nonhypertrophic skeletal muscle remodeling in humans. FASEB J. 27, 4596-4605. (doi:10.1096/fj.13-229799) Crossref, PubMed, Web of Science, Google Scholar - 126.
Abreu P, Mendes SV, Ceccatto VM, Hirabara SM . 2017 Satellite cell activation induced by aerobic muscle adaptation in response to endurance exercise in humans and rodents. Life Sci. 170, 33-40. (doi:10.1016/j.lfs.2016.11.016) Crossref, PubMed, Web of Science, Google Scholar - 127.
Rosenblatt JD, Parry DJ . 1992 Gamma irradiation prevents compensatory hypertrophy of overloaded mouse extensor digitorum longus muscle. J. Appl. Physiol. 73, 2538-2543. (doi:10.1152/jappl.1992.73.6.2538) Crossref, PubMed, Web of Science, Google Scholar - 128.
Adams GR, Caiozzo VJ, Haddad F, Baldwin KM . 2002 Cellular and molecular responses to increased skeletal muscle loading after irradiation. Am. J. Physiol. Cell Physiol. 283, C1182-C1195. (doi:10.1152/ajpcell.00173.2002) Crossref, PubMed, Web of Science, Google Scholar - 129.
Bruusgaard JC, Johansen IB, Egner IM, Rana ZA, Gundersen K . 2010 Myonuclei acquired by overload exercise precede hypertrophy and are not lost on detraining. Proc. Natl Acad. Sci. USA 107, 15 111-15 116. (doi:10.1073/pnas.0913935107) Crossref, Web of Science, Google Scholar - 130.
Guerci A 2012 Srf-dependent paracrine signals produced by myofibers control satellite cell-mediated skeletal muscle hypertrophy. Cell Metab. 15, 25-37. (doi:10.1016/j.cmet.2011.12.001) Crossref, PubMed, Web of Science, Google Scholar - 131.
Blaauw B, Reggiani C . 2014 The role of satellite cells in muscle hypertrophy. J. Muscle Res. Cell Motil. 35, 3-10. (doi:10.1007/s10974-014-9376-y) Crossref, PubMed, Web of Science, Google Scholar - 132.
Berg HE, Dudley GA, Haggmark T, Ohlsen H, Tesch PA . 1991 Effects of lower limb unloading on skeletal muscle mass and function in humans. J. Appl. Physiol. 70, 1882-1885. (doi:10.1152/jappl.1991.70.4.1882) Crossref, PubMed, Web of Science, Google Scholar - 133.
Buford TW, Cooke MB, Manini TM, Leeuwenburgh C, Willoughby DS . 2010 Effects of age and sedentary lifestyle on skeletal muscle NF-κB signaling in men. J. Gerontol. A Biol. Sci. Med. Sci. 65, 532-537. (doi:10.1093/gerona/glp196) Crossref, PubMed, Web of Science, Google Scholar - 134.
Bogdanis GC . 2012 Effects of physical activity and inactivity on muscle fatigue. Front. Physiol. 3, 142. (doi:10.3389/fphys.2012.00142) Crossref, PubMed, Web of Science, Google Scholar - 135.
Vandenburgh H, Chromiak J, Shansky J, Del Tatto M, Lemaire J . 1999 Space travel directly induces skeletal muscle atrophy. FASEB J. 13, 1031-1038. (doi:10.1096/fasebj.13.9.1031) Crossref, PubMed, Web of Science, Google Scholar - 136.
Geirsdottir OG, Arnarson A, Ramel A, Briem K, Jonsson PV, Thorsdottir I . 2015 Muscular strength and physical function in elderly adults 6–18 months after a 12-week resistance exercise program. Scand. J. Public Health 43, 76-82. (doi:10.1177/1403494814560842) Crossref, PubMed, Web of Science, Google Scholar - 137.
Peterson MD, Rhea MR, Sen A, Gordon PM . 2010 Resistance exercise for muscular strength in older adults: a meta-analysis. Ageing Res. Rev. 9, 226-237. (doi:10.1016/j.arr.2010.03.004) Crossref, PubMed, Web of Science, Google Scholar - 138.
Bottaro M, Machado SN, Nogueira W, Scales R, Veloso J . 2007 Effect of high versus low-velocity resistance training on muscular fitness and functional performance in older men. Eur. J. Appl. Physiol. 99, 257-264. (doi:10.1007/s00421-006-0343-1) Crossref, PubMed, Web of Science, Google Scholar - 139.
Galvao DA, Taaffe DR . 2005 Resistance exercise dosage in older adults: single- versus multiset effects on physical performance and body composition. J. Am. Geriatr. Soc. 53, 2090-2097. (doi:10.1111/j.1532-5415.2005.00494.x) Crossref, PubMed, Web of Science, Google Scholar - 140.
Binder EF, Schechtman KB, Ehsani AA, Steger-May K, Brown M, Sinacore DR, Yarasheski KE, Holloszy JO . 2002 Effects of exercise training on frailty in community-dwelling older adults: results of a randomized, controlled trial. J. Am. Geriatr. Soc. 50, 1921-1928. (doi:10.1046/j.1532-5415.2002.50601.x) Crossref, PubMed, Web of Science, Google Scholar - 141.
Chan DC, Chang CB, Han DS, Hong CH, Hwang JS, Tsai KS, Yang RS . 2018 Effects of exercise improves muscle strength and fat mass in patients with high fracture risk: a randomized control trial. J. Formos. Med. Assoc. 117, 572-582. (doi:10.1016/j.jfma.2017.05.004) Crossref, PubMed, Web of Science, Google Scholar - 142.
Lambert CP, Evans WJ . 2002 Effects of aging and resistance exercise on determinants of muscle strength. J. Am. Aging Assoc. 25, 73-78. (doi:10.1007/s11357-002-0005-0) PubMed, Google Scholar - 143.
Kwak S-E, Lee J-H, Zhang D, Song W . 2018 Angiogenesis: focusing on the effects of exercise in aging and cancer. J. Exerc. Nutrition Biochem. 22, 21-26. (doi:10.20463/jenb.2018.0020) Crossref, PubMed, Google Scholar - 144.
Lee S, Barton ER, Sweeney HL, Farrar RP . 2004 Viral expression of insulin-like growth factor-I enhances muscle hypertrophy in resistance-trained rats. J. Appl. Physiol. 96, 1097-1104. (doi:10.1152/japplphysiol.00479.2003) Crossref, PubMed, Web of Science, Google Scholar - 145.
Begue G, Douillard A, Galbes O, Rossano B, Vernus B, Candau R, Py G . 2013 Early activation of rat skeletal muscle IL-6/STAT1/STAT3 dependent gene expression in resistance exercise linked to hypertrophy. PLoS ONE 8, e57141. (doi:10.1371/journal.pone.0057141) Crossref, PubMed, Web of Science, Google Scholar - 146.
Eliazer S, Muncie JM, Christensen J, Sun X, D'Urso RS, Weaver VM, Brack AS . 2019 Wnt4 from the niche controls the mechano-properties and quiescent state of muscle stem cells. Cell Stem Cell 25, 654-665.e654. (doi:10.1016/j.stem.2019.08.007) Crossref, PubMed, Web of Science, Google Scholar - 147.
Ryall JG 2015 The NAD+-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells. Cell Stem Cell 16, 171-183. (doi:10.1016/j.stem.2014.12.004) Crossref, PubMed, Web of Science, Google Scholar - 148.
Goldspink G . 1999 Changes in muscle mass and phenotype and the expression of autocrine and systemic growth factors by muscle in response to stretch and overload. J. Anat. 194(Pt 3), 323-334. (doi:10.1046/j.1469-7580.1999.19430323.x) Crossref, PubMed, Web of Science, Google Scholar - 149.
Barton-Davis ER, Shoturma DI, Sweeney HL . 1999 Contribution of satellite cells to IGF-I induced hypertrophy of skeletal muscle. Acta Physiol. Scand. 167, 301-305. (doi:10.1046/j.1365-201x.1999.00618.x) Crossref, PubMed, Google Scholar - 150.
Fiorotto ML, Schwartz RJ, Delaughter MC . 2003 Persistent IGF-I overexpression in skeletal muscle transiently enhances DNA accretion and growth. FASEB J. 17, 59-60. (doi:10.1096/fj.02-0289fje) Crossref, PubMed, Web of Science, Google Scholar - 151.
McKay BR, O'Reilly CE, Phillips SM, Tarnopolsky MA, Parise G . 2008 Co-expression of IGF-1 family members with myogenic regulatory factors following acute damaging muscle-lengthening contractions in humans. J. Physiol. 586, 5549-5560. (doi:10.1113/jphysiol.2008.160176) Crossref, PubMed, Web of Science, Google Scholar - 152.
Zablocka B, Goldspink P, Goldspink G, Gorecki D . 2012 Mechano-growth factor: an important cog or a loose screw in the repair machinery? Front. Endocrinol. 3, 131. (doi:10.3389/fendo.2012.00131) Crossref, PubMed, Google Scholar - 153.
Fornaro M 2014 Mechano-growth factor peptide, the COOH terminus of unprocessed insulin-like growth factor 1, has no apparent effect on myoblasts or primary muscle stem cells. Am. J. Physiol. Endocrinol. Metab. 306, E150-E156. (doi:10.1152/ajpendo.00408.2013) Crossref, PubMed, Web of Science, Google Scholar - 154.
Serrano AL, Baeza-Raja B, Perdiguero E, Jardi M, Munoz-Canoves P . 2008 Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell Metab. 7, 33-44. (doi:10.1016/j.cmet.2007.11.011) Crossref, PubMed, Web of Science, Google Scholar - 155.
Joe AW, Yi L, Natarajan A, Le Grand F, So L, Wang J, Rudnicki MA, Rossi FM . 2010 Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153-163. (doi:10.1038/ncb2015) Crossref, PubMed, Web of Science, Google Scholar - 156.
Munoz-Canoves P, Scheele C, Pedersen BK, Serrano AL . 2013 Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J. 280, 4131-4148. (doi:10.1111/febs.12338) Crossref, PubMed, Web of Science, Google Scholar - 157.
Saclier M 2013 Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration. Stem Cells 31, 384-396. (doi:10.1002/stem.1288) Crossref, PubMed, Web of Science, Google Scholar - 158.
Tierney MT, Aydogdu T, Sala D, Malecova B, Gatto S, Puri PL, Latella L, Sacco A . 2014 STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat. Med. 20, 1182-1186. (doi:10.1038/nm.3656) Crossref, PubMed, Web of Science, Google Scholar - 159.
Rodeheffer MS . 2010 Tipping the scale: muscle versus fat. Nat. Cell Biol. 12, 102-104. (doi:10.1038/ncb0210-102) Crossref, PubMed, Web of Science, Google Scholar - 160.
Heredia JE, Mukundan L, Chen FM, Mueller AA, Deo RC, Locksley RM, Rando TA, Chawla A . 2013 Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell 153, 376-388. (doi:10.1016/j.cell.2013.02.053) Crossref, PubMed, Web of Science, Google Scholar - 161.
Mozzetta C 2013 Fibroadipogenic progenitors mediate the ability of HDAC inhibitors to promote regeneration in dystrophic muscles of young, but not old Mdx mice. EMBO Mol. Med. 5, 626-639. (doi:10.1002/emmm.201202096) Crossref, PubMed, Web of Science, Google Scholar - 162.
Dong Y, Silva KA, Dong Y, Zhang L . 2014 Glucocorticoids increase adipocytes in muscle by affecting IL-4 regulated FAP activity. FASEB J. 28, 4123-4132. (doi:10.1096/fj.14-254011) Crossref, PubMed, Web of Science, Google Scholar - 163.
Uezumi A 2014 Identification and characterization of PDGFRα+ mesenchymal progenitors in human skeletal muscle. Cell Death Dis. 5, e1186. (doi:10.1038/cddis.2014.161) Crossref, PubMed, Web of Science, Google Scholar - 164.
Biferali B, Proietti D, Mozzetta C, Madaro L . 2019 Fibro-adipogenic progenitors cross-talk in skeletal muscle: the social network. Front. Physiol. 10, 1074. (doi:10.3389/fphys.2019.01074) Crossref, PubMed, Web of Science, Google Scholar - 165.
Rao RR 2014 Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279-1291. (doi:10.1016/j.cell.2014.03.065) Crossref, PubMed, Web of Science, Google Scholar - 166.
Judson RN, Tremblay AM, Knopp P, White RB, Urcia R, De Bari C, Zammit PS, Camargo FD, Wackerhage H . 2012 The Hippo pathway member Yap plays a key role in influencing fate decisions in muscle satellite cells. J. Cell Sci. 125, 6009-6019. (doi:10.1242/jcs.109546) Crossref, PubMed, Web of Science, Google Scholar - 167.
Tremblay AM 2014 The Hippo transducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation. Cancer Cell 26, 273-287. (doi:10.1016/j.ccr.2014.05.029) Crossref, PubMed, Web of Science, Google Scholar - 168.
Park GH, Jeong H, Jeong MG, Jang EJ, Bae MA, Lee YL, Kim NJ, Hong JH, Hwang ES . 2014 Novel TAZ modulators enhance myogenic differentiation and muscle regeneration. Br. J. Pharmacol. 171, 4051-4061. (doi:10.1111/bph.12755) Crossref, PubMed, Web of Science, Google Scholar - 169.
Xia P, Gutl D, Zheden V, Heisenberg CP . 2019 Lateral inhibition in cell specification mediated by mechanical signals modulating TAZ activity. Cell 176, 1379-1392. (doi:10.1016/j.cell.2019.01.019) Crossref, PubMed, Web of Science, Google Scholar - 170.
Lundin V 2020 YAP regulates hematopoietic stem cell formation in response to the biomechanical forces of blood flow. Dev. Cell 52, 446-460. (doi:10.1016/j.devcel.2020.01.006) Crossref, PubMed, Web of Science, Google Scholar - 171.
Hunt ER, Confides AL, Abshire SM, Dupont-Versteegden EE, Butterfield TA . 2019 Massage increases satellite cell number independent of the age-associated alterations in sarcolemma permeability. Physiol. Rep. 7, e14200. (doi:10.14814/phy2.14200) Crossref, PubMed, Web of Science, Google Scholar - 172.
Huang CC, Wang T, Tung YT, Lin WT . 2016 Effect of exercise training on skeletal muscle SIRT1 and PGC-1α expression levels in rats of different age. Int. J. Med. Sci. 13, 260-270. (doi:10.7150/ijms.14586) Crossref, PubMed, Web of Science, Google Scholar - 173.
Houtkooper RH, Pirinen E, Auwerx J . 2012 Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225-238. (doi:10.1038/nrm3293) Crossref, PubMed, Web of Science, Google Scholar - 174.
Myers MJ, Shepherd DL, Durr AJ, Stanton DS, Mohamed JS, Hollander JM, Alway SE . 2019 The role of SIRT1 in skeletal muscle function and repair of older mice. J. Cachexia Sarcopenia Muscle 10, 929-949. (doi:10.1002/jcsm.12437) Crossref, PubMed, Web of Science, Google Scholar - 175.
Verdijk LB, Gleeson BG, Jonkers RA, Meijer K, Savelberg HH, Dendale P, van Loon LJ . 2009 Skeletal muscle hypertrophy following resistance training is accompanied by a fiber type-specific increase in satellite cell content in elderly men. J. Gerontol. A Biol. Sci. Med. Sci. 64, 332-339. (doi:10.1093/gerona/gln050) Crossref, PubMed, Web of Science, Google Scholar - 176.
Verdijk LB, Snijders T, Drost M, Delhaas T, Kadi F, van Loon LJ . 2014 Satellite cells in human skeletal muscle; from birth to old age. Age (Dordr.) 36, 545-547. (doi:10.1007/s11357-013-9583-2) Crossref, PubMed, Google Scholar - 177.
Mackey AL, Karlsen A, Couppe C, Mikkelsen UR, Nielsen RH, Magnusson SP, Kjaer M . 2014 Differential satellite cell density of type I and II fibres with lifelong endurance running in old men. Acta Physiol. (Oxf.) 210, 612-627. (doi:10.1111/apha.12195) Crossref, PubMed, Web of Science, Google Scholar - 178.
McKay BR, Ogborn DI, Bellamy LM, Tarnopolsky MA, Parise G . 2012 Myostatin is associated with age-related human muscle stem cell dysfunction. FASEB J. 26, 2509-2521. (doi:10.1096/fj.11-198663) Crossref, PubMed, Web of Science, Google Scholar - 179.
Suetta C 2013 Ageing is associated with diminished muscle re-growth and myogenic precursor cell expansion early after immobility-induced atrophy in human skeletal muscle. J. Physiol. 591, 3789-3804. (doi:10.1113/jphysiol.2013.257121) Crossref, PubMed, Web of Science, Google Scholar - 180.
Elabd C, Cousin W, Upadhyayula P, Chen RY, Chooljian MS, Li J, Kung S, Jiang KP, Conboy IM . 2014 Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat. Commun. 5, 4082. (doi:10.1038/ncomms5082) Crossref, PubMed, Web of Science, Google Scholar - 181.
Snijders T, Verdijk LB, Smeets JS, McKay BR, Senden JM, Hartgens F, Parise G, Greenhaff P, van Loon LJ . 2014 The skeletal muscle satellite cell response to a single bout of resistance-type exercise is delayed with aging in men. Age (Dordr.) 36, 9699. (doi:10.1007/s11357-014-9699-z) Crossref, PubMed, Google Scholar - 182.
McCroskery S, Thomas M, Maxwell L, Sharma M, Kambadur R . 2003 Myostatin negatively regulates satellite cell activation and self-renewal. J. Cell Biol. 162, 1135-1147. (doi:10.1083/jcb.200207056) Crossref, PubMed, Web of Science, Google Scholar
