Depletion of resident muscle stem cells negatively impacts running volume, physical function, and muscle fiber hypertrophy in response to lifelong physical activity

Abstract

To date, studies that have aimed to investigate the role of satellite cells during adult skeletal muscle adaptation and hypertrophy have utilized a nontranslational stimulus and/or have been performed over a relatively short time frame. Although it has been shown that satellite cell depletion throughout adulthood does not drive skeletal muscle loss in sedentary mice, it remains unknown how satellite cells participate in skeletal muscle adaptation to long-term physical activity. The current study was designed to determine whether reduced satellite cell content throughout adulthood would influence the transcriptome-wide response to physical activity and diminish the adaptive response of skeletal muscle. We administered vehicle or tamoxifen to adult Pax7-diphtheria toxin A (DTA) mice to deplete satellite cells and assigned them to sedentary or wheel-running conditions for 13 mo. Satellite cell depletion throughout adulthood reduced balance and coordination, overall running volume, and the size of muscle proprioceptors (spindle fibers). Furthermore, satellite cell participation was necessary for optimal muscle fiber hypertrophy but not adaptations in fiber type distribution in response to lifelong physical activity. Transcriptome-wide analysis of the plantaris and soleus revealed that satellite cell function is muscle type specific; satellite cell-dependent myonuclear accretion was apparent in oxidative muscles, whereas initiation of G protein-coupled receptor (GPCR) signaling in the glycolytic plantaris may require satellite cells to induce optimal adaptations to long-term physical activity. These findings suggest that satellite cells play a role in preserving physical function during aging and influence muscle adaptation during sustained periods of physical activity.

Nuclear numbers in syncytial muscle fibers promote size but limit the development of larger myonuclear domains

“…Our models where myonuclear numbers have been titrated may explain the conundrum of myonuclear flexibility during development and inflexibility in the adult. Based on multiple studies where the function of muscle stem cells was genetically inhibited, accrual of new myonuclei is required for adult adaptations including hypertrophy [26][27][28][29][30][31] . Thus, in the adult there seems to be limited flexibility of hundreds of myonuclei that were added during development to increase mRNA concentration, although there is an ability to upregulate rRNA 44 .…”

“…Given that skeletal muscle stem cells provide a mechanism for myofibers to accrue new nuclei through cellular fusion, increases in the cytoplasmic volume of adult myofibers can be achieved by regulating resident myonuclei, adding new myonuclei, or both. The majority of evidence indicates new myonuclei are required for functional adaptations, including hypertrophy in the adult, suggesting limited flexibility of resident myonuclei in adult myofibers [26][27][28][29][30][31] . Taken together, the decision for muscle to either add a new myonucleus or regulate nuclei that are already present in the myofiber is unclear and there is minimal understanding about the requirements for the full complement of resident myonuclei to establish functional cytoplasmic volumes during maturational growth.…”

Fusion-Independent Satellite Cell Communication to Muscle Fibers During Load-Induced Hypertrophy

“…Our laboratory and others report that adult muscle fibers can grow in the absence of satellite cell fusion and myonuclear addition, indicating flexibility within the myonuclear domain. 18 , 19 Hypertrophy without increased myonuclear number has been demonstrated with mechanical, 6–8 , 10 , 11 , 66 pharmacological, 13 , 67–69 and genetic approaches, 68 , 70–74 although this finding is not universal, 4 , 12 , 13 , 75–79 which could be explained by a variety of factors. 5 , 19 In recent years, a deeper appreciation for the secretory function of muscle stem cells in general, 80–84 and satellite cells specifically 7 , 8 , 21 , 22 has emerged in the context of skeletal muscle remodeling, with evidence for EV communication between mononuclear cells.…”

“… 4–6 Conversely, adult (>4 months old) murine muscle can sustain short-term load-mediated hypertrophy (≤2 weeks) in the absence of satellite cells, 6 – 10 although long-term hypertrophy (≥8 weeks) is attenuated. 7 , 8 , 11 Some evidence suggests that the addition of new myonuclei to muscle fibers undergoing hypertrophy is necessary before growth ensues 12 , 13 or is required beyond a certain threshold of growth to control the “myonuclear domain,” 14 – 16 which is the maximal area that each myonucleus can transcriptionally govern, although this limit is equivocal and may be muscle and/or fiber type specific. 9 , 14 , 17–19 …”

Regulation of microRNAs in Satellite Cell Renewal, Muscle Function, Sarcopenia and the Role of Exercise

“…Study in mice have demonstrated that reduction of satellite cells affects muscle regenerative capacity without affecting sarcopenia, and does not contribute to the maintenance of muscle size during aging, however in sedentary adult mice, in the absence of injury, satellite cells may contribute to myfibers at different extent between muscle and with age [43,44]. More recently, it has been also demonstrated that satellite cells depletion in adult mice contributes to preserve physical function and to increase in muscle fiber size when physical activity is lifelong sustained [45]. In humans, the role of satellite cells in contributing to hypertrophy and to regeneration in the elderly is not clearly defined, also due to the difficulty of studying muscle regeneration in human subjects.…”