Effective fiber hypertrophy in satellite cell-depleted skeletal muscle

Abstract

SUMMARYAn important unresolved question in skeletal muscle plasticity is whether satellite cells are necessary for muscle fiber hypertrophy. To address this issue, a novel mouse strain (Pax7-DTA) was created which enabled the conditional ablation of >90% of satellite cells in mature skeletal muscle following tamoxifen administration. To test the hypothesis that satellite cells are necessary for skeletal muscle hypertrophy, the plantaris muscle of adult Pax7-DTA mice was subjected to mechanical overload by surgical removal of the synergist muscle. Following two weeks of overload, satellite cell-depleted muscle showed the same increases in muscle mass (approximately twofold) and fiber cross-sectional area with hypertrophy as observed in the vehicle-treated group. The typical increase in myonuclei with hypertrophy was absent in satellite cell-depleted fibers, resulting in expansion of the myonuclear domain. Consistent with lack of nuclear addition to enlarged fibers, long-term BrdU labeling showed a significant reduction in the number of BrdU-positive myonuclei in satellite cell-depleted muscle compared with vehicle-treated muscle. Single fiber functional analyses showed no difference in specific force, Ca 2+ sensitivity, rate of cross-bridge cycling and cooperativity between hypertrophied fibers from vehicle and tamoxifen-treated groups. Although a small component of the hypertrophic response, both fiber hyperplasia and regeneration were significantly blunted following satellite cell depletion, indicating a distinct requirement for satellite cells during these processes. These results provide convincing evidence that skeletal muscle fibers are capable of mounting a robust hypertrophic response to mechanical overload that is not dependent on satellite cells.

p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

“…Satellite cells are the principal muscle stem cell [1][2][3][4], responsible for the majority of postnatal growth and repair [5], and are capable of remarkable regenerative capability [6]. In response to extracellular stimuli, they activate and undergo a crucial proliferative expansion, before either returning to quiescence or differentiating and fusing to existing myofibers.…”

Influence of Mesterolone on Satellite Cell Distribution and Fiber Morphology within Maturing Chicken Pectoralis Muscle

“…It is thought that this occurs by enhanced transcription of muscle genes within preexisting myonuclei. McCarthy et al (2011) recently reported robust fiber hypertrophy in SC-depleted mouse skeletal muscle. We believe that skeletal muscle fiber hypertrophy in normal subjects occurs coordinately through both SC differentiation to new myonuclei and accelerated transcriptional and translational responses.…”

Role of satellite cells in skeletal muscle plasticity: Beyond muscle regeneration

“…Muscular hypertrophy after satellite cell ablation was examined in a few studies, where the plantaris muscle of adult tamoxifen-inducible Pax7-DTA mice was subjected to mechanical overload for 2 weeks by removing synergistic muscles 11,14) . The same hypertrophy level (increase in muscle mass and fiber cross-sectional area) was observed in the satellite cell ablation mice as in control mice, despite more than 90% absence of satellite cells 11) .…”

“…Recently, a novel strategy using Pax7-driven Cre recombination to genetically ablate satellite cells in a temporally defined manner has been reported by three different groups [9][10][11] . The precise method to ablate satellite cells was well reviewed in a previous report 12) .…”

“…The studies using tamoxifen-inducible Pax7-DTA mice clearly demonstrated that muscle regeneration after acute injury failed in the absence of satellite cells [9][10][11] . Additionally, under such a condition, ablated satellite cells were not replaced and non-satellite cells were unable to compensate for their function.…”