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

To date, studies that have aimed to investigate the role of satellite cells during adult skeletal muscle adaptation and hypertrophy have utilized a non-translational stimulus and/or have been carried out over a relatively short time frame. While 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 if 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-DTA mice to deplete satellite cells and assigned them to sedentary or wheel-running conditions for 13 months. Satellite cell depletion throughout adulthood reduced balance and coordination, overall running volume and the size of muscle proprioceptors (spindle fibers). Further, 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 GPCR signaling in the glycolytic plantaris may require satellite cells to induce optimal adaptations to long term physical activity. These findings suggest targeting satellite cells may be a viable strategy to preserve physical function during aging and promote muscle growth during sustained periods of physical activity.