Abstract

Muscle represents an abundant, accessible, and replenishable source of adult stem cells. Skeletal muscle-derived stem cells, called satellite cells, play essential roles in regeneration after muscle injury in adult skeletal muscle. Although the molecular mechanism of muscle regeneration process after an injury has been extensively investigated, the regulation of satellite cells under steady state during the adult stage, including the reaction to exercise stimuli, is relatively unknown. Here, we show that voluntary wheel running exercise, which is a low stress exercise, converts satellite cells to the activated state due to accelerated Wnt signaling. Our analysis showed that up-regulated canonical Wnt/β-catenin signaling directly modulated chromatin structures of both MyoD and Myf5 genes, resulting in increases in the mRNA expression of Myf5 and MyoD and the number of proliferative Pax7(+)Myf5(+) and Pax7(+) MyoD(+) cells in skeletal muscle. The effect of Wnt signaling on the activation of satellite cells, rather than Wnt-mediated fibrosis, was observed in both adult and aged mice. The association of β-catenin, T-cell factor, and lymphoid enhancer transcription factors of multiple T-cell factor/lymphoid enhancer factor regulatory elements, conserved in mouse, rat, and human species, with the promoters of both the Myf5 and MyoD genes drives the de novo myogenesis in satellite cells even in aged muscle. These results indicate that exercise-stimulated extracellular Wnts play a critical role in the regulation of satellite cells in adult and aged skeletal muscle.

Highlights

  • Satellite cells are activated in response to muscle injury or mechanical stimuli

  • We investigated the characteristic changes in satellite cells and the molecular mechanisms regulating their activation in mouse skeletal muscle following voluntary wheel running

  • Myf5 is expressed in only Pax7ϩ cells, satellite cells but not in myofibers, and MyoD is expressed in satellite cells or differentiating myoblasts (Fig. 2) [44]

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Summary

Background

Satellite cells are activated in response to muscle injury or mechanical stimuli. Results: Running-induced up-regulation of Wnt/␤-catenin signaling activates Myf and MyoD transcription. We investigated the effects of Wnt/␤-catenin signaling on the regulation of satellite cells after voluntary wheel running in both adult and aged mice. Exercise significantly up-regulated the expression of Wnt, Wnt5a, and Wnt5b, and the up-regulation of Wnt signaling altered the quiescent state of satellite cells into the activated state, even in aged skeletal muscle without fibrosis. This report is the first to show the Wnt-mediated positive myogenic effects of exercise on satellite cells in adult and aged skeletal muscle and to describe the regulatory mechanism underlying chromatin remodeling of the Myf and MyoD genes

EXPERIMENTAL PROCEDURES
RESULTS
A Adult group
DISCUSSION
B Mouse MyoD promoter
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