ACS DIVISION OF BIOLOGICAL CHEMISTRY

January 30th, 2014 by Fujimaki, S., Hidaka, R., Asashima, M., Takemasa, T., Kuwabara, T.

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 the 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 activated state due to accelerated Wnt signaling. Our analysis showed that upregulated 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, TCF, and LEF transcription factors of multiple TCF/LEF 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.