Wnt protein-mediated satellite cell conversion in adult and aged mice following voluntary wheel running.
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.
From the Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-0046 and.
Shin
S
Fujimaki
Ryo
R
Hidaka
Makoto
M
Asashima
Tohru
T
Takemasa
Tomoko
T
Kuwabara
D000375:Aging; D000818:Animals; D002843:Chromatin / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D017570:MyoD Protein / Q000378:metabolism; D051787:Myogenic Regulatory Factor 5 / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
D002843:Chromatin; C497418:Myf5 protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C503801:Myog protein, mouse; D051787:Myogenic Regulatory Factor 5; D018008:Myogenin; D051153:Wnt Proteins; D051176:beta Catenin
Adult Stem Cells; Aging; Exercise; Fibrosis; Sarcopenia; Satellite Cells; Wnt Signaling