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Abstract
Skeletal muscle stem/progenitor cells, which give rise to terminally differentiated muscle, represent potential therapies for skeletal muscle diseases. Delineating the factors regulating these precursors will facilitate their reliable application in human muscle repair. During embryonic development and adult regeneration, skeletal muscle progenitors reside in low-O2 environments before local blood vessels and differentiated muscle form. Prior studies established that low O2 levels (hypoxia) maintained muscle progenitors in an undifferentiated state in vitro, although it remained unclear if progenitor differentiation was coordinated with O2 availability in vivo. In addition, the molecular signals linking O2 to progenitor differentiation are incompletely understood. Here we show that the muscle differentiation program is repressed by hypoxia in vitro and ischemia in vivo. Surprisingly, hypoxia can significantly impair differentiation in the absence of hypoxia-inducible factors (HIFs), the primary developmental effectors of O2. In order to maintain the undifferentiated state, low O2 levels block the phosphatidylinositol 3-kinase/AKT pathway in a predominantly HIF1α-independent fashion. O2 deprivation affects AKT activity by reducing insulin-like growth factor I receptor sensitivity to growth factors. We conclude that AKT represents a key molecular link between O2 and skeletal muscle differentiation.
ACKNOWLEDGMENTS
We thank Jonathan Epstein, Mark Kahn, Gary Koretzky, Elisabeth Barton, Sarah Millar, Morris Birnbaum, Matt Buas, and Thomas Kadesch for helpful discussions during the formulation of these studies; Anthony Chi, Avinash Bhandoola, James Alwine, and David Sabatini for reagents; and Zachary Quinn and Theresa Richardson for technical assistance.
We report no conflicts of interest regarding this article.
We acknowledge funding support from NIH grant 5-R01-8L-066310. A.J.M. was supported through NIH training grant T32-AR053461-03 in Muscle Biology and Muscle Disease through the Pennsylvania Muscle Institute. M.C.S. is an investigator of the Howard Hughes Medical Institute.