Editors' ChoicePhysiology

HIF1α slows muscle regeneration

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Sci. Signal.  04 Aug 2015:
Vol. 8, Issue 388, pp. ec215
DOI: 10.1126/scisignal.aad1180

In vitro, hypoxia inhibits differentiation of myoblasts partly through stabilization of the transcription factor hypoxia-inducible factor 1α (HIF1α). However, in vivo, skeletal muscle stem and progenitor cells (SMSPCs) that reside in hypoxic environments drive embryonic myogenesis and myogenesis in response to ischemic injury in adults. Majmundar et al. found that knocking out Hif1a specifically in SMSPCs had no effect on skeletal muscle development in mouse embryos but accelerated skeletal muscle regeneration following femoral artery ligation in adults. Femoral artery ligation induces ischemia, muscle injury, an increase in HIF1α abundance, and a decrease in expression of the myogenic marker myogenin in the muscles of the hindlimb. Expression of myogenin increases, HIF1α abundance decreases, and the muscles regenerate as new blood vessels bring oxygen to the tissue. During the first seven days following ligation, muscle regeneration in mice lacking HIF1α in SMSPCs was similar to that in wild-type control mice. However, the mutant mice had a greater density of muscle fibers and larger muscle fibers than controls 14 days after ligation. The number of SMSPCs was not altered in mutant mice compared to controls, but the number of myogenin-positive cells (myocytes) was increased, implying that HIF1α restrains the differentiation of SMSPC-derived myocytes rather than affecting the proliferation of SMSPCs. HIF1α inhibits Wnt–β-catenin signaling in other contexts, and the authors found that the regenerating muscles of mutant mice exhibited increased expression of Wnt–β-catenin target genes relative to controls. In vitro experiments showed that HIF1α inhibited myoblast differentiation by repressing Wnt signaling, and injecting the Wnt signaling inhibitor Dkk1 into regenerating muscles prevented the enhanced regeneration exhibited by SMSPC-specific deletion of Hif1a. These results imply that HIF1α prevents differentiation of regenerating skeletal muscle cells until adequate blood flow has been established.

A. J. Majmundar, D. S. M. Lee, N. Skuli, R. C. Mesquita, M. N. Kim, A. G. Yodh, M. Nguyen-McCarty, B. Li, M. C. Simon, HIF modulation of Wnt signaling regulates skeletal myogenesis in vivo. Development 142, 2405–2412 (2015). [PubMed]