Activation of the hypoxia‐inducible factor 1a promotes myogenesis through the noncanonical Wnt pathway, leading to hypertrophic myotubes

Abstract

Regeneration of skeletal muscle is a complex process that requires the activation of quiescent adult stem cells, called satellite cells, which are resident in hypoxic niches in the tissue. Hypoxia has been recognized as a key factor to maintain stem cells in an undifferentiated state. Herein we report that hypoxia plays a fundamental role also in activating myogenesis. In particular, we found that the activation of the hypoxia-inducible factor (HIF)-1α under hypoxia, in murine skeletal myoblasts, leads to activation of MyoD through the noncanonical Wnt/β-catenin pathway. Moreover, chemical inhibition of HIF-1α activity significantly reduces differentiation, thus confirming its crucial role in the process. Furthermore, hypoxia-preconditioned myoblasts, once induced to differentiate under normoxic conditions, tend to form hypertrophic myotubes. These results support the notion that hypoxia plays a pivotal role in activating the regeneration process by directly inducing myogenesis through HIF-1α. Although preliminary, these findings may suggest new perspective for novel therapeutic targets in the treatment of several muscle diseases.-Cirillo, F., Resmini, G., Ghiroldi, A., Piccoli, M., Bergante, S., Tettamanti, G., Anastasia, L. Activation of the hypoxia-inducible factor 1α promotes myogenesis through the noncanonical Wnt pathway, leading to hypertrophic myotubes.

Pharmacological inhibition of REV-ERB stimulates differentiation, inhibits turnover and reduces fibrosis in dystrophic muscle

“…During muscle repair, the Wnt transcription factor β-catenin (CTNNB1) mediates Wnt target-gene transcriptional regulation during satellite cell, proliferation, differentiation and fusion with myotubes 34 – 41 . Previous studies have also shown that activation of canonical Wnt signaling was therapeutic in rodent models of muscular dystrophy and acute injury 39 , 42 – 45 . We examined whether REV-ERB antagonism may also be modulating Notch and Wnt signaling activity in SkM.…”

Hypoxia‐inducible factor 1α (HIF‐1α) is a major determinant in the enhanced function of muscle‐derived progenitors from MRL/MpJ mice

“…One study showed that HIF-1a promotes stem cell quiescence while downregulating the WNT/b-Catenin pathway and inhibits myogenesis by degrading the early muscle-specific transcription factor MyoD1 (42), whereas another report has indicated that deletion of both HIF-1a and HIF-2a impairs satellite function and, subsequently, skeletal muscle regeneration (43). Furthermore, a very recent study indicated that activation of HIF-1a promotes myogenesis through the noncanonical WNT pathway (57). Our results demonstrated that inactivation of HIF-1a with the inhibitor PX487 during myogenic differentiation of WT and MRL/MpJ MDSPCs led to increase in myotube formation, which is consistent with other reports and suggests an inhibitory role of HIF-1a in myogenic differentiation.…”

BMP7 antagonizes proliferative vitreoretinopathy through retinal pigment epithelial fibrosis in vivo and in vitro

“…Western blotting was performed as previously described (27,28). Experiments were repeated 3 times, and GAPDH expression was used for normalization.…”