Gli3 Regulation of Myogenesis Is Necessary for Ischemia-Induced Angiogenesis

Abstract

Rationale A better understanding of the mechanism underlying skeletal muscle repair is required to develop therapies that promote tissue regeneration in adults. Hedgehog signaling has been shown previously to be involved in myogenesis and angiogenesis: 2 crucial processes for muscle development and regeneration. Objective The objective of this study was to identify the role of the hedgehog transcription factor Gli3 in the crosstalk between angiogenesis and myogenesis in adults. Methods and Results Using conditional knockout mice, we found that Gli3 deficiency in endothelial cells did not affect ischemic muscle repair, whereas in myocytes, Gli3 deficiency resulted in severely delayed ischemia-induced myogenesis. Moreover, angiogenesis was also significantly impaired in HSA-CreERT2; Gli3Flox/Flox mice, demonstrating that impaired myogenesis indirectly affects ischemia-induced angiogenesis. The role of Gli3 in myocytes was then further investigated. We found that Gli3 promotes myoblast differentiation through myogenic factor 5 regulation. In addition, we found that Gli3 regulates several proangiogenic factors, including thymidine phosphorylase and angiopoietin-1 both in vitro and in vivo, which indirectly promote endothelial cell proliferation and arteriole formation. In addition, we found that Gli3 is upregulated in proliferating myoblasts by the cell cycle–associated transcription factor E2F1. Conclusions This study shows for the first time that Gli3-regulated postnatal myogenesis is necessary for muscle repair–associated angiogenesis. Most importantly, it implies that myogenesis drives angiogenesis in the setting of skeletal muscle repair and identifies Gli3 as a potential target for regenerative medicine.

The Smoothened Receptor in Cancer and Regenerative Medicine

“…The mechanism is rapid and independent of Gli-dependent transcription. Remarkably, this study and a previous one also showed evidences of activation of G 12 by Smo [152,153]. Altogether, numerous evidences demonstrate that Smo does couple to heterotrimeric G proteins of the G i family.…”

Synergizing Engineering and Biology to Treat and Model Skeletal Muscle Injury and Disease

“…As we move toward this goal, a large body of ongoing tissue-engineering work revolves around establishing perfusable capillary networks in vitro and inducing the ingrowth of functional vasculature in vivo (114, 187). Additionally, complex bidirectional interactions between myogenic and vascular cells are increasingly recognized as being critical for muscle function, disease, and regeneration (188–190). As such, the ability to engineer 3D skeletal muscle tissues with native-like architecture, mature contractile function, and a vascular bed—feats not yet accomplished—would promote both basic studies of muscle biology and the development of improved cell- and material-based therapies for VML.…”

Disruption of mitochondrial quality control in peripheral artery disease: New therapeutic opportunities

“…Recent evidence demonstrates that therapies capable of coordinately improving local skeletal muscle angiogenesis and myogenesis have a better impact on tissue regeneration during hindlimb ischemia in rodents (61, 62). However, dissecting the contribution of specific population of cells located at the skeletal muscle microenvironment to PAD establishment and/or progression remains a challenge.…”