M.I.4 - Regulation of skeletal muscle metabolic and angiogenic properties by nuclear hormone receptors: Implications for skeletal muscle regeneration

Abstract

Skeletal muscle oxidative properties and its vascularization are tightly coupled. In particular, oxidative myofibers express high levels of angiogenic factors, have dense vasculature, and promptly re-vascularize after ischemic events. Recent evidence suggests that members of the nuclear hormone receptor superfamily act as powerful molecular switches and transcriptional co-regulators for fatty acid oxidation, oxidative phosphorylation, and mitochondrial biogenesis in skeletal muscle. The estrogen-related receptor γ (ERRγ) is a constitutively active orphan nuclear receptor, and unlike ERRα and β, it is selectively expressed in metabolically active and highly vascularized tissues such as heart, kidney, brain, and skeletal muscles. ERRγ has emerged as a key regulator of multiple key genes linked to both fatty acid oxidation, angiogenesis as well as mitochondrial biogenesis. We here discuss recently accumulated evidence on the role of ERRγ in skeletal muscle angiometabolic remodelling in response to ischemic injury, exercise training and skeletal muscle dystrophy. Overexpression of ERRγ selectively in skeletal muscles of mice with ischemic muscle damage or muscular dystrophy restores metabolic and angiogenic gene expression patterns compared with control mice. Further, ERRγ enhances muscle oxidative myofibers, vasculature, and blood flow and improves exercise tolerance in the dystrophic mice. Restoration of muscle ERRγ pathway ameliorates ischemic damage and also prevents muscular dystrophy hallmarks of post-exercise muscle damage, hypoxia, and fatigue in mdx mice. In conclusion, targeting of ERRγ-dependent metabolic and angiogenic gene program has clear implications for promoting myofiber regeneration and may be used as the basis for developing new strategies for treating muscle wasting and degenerative conditions.