Dataset Information

Revascularization of ischemic skeletal muscle by estrogen-related receptor-?.

ABSTRACT: Oxidative myofibers in the skeletal muscles express high levels of angiogenic factors, have dense vasculature, and promptly revascularize during ischemia. Estrogen-related receptor-gamma (ERR?) activates genes that govern metabolic and vascular features typical to oxidative myofibers. Therefore, ERR?-dependent remodeling of the myofibers may promote neoangiogenesis and restoration of blood perfusion in skeletal muscle ischemia.To investigate the muscle fiber type remodeling by ERR? and its role in the vascular recovery of ischemic muscle.Using immunohistology, we show that skeletal muscle-specific transgenic overexpression of ERR? increases the proportions of oxidative and densely vascularized type IIA and IIX myofibers and decreases glycolytic and less vascularized type IIB myofibers. This myofiber remodeling results in a higher basal blood flow in the transgenic skeletal muscle. By applying unilateral hind limb ischemia to transgenic and wild-type mice, we found accelerated revascularization (fluorescent microangiography), restoration of blood perfusion (laser Doppler flowmetry), and muscle repair (Evans blue dye exclusion) in transgenic compared to wild-type ischemic muscles. This ameliorative effect is linked to enhanced neoangiogenesis (CD31 staining and microfil perfusion) by ERR?. Using cultured muscle cells in which ERR? is inactivated, we show that the receptor is dispensable for the classical hypoxic response of transcriptional upregulation and secretion of vascular endothelial growth factor A. Rather, the ameliorative effect of ERR? is linked to the receptor-mediated increase in oxidative myofibers that inherently express and secrete high levels of angiogenic factors.The ERR? is a hypoxia-independent inducer of neoangiogenesis that can promote reparative revascularization.

SUBMITTER: Matsakas A

PROVIDER: S-EPMC3610573 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Revascularization of ischemic skeletal muscle by estrogen-related receptor-γ.

Matsakas Antonios A Yadav Vikas V Lorca Sabina S Evans Ronald M RM Narkar Vihang A VA

Circulation research 20120313 8

<h4>Rationale</h4>Oxidative myofibers in the skeletal muscles express high levels of angiogenic factors, have dense vasculature, and promptly revascularize during ischemia. Estrogen-related receptor-gamma (ERRγ) activates genes that govern metabolic and vascular features typical to oxidative myofibers. Therefore, ERRγ-dependent remodeling of the myofibers may promote neoangiogenesis and restoration of blood perfusion in skeletal muscle ischemia.<h4>Objective</h4>To investigate the muscle fiber t ...[more]

PMID: 22415017

Similar Datasets

Project description:ObjectiveSkeletal muscle oxidative capacity is central to physical activity, exercise capacity and whole-body metabolism. The three estrogen-related receptors (ERRs) are regulators of oxidative metabolism in many cell types, yet their roles in skeletal muscle remain unclear. The main aim of this study was to compare the relative contributions of ERRs to oxidative capacity in glycolytic and oxidative muscle, and to determine defects associated with loss of skeletal muscle ERR function.MethodsWe assessed ERR expression, generated mice lacking one or two ERRs specifically in skeletal muscle and compared the effects of ERR loss on the transcriptomes of EDL (predominantly glycolytic) and soleus (oxidative) muscles. We also determined the consequences of the loss of ERRs for exercise capacity and energy metabolism in mice with the most severe loss of ERR activity.ResultsERRs were induced in human skeletal muscle in response to an exercise bout. Mice lacking both ERRα and ERRγ (ERRα/γ dmKO) had the broadest and most dramatic disruption in skeletal muscle gene expression. The most affected pathway was "mitochondrial function", in particular Oxphos and TCA cycle genes, and transcriptional defects were more pronounced in the glycolytic EDL than the oxidative soleus. Mice lacking ERRβ and ERRγ, the two isoforms expressed highly in oxidative muscles, also exhibited defects in lipid and branch chain amino acid metabolism genes, specifically in the soleus. The pronounced disruption of oxidative metabolism in ERRα/γ dmKO mice led to pale muscles, decreased oxidative capacity, histochemical patterns reminiscent of minicore myopathies, and severe exercise intolerance, with the dmKO mice unable to switch to lipid utilization upon running. ERRα/γ dmKO mice showed no defects in whole-body glucose and energy homeostasis.ConclusionsOur findings define gene expression programs in skeletal muscle that depend on different combinations of ERRs, and establish a central role for ERRs in skeletal muscle oxidative metabolism and exercise capacity. Our data reveal a high degree of functional redundancy among muscle ERR isoforms for the protection of oxidative capacity, and show that ERR isoform-specific phenotypes are driven in part, but not exclusively, by their relative levels in different muscles.

Dataset Information

Revascularization of ischemic skeletal muscle by estrogen-related receptor-?.

Publications

Revascularization of ischemic skeletal muscle by estrogen-related receptor-γ.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets