Estrogen‐related receptor‐α (ERRα) deficiency in skeletal muscle impairs regeneration in response to injury

Abstract

The estrogen-related receptor-α (ERRα) regulates mitochondrial biogenesis and glucose and fatty acid oxidation during differentiation in skeletal myocytes. However, whether ERRα controls metabolic remodeling during skeletal muscle regeneration in vivo is unknown. We characterized the time course of skeletal muscle regeneration in wild-type (M-ERRαWT) and muscle-specific ERRα(-/-) (M-ERRα(-/-)) mice after injury by intramuscular cardiotoxin injection. M-ERRα(-/-) mice exhibited impaired regeneration characterized by smaller myofibers with increased centrally localized nuclei and reduced mitochondrial density and cytochrome oxidase and citrate synthase activities relative to M-ERRαWT. Transcript levels of mitochondrial transcription factor A, nuclear respiratory factor-2a, and peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC)-1β, were downregulated in the M-ERRα(-/-) muscles at the onset of myogenesis. Furthermore, coincident with delayed myofiber recovery, we observed reduced muscle ATP content (-45% vs. M-ERRαWT) and enhanced AMP-activated protein kinase (AMPK) activation in M-ERRα(-/-) muscle. We subsequently demonstrated that pharmacologic postinjury AMPK activation was sufficient to delay muscle regeneration in WT mice. AMPK activation induced ERRα transcript expression in M-ERRαWT muscle and in C2C12 myotubes through induction of the Esrra promoter, indicating that ERRα may control gene regulation downstream of the AMPK pathway. Collectively, these results suggest that ERRα deficiency during muscle regeneration impairs recovery of mitochondrial energetic capacity and perturbs AMPK activity, resulting in delayed myofiber repair.

Ligands for FKBP12 Increase Ca2+ Influx and Protein Synthesis to Improve Skeletal Muscle Function

“…9B). However, muscle levels of ERR␣, which has many overlapping functions with ERR␥, enhances PGC-1␣ signaling (35), and is involved in muscle repair (36), were elevated in the muscle of FKBP12D mice (Fig. 9C).…”

PPARs and ERRs: molecular mediators of mitochondrial metabolism

“…The knockout of ERRα in skeletal muscle causes no phenotypic change in the basal state [53] [54]. However, in a cardiotoxin induced injury model, its deficiency reduces mitochondrial activity and impairs muscle regeneration [54]. …”

CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation

“…In contrast some studies show that AMPK inhibits myoblast differentiation though PGC1α transcription, and demonstrates that AICAR-induced AMPK phosphorylation reduces differentiation of myoblasts into myotubes through PGC1α transcription [19]. Regeneration in CTX-treated tibialis anterior muscle was dramatically impaired in mice treated with AICAR [45]. Here, we showed that AMPK activation by CaMKK2 (Figure 5A) in C2C12 cells was accompanied by an elevation of PGC1α expression (Figure 6A,B) and a suppression of myoblast differentiation (Figure 3A–C), while AMPK inactivation by the knockdown of CaMKK2 expression (Figure 4E) in C2C12 cells was accompanied by a reduce in PGC1α expression (Figure 6C,D) and an increase in myoblast differentiation (Figure 4G,H,I).…”