719-P: Inducible Estrogen-Related Receptor Alpha Overexpression Stimulates Skeletal Muscle Oxidative Metabolism and Improves Exercise Endurance in Mice

Abstract

Aerobic exercise promotes skeletal muscle insulin sensitivity by enhancing glucose uptake and storage and by increasing mitochondrial oxidative capacity. Exercise-responsive transcriptional pathways that regulate metabolism represent potential therapeutic targets to combat insulin resistance. The ERRα nuclear receptor regulates mitochondrial oxidative metabolism and is required for the skeletal muscle metabolic response to exercise. In the current study investigated whether ERRα expression is sufficient to drive exercise-induced adaptations in muscle. We generated conditional ERRα transgenic mice that overexpress human ERRα in a tetracycline-inducible and skeletal muscle-specific manner (ERRαMOEiHSA). Dox-induced ERRαMOEiHSA (versus non-induced) mice exhibited reddening in glycolytic muscles, a characteristic of oxidative muscle. Mitochondrial content was increased in these muscles, based on mtDNA quantitation and citrate synthase activity. Consistently, ERRα-overexpressing muscles had higher O2 consumption rates and increased glycogen content. To determine if these metabolic changes altered exercise capacity, run performance was assessed in untrained mice. Dox-induced ERRαMOEiHSA mice tested at constant speed (endurance test) or at increasing speeds (aerobic test) ran longer compared to controls. Post-run blood glucose levels were higher in both testing paradigms, which may be due to greater reliance on β-oxidation and higher basal glycogen stores in ERRα-expressing muscles. Using ChIP and reporters assays we showed that ERRα directly activates gene encoding the catalytic (Ppp1ca) and regulatory subunits (Ppp1r3c) of protein phosphatase 1, involved in hormonal and contractile-activity control of glycogen metabolism. Collectively, these results demonstrate that short-term ERRα activation promotes muscle metabolic adaptations and exercise performance similar to exercise training. Disclosure J. Li: None. A. Hamilton: None. J.M. Huss: None. Funding American Diabetes Association (1-18-IBS-103 to J.M.H.)