Muscle Specific ERa Overexpression Remodels Mitochondrial Cristae Architecture and Drives mtDNA Replication to Enhance Oxidative Metabolism

Reduced estrogen action is associated with obesity and insulin resistance in both males and females. However, the tissues and cell-specific targets essential for estrogen-mediated effects on metabolism remain inadequately understood. We have previously shown that muscle-specific estrogen-recpeptor alpha (ERa) knockout reduces metabolism and insulin sensitivity and blunts adaptations to exercise training. PURPOSE: The purpose of this study was to investigate the role of skeletal muscle ERa overexpression on whole-body metabolism, exercise capacity, and mitochondrial function. METHODS: A tamoxifen-inducible and muscle-specific ERa overexpression model (mERaOE) was generated in male mice. Body weight was tracked and a glucose tolerance test was used to measure insulin sensitivity. Baseline VO2 and voluntary wheel-running were recorded. Mitochondria-associated gene and protein levels were measured, as well as mitochondrial DNA copy number (mtDNAcn). Mitochondria morphology was imaged using electron microscopy. RESULTS: mERaOE mice were resistant to high-fat diet (HFD)-induced weight gain and decrements in glucose tolerance, compared to wild-type (WT). mERaOE also had greater daily wheel running volume. Mitochondria in mERaOE were smaller and more spherical with denser cristae architecture. Mitochondria gene expresson (CO1, CO3, ND1, ND4) were higher in mERaOE mice. Polg1 mRNA and Polg protein expression were higher in mERaOE mice which coincided with an increase in mtDNAcn. CONCLUSION: ERa is a critical regulator of muscle oxidative metabolism and insulin sensitivity. Specifically, ERa governs elemental aspects of mitochondrial biology including mtDNA replication and mitochondrial structure. ERa-induced improvements in mitochondrial function enhance metabolic health and recapitulate many of the molecular adaptations observed in muscle following exercise training, thus providing protection against the development of metabolic-related disease.