The Impact of Skeletal Muscle ERα on Mitochondrial Function and Metabolic Health

The incidence of chronic disease is elevated in women after menopause. Increased expression of ESR1 (the gene that encodes the estrogen receptor alpha, ER alpha) in muscle is highly associated with metabolic health and insulin sensitivity. Moreover, reduced muscle expression levels of ESR1 are observed in women, men, and animals presenting clinical features of the metabolic syndrome (MetSyn). Considering that metabolic dysfunction elevates chronic disease risk, including type 2 diabetes, heart disease, and certain cancers, treatment strategies to combat metabolic dysfunction and associated pathologies are desperately needed. This review will provide published work supporting a critical and protective role for skeletal muscle ER alpha in the regulation of mitochondrial function, metabolic homeostasis, and insulin action. We will provide evidence that muscle-selective targeting of ER alpha may be effective for the preservation of mitochondrial and metabolic health. Collectively published findings support a compelling role for ER alpha in the control of muscle metabolism via its regulation of mitochondrial function and quality control. Studies identifying ER alpha-regulated pathways essential for disease prevention will lay the important foundation for the design of novel therapeutics to improve metabolic health of women while limiting secondary complications that have historically plagued traditional hormone replacement interventions.