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

Abstract

The incidence of chronic disease is elevated in women after menopause. Increased expression of ESR1 (the gene that encodes the estrogen receptor alpha, ERα) 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 ERα in the regulation of mitochondrial function, metabolic homeostasis, and insulin action. We will provide evidence that muscle-selective targeting of ERα may be effective for the preservation of mitochondrial and metabolic health. Collectively published findings support a compelling role for ERα in the control of muscle metabolism via its regulation of mitochondrial function and quality control. Studies identifying ERα-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.

Keywords: estradiol action; estrogen receptor alpha; metabolic health; mitochondrial function; skeletal muscle metabolism.

Figure 1.

Molecular actions of ERα to activate or repress target genes by classical DNA binding, non-ERE genomic action, or non-genomic actions. ERE, estrogen response element in target gene promoters; P, phosphorylation; TF, transcription factor.

Figure 2.

ERα structure (A) and DNA binding at estrogen response elements (B). From (25).

Figure 3.

The impact of whole body ERα deletion on metabolic phenotypes. From (43–45,46–48).

Figure 4.

The impact of skeletal muscle-specific ERα deletion on metabolism and insulin sensitivity. Skeletal muscle-specific ERα knockout (MERKO) reduced mitochondrial DNA replication and impaired muscle oxidative metabolism, despite maintenance of mtDNA copy number. Increased PKA and reduced calcineurin activity promoted elongated, hyperfused mitochondria in MERKO muscle. The morphological changes coupled with an imbalanced PKA-calcineurin axis blunted mitochondrial fission signaling through DRP1 and impaired macroautophagy, both processes critical for mitochondrial turnover by mitophagy. Collectively, the retention of damaged mitochondria to the network was paralleled by increased ROS production, inflammation, and insulin resistance in skeletal muscle of MERKO mice. Findings implicate a critical role for ERα in the maintenance of muscle mitochondrial and metabolic health. From (81,113).

Figure 5.

Genomic and non-genomic targets of estradiol/ERα action on mitochondrial function and metabolism. ERα is shown to bind estrogen response elements (EREs) or tether other transcription factors in promoters of genes controlling mitochondrial function. Nongenomic ERα membrane signaling activates kinases that alter mitochondrial remodeling and activate oxidative metabolism. Whether ERα directly tethers to the outer mitochondrial membrane has yet to be shown. Recently, estradiol was found to localize to mitochondrial membranes (independently of receptor) altering membrane microviscosity and bioenergetic function (158).