Estrogen receptor-α in female skeletal muscle is not required for regulation of muscle insulin sensitivity and mitochondrial regulation

Abstract

Objective: Estrogen receptor-α (ERα) is a nuclear receptor family member thought to substantially contribute to the metabolic regulation of skeletal muscle. However, previous mouse models utilized to assess the necessity of ERα signaling in skeletal muscle were confounded by altered developmental programming and/or influenced by secondary effects, making it difficult to assign a causal role for ERα. The objective of this study was to determine the role of skeletal muscle ERα in regulating metabolism in the absence of confounding factors of development.

Methods: A novel mouse model was developed allowing for induced deletion of ERα in adult female skeletal muscle (ERαKO^ism). ERαshRNA was also used to knockdown ERα (ERαKD) in human myotubes cultured from primary human skeletal muscle cells isolated from muscle biopsies from healthy and obese insulin-resistant women.

Results: Twelve weeks of HFD exposure had no differential effects on body composition, VO₂, VCO₂, RER, energy expenditure, and activity counts across genotypes. Although ERαKO^ism mice exhibited greater glucose intolerance than wild-type (WT) mice after chronic HFD, ex vivo skeletal muscle glucose uptake was not impaired in the ERαKO^ism mice. Expression of pro-inflammatory genes was altered in the skeletal muscle of the ERαKO^ism, but the concentrations of these inflammatory markers in the systemic circulation were either lower or remained similar to the WT mice. Finally, skeletal muscle mitochondrial respiratory capacity, oxidative phosphorylation efficiency, and H₂O₂ emission potential was not affected in the ERαKO^ism mice. ERαKD in human skeletal muscle cells neither altered differentiation capacity nor caused severe deficits in mitochondrial respiratory capacity.

Conclusions: Collectively, these results suggest that ERα function is superfluous in protecting against HFD-induced skeletal muscle metabolic derangements after postnatal development is complete.

Keywords: Estrogen receptor-alpha; Inflammation; Insulin sensitivity; Metabolism; Mitochondrial function; Skeletal muscle.