Ontology highlight
ABSTRACT: Objective
Estrogen receptor-? (ER?) 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 ER? 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 ER?. The objective of this study was to determine the role of skeletal muscle ER? in regulating metabolism in the absence of confounding factors of development.Methods
A novel mouse model was developed allowing for induced deletion of ER? in adult female skeletal muscle (ER?KOism). ER?shRNA was also used to knockdown ER? (ER?KD) 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 ER?KOism mice exhibited greater glucose intolerance than wild-type (WT) mice after chronic HFD, ex vivo skeletal muscle glucose uptake was not impaired in the ER?KOism mice. Expression of pro-inflammatory genes was altered in the skeletal muscle of the ER?KOism, 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 ER?KOism mice. ER?KD in human skeletal muscle cells neither altered differentiation capacity nor caused severe deficits in mitochondrial respiratory capacity.Conclusions
Collectively, these results suggest that ER? function is superfluous in protecting against HFD-induced skeletal muscle metabolic derangements after postnatal development is complete.
SUBMITTER: Inigo MR
PROVIDER: S-EPMC6994285 | biostudies-literature | 2020 Apr
REPOSITORIES: biostudies-literature
Iñigo Melissa R MR Amorese Adam J AJ Tarpey Michael D MD Balestrieri Nicholas P NP Jones Keith G KG Patteson Daniel J DJ Jackson Kathryn C KC Torres Maria J MJ Lin Chien-Te CT Smith Cody D CD Heden Timothy D TD McMillin Shawna L SL Weyrauch Luke A LA Stanley Erin C EC Schmidt Cameron A CA Kilburg-Basnyat Brita B BB Reece Sky W SW Psaltis Christine E CE Leinwand Leslie A LA Funai Katsuhiko K McClung Joseph M JM Gowdy Kymberly M KM Witczak Carol A CA Lowe Dawn A DA Neufer P Darrell PD Spangenburg Espen E EE
Molecular metabolism 20191223
<h4>Objective</h4>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 ...[more]