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

Melissa R Iñigo; Adam J Amorese; Michael D Tarpey; Nicholas P Balestrieri; Keith G Jones; Daniel J Patteson; Kathryn C Jackson; Maria J Torres; Chien-Te Lin; Cody D Smith; Timothy D Heden; Shawna L McMillin; Luke A Weyrauch; Erin C Stanley; Cameron A Schmidt; Brita B Kilburg-Basnyat; Sky W Reece; Christine E Psaltis; Leslie A Leinwand; Katsuhiko Funai; Joseph M McClung; Kymberly M Gowdy; Carol A Witczak; Dawn A Lowe; P Darrell Neufer; Espen E Spangenburg

doi:10.1016/j.molmet.2019.12.010

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

Mol Metab. 2020 Apr:34:1-15. doi: 10.1016/j.molmet.2019.12.010. Epub 2019 Dec 23.

Authors

Melissa R Iñigo¹, Adam J Amorese¹, Michael D Tarpey¹, Nicholas P Balestrieri², Keith G Jones², Daniel J Patteson², Kathryn C Jackson³, Maria J Torres⁴, Chien-Te Lin², Cody D Smith¹, Timothy D Heden⁴, Shawna L McMillin⁴, Luke A Weyrauch⁴, Erin C Stanley⁴, Cameron A Schmidt¹, Brita B Kilburg-Basnyat⁵, Sky W Reece⁵, Christine E Psaltis⁵, Leslie A Leinwand⁶, Katsuhiko Funai⁷, Joseph M McClung⁸, Kymberly M Gowdy⁹, Carol A Witczak¹⁰, Dawn A Lowe¹¹, P Darrell Neufer⁷, Espen E Spangenburg¹²

Affiliations

¹ East Carolina University Brody School of Medicine, Department of Physiology, Greenville, NC, USA.
² East Carolina University, East Carolina Diabetes and Obesity Institute, Greenville, NC, USA.
³ University of Maryland, School of Public Health, Department of Kinesiology, College Park, MD, USA.
⁴ East Carolina University, Department of Kinesiology, Greenville, NC, USA.
⁵ East Carolina University Brody School of Medicine, Department of Pharmacology and Toxicology, Greenville, NC, USA.
⁶ University of Colorado, Department of Molecular, Cellular, and Developmental Biology and BioFrontiers Institute, Boulder, CO, USA.
⁷ East Carolina University Brody School of Medicine, Department of Physiology, Greenville, NC, USA; East Carolina University, East Carolina Diabetes and Obesity Institute, Greenville, NC, USA; East Carolina University, Department of Kinesiology, Greenville, NC, USA.
⁸ East Carolina University Brody School of Medicine, Department of Physiology, Greenville, NC, USA; East Carolina University, East Carolina Diabetes and Obesity Institute, Greenville, NC, USA.
⁹ East Carolina University, East Carolina Diabetes and Obesity Institute, Greenville, NC, USA; East Carolina University Brody School of Medicine, Department of Pharmacology and Toxicology, Greenville, NC, USA.
¹⁰ East Carolina University Brody School of Medicine, Department of Physiology, Greenville, NC, USA; East Carolina University, East Carolina Diabetes and Obesity Institute, Greenville, NC, USA; East Carolina University, Department of Kinesiology, Greenville, NC, USA; East Carolina University, Department of Biochemistry and Molecular Biology, Greenville, NC, USA.
¹¹ University of Minnesota, Department of Rehabilitation Medicine, Division of Rehabilitation Science and Division of Physical Therapy, Minneapolis, MN, USA.
¹² East Carolina University Brody School of Medicine, Department of Physiology, Greenville, NC, USA; East Carolina University, East Carolina Diabetes and Obesity Institute, Greenville, NC, USA; East Carolina University, Department of Kinesiology, Greenville, NC, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Estrogen Receptor alpha / deficiency
Estrogen Receptor alpha / metabolism*
Female
Humans
Insulin / metabolism*
Mice
Mice, Knockout
Mitochondria / metabolism*
Muscle, Skeletal / cytology
Muscle, Skeletal / metabolism*

Substances

ESR1 protein, human
Estrogen Receptor alpha
Insulin

Abstract

Publication types

MeSH terms

Substances

Grants and funding