Skeletal muscle action of estrogen receptor a is critical for the maintenance of mitochondrial function and metabolic homeostasis in females

Vicent Ribas, Brian G. Drew, Zhenqi Zhou, Jennifer Phun, Nareg Y. Kalajian, Teo Soleymani, Pedram Daraei, Kevin Widjaja, Jonathan Wanagat, Thomas Q.De Aguiar Vallim, Amy H. Fluitt, Steven Bensinger, Thuc Le, Caius Radu, Julian P. Whitelegge, Simon W. Beaven, Peter Tontonoz, Aldons J. Lusis, Brian W. Parks, Laurent VergnesKaren Reue, Harpreet Singh, Jean C Bopassa, Ligia Toro, Enrico Stefani, Matthew J. Watt, Simon Schenk, Thorbjorn Akerstrom, Meghan Kelly, Bente K. Pedersen, Sylvia C. Hewitt, Kenneth S. Korach, Andrea L. Hevener

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

Impaired estrogen receptor a (ERa) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERa expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERa knockout (MERKO) mice. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in MERKO mice. Aberrant mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial fission dynamics, driven by imbalanced protein kinase A-regulator of calcineurin 1-calcineurin signaling through dynamin-related protein 1, tracked with reduced oxidative metabolism in MERKO muscle. Although muscle mitochondrial DNA (mtDNA) abundance was similar between the genotypes, ERa deficiency diminished mtDNA turnover by a balanced reduction inmtDNAreplication and degradation.Our findings indicate the retention of dysfunctionalmitochondria inMERKO muscle and implicate ERa in the preservation ofmitochondrial health and insulin sensitivity as a defense against metabolic disease in women.

Original languageEnglish (US)
Article number334ra54
JournalScience Translational Medicine
Volume8
Issue number334
DOIs
StatePublished - Apr 13 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ribas, V., Drew, B. G., Zhou, Z., Phun, J., Kalajian, N. Y., Soleymani, T., Daraei, P., Widjaja, K., Wanagat, J., Vallim, T. Q. D. A., Fluitt, A. H., Bensinger, S., Le, T., Radu, C., Whitelegge, J. P., Beaven, S. W., Tontonoz, P., Lusis, A. J., Parks, B. W., ... Hevener, A. L. (2016). Skeletal muscle action of estrogen receptor a is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Science Translational Medicine, 8(334), [334ra54]. https://doi.org/10.1126/scitranslmed.aad3815