RT Journal Article SR Electronic T1 Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females JF Science Translational Medicine FD American Association for the Advancement of Science SP 334ra54 OP 334ra54 DO 10.1126/scitranslmed.aad3815 VO 8 IS 334 A1 Ribas, Vicent A1 Drew, Brian G. A1 Zhou, Zhenqi A1 Phun, Jennifer A1 Kalajian, Nareg Y. A1 Soleymani, Teo A1 Daraei, Pedram A1 Widjaja, Kevin A1 Wanagat, Jonathan A1 de Aguiar Vallim, Thomas Q. A1 Fluitt, Amy H. A1 Bensinger, Steven A1 Le, Thuc A1 Radu, Caius A1 Whitelegge, Julian P. A1 Beaven, Simon W. A1 Tontonoz, Peter A1 Lusis, Aldons J. A1 Parks, Brian W. A1 Vergnes, Laurent A1 Reue, Karen A1 Singh, Harpreet A1 Bopassa, Jean C. A1 Toro, Ligia A1 Stefani, Enrico A1 Watt, Matthew J. A1 Schenk, Simon A1 Akerstrom, Thorbjorn A1 Kelly, Meghan A1 Pedersen, Bente K. A1 Hewitt, Sylvia C. A1 Korach, Kenneth S. A1 Hevener, Andrea L. YR 2016 UL http://stm.sciencemag.org/content/8/334/334ra54.abstract AB Menopause ushers in a host of changes that range from unpleasant to undesirable. One undesirable shift is a loss of protection against insulin resistance, which brings with it a constellation of consequences in the form of chronic disease associated with metabolic dysfunction. Now, Ribas et al. investigate the mechanism underlying the postmenopausal chinks in a woman’s energy homeostasis armor.The estrogen receptor (ER) is known to participate in the preservation of mitochondrial health and insulin sensitivity in mice, but the precise tissue-specific mechanisms remain unclear. Because skeletal muscle is a main tissue responsible for insulin-stimulated glucose disposal, the authors first showed that ERα expression in muscle correlated with metabolic health in human females. They then created a muscle-specific ERα knockout (MERKO) mouse and found that glucose homeostasis was disrupted, fat accumulation increased, and mitochondrial function impaired. These findings imply that ERα action in skeletal muscle helps maintain mitochondrial function and metabolic homeostasis in females.Impaired estrogen receptor α (ERα) 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 ERα expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERα 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, ERα deficiency diminished mtDNA turnover by a balanced reduction in mtDNA replication and degradation. Our findings indicate the retention of dysfunctional mitochondria in MERKO muscle and implicate ERα in the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women.