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

• Published in: Science translational medicine Vol. 8; no. 334; p. 334ra54
• Main Authors: Ribas, Vicent, Drew, Brian G, Zhou, Zhenqi, Phun, Jennifer, Kalajian, Nareg Y, Soleymani, Teo, Daraei, Pedram, Widjaja, Kevin, Wanagat, Jonathan, de Aguiar Vallim, Thomas Q, Fluitt, Amy H, Bensinger, Steven, Le, Thuc, Radu, Caius, Whitelegge, Julian P, Beaven, Simon W, Tontonoz, Peter, Lusis, Aldons J, Parks, Brian W, Vergnes, Laurent, Reue, Karen, Singh, Harpreet, Bopassa, Jean C, Toro, Ligia, Stefani, Enrico, Watt, Matthew J, Schenk, Simon, Akerstrom, Thorbjorn, Kelly, Meghan, Pedersen, Bente K, Hewitt, Sylvia C, Korach, Kenneth S, Hevener, Andrea L
• Format: Journal Article
• Language: English
• Published: United States 13.04.2016
• Subjects: Animals; Autophagy - drug effects; Calcium-Binding Proteins; DNA Replication - drug effects; DNA, Mitochondrial - genetics; Dynamins - metabolism; Estrogen Receptor alpha - metabolism; Female; Gene Deletion; Glucose - metabolism; Homeostasis - drug effects; Humans; Insulin - pharmacology; Intracellular Signaling Peptides and Proteins - metabolism; Lipid Metabolism - drug effects; Mice; Mice, Knockout; Mitochondria, Muscle - drug effects; Mitochondria, Muscle - metabolism; Mitochondrial Dynamics - drug effects; Muscle Proteins - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Organ Specificity - drug effects; Oxidation-Reduction - drug effects; Oxidative Stress - drug effects; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aad3815

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.