title: Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females.
abstract: 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.
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Vicent
authors.initials: V
authors.lastname: Ribas
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Drew
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Phun
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Nareg Y
authors.initials: NY
authors.lastname: Kalajian
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Teo
authors.initials: T
authors.lastname: Soleymani
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Daraei
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Widjaja
authors.affiliation: Division of Geriatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wanagat
authors.affiliation: Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Thomas Q
authors.initials: TQ
authors.lastname: de Aguiar Vallim
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Fluitt
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Bensinger
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Ahmanson Translational Imaging Division, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Thuc
authors.initials: T
authors.lastname: Le
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Ahmanson Translational Imaging Division, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Caius
authors.initials: C
authors.lastname: Radu
authors.affiliation: Pasarow Mass Spectrometry Laboratory and Neuropsychiatric Institute-Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Julian P
authors.initials: JP
authors.lastname: Whitelegge
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Beaven
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.affiliation: Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Parks
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.affiliation: Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Singh
authors.affiliation: Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Bopassa
authors.affiliation: Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Ligia
authors.initials: L
authors.lastname: Toro
authors.affiliation: Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Enrico
authors.initials: E
authors.lastname: Stefani
authors.affiliation: Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.affiliation: Department of Orthopaedic Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Schenk
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Thorbjorn
authors.initials: T
authors.lastname: Akerstrom
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Meghan
authors.initials: M
authors.lastname: Kelly
authors.affiliation: Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2200, Denmark.
authors.forename: Bente K
authors.initials: BK
authors.lastname: Pedersen
authors.affiliation: Receptor Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC 27709, USA.
authors.forename: Sylvia C
authors.initials: SC
authors.lastname: Hewitt
authors.affiliation: Receptor Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC 27709, USA.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Korach
authors.affiliation: Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. UCLA Iris Cantor Women's Health Research Center, Los Angeles, CA 90095, USA. ahevener@mednet.ucla.edu.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002135:Calcium-Binding Proteins; D004261:DNA Replication / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics; D034281:Dynamins / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009928:Organ Specificity / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002135:Calcium-Binding Proteins; D004272:DNA, Mitochondrial; C511512:DSCR1 protein, mouse; D047628:Estrogen Receptor alpha; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D017382:Reactive Oxygen Species; C486391:Dnm1l protein, mouse; D034281:Dynamins; D005947:Glucose