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Sci Transl Med. 2016 Apr 13;8(334):334ra54. doi: 10.1126/scitranslmed.aad3815.

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

Author information

1
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.
2
Division of Geriatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
3
Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
4
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.
5
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
6
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.
7
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.
8
Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
9
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.
10
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
11
Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
12
Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
13
Department of Orthopaedic Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
14
Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2200, Denmark.
15
Receptor Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC 27709, USA.
16
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.

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.

PMID:
27075628
PMCID:
PMC4934679
DOI:
10.1126/scitranslmed.aad3815
[Indexed for MEDLINE]
Free PMC Article

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