Skeletal muscle action of estrogen receptor Œ± is critical for the maintenance of mitochondrial function and metabolic homeostasis in females
Authors: Jennifer Phun
Laurent Vergnes
Kenneth S Korach
Pedram Daraei
Bente K Pedersen
Julian P Whitelegge
Andrea L Hevener
Vicent Ribas
Jean C Bopassa
Peter Tontonoz
Teo Soleymani
Caius Radu
Thomas Q de Aguiar Vallim
Zhenqi Zhou
Karen Reue
Enrico Stefani
Aldons J Lusis
Sylvia C Hewitt
Amy H Fluitt
Meghan Kelly
Nareg Y Kalajian
Jonathan Wanagat
Kevin Widjaja
Thuc Le
Ligia Toro
Simon Schenk
Brian W Parks
Thorbjorn Akerstrom
Steven Bensinger
Matthew J Watt
Harpreet Singh
Simon W Beaven
Brian G Drew
Journal: Science Translational Medicine (2016)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Estrogen receptor Œ±; muscle; glucose intolerance; adiposity; oxidative metabolism
Affiliations: 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., Division of Geriatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA., Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA., 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., Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA., 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., 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., Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA., 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., Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA., Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA., Department of Physiology, Monash University, Clayton, Victoria 3800, Australia., Department of Orthopaedic Surgery, University of California, San Diego, La Jolla, CA 92093, USA., Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2200, Denmark., Receptor Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, Durham, NC 27709, USA., 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. .

Abstract:  Impaired estrogen receptor Œ± (ERŒ±) 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 ERŒ± expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERŒ± 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, ERŒ± 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 ERŒ± in the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women. 

Retracted: No

PubPeer comments:
 The conclusions of thiss article could not be reproduced by a recent article published in Molecular Metabolism; Iu00f1igo et al., 2020, doi: 10.1016 j.molmet.2019.12.010  In skeletal muscle, MERKO mice exhibit a reduction in insulin sensitivity that is associated with reduced mitochondrial fission, fusion dynamics, and mitochondrial calcium retention capacity [20]. In addition, using indirect measures of ROS emission, MERKO mice appear to have disruptions in ROS regulation, suggesting that ERu03b1 is critical for mitochondrial regulation in skeletal muscle [20]. **However, our data collected in the ERu03b1KOism mice contradict this concept. Specifically, we found no differences in the respiration kinetics between the ERu03b1KOism and WT mice when using fiber bundles to assess complex specific-driven mitochondrial respiration.** Furthermore, we found no genotype differences when assessing mitochondrial efficiency (ATP O ratio) in the fiber bundles; however, we found trends for differences in the same measure when using isolated mitochondria, which may suggest that the preparation had an effect on the outcome. Since the mitochondrial structure was maintained in the fiber bundle preparation, we feel it was a better representation of the in vivo environment. We also did not find differences in the H2O2 emitting potential between the genotypes. Thus, our data suggest that genetic ablation of ERu03b1 in the skeletal muscle of adult female mice does not affect skeletal muscle mitochondrial function and  Ribas et al. (2016) found that basal and maximal respiratory capacity, ATP synthesis, and palmitate oxidation rate were drastically (u223c50%) lower in C2C12 myotubes transduced with ERu03b1shRNA compared to scrambled shRNA myotubes [20]. **In contrast, we found that ERu03b1 knockdown in human myotubes isolated from adult healthy and obese insulin-resistant women resulted in minimal effects on OCR, which is unlikely to be physiologically meaningful as the calculated ATP production rates were largely unaffected by ERu03b1 knockdown (only u223c16u201318% in the healthy and OIR ERu03b1KD groups).** Together, the data suggest that the induced deletion of ERu03b1 in adult animals or human muscle cells has a minimal impact on mitochondrial respiratory function ,