. 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

Vicent Ribas¹, Brian G Drew¹, Zhenqi Zhou¹, Jennifer Phun¹, Nareg Y Kalajian¹, Teo Soleymani¹, Pedram Daraei¹, Kevin Widjaja¹, Jonathan Wanagat², Thomas Q de Aguiar Vallim³, Amy H Fluitt⁴, Steven Bensinger⁵, Thuc Le⁶, Caius Radu⁶, Julian P Whitelegge⁷, Simon W Beaven⁸, Peter Tontonoz⁸, Aldons J Lusis⁹, Brian W Parks¹⁰, Laurent Vergnes¹⁰, Karen Reue¹⁰, Harpreet Singh¹¹, Jean C Bopassa¹¹, Ligia Toro¹¹, Enrico Stefani¹¹, Matthew J Watt¹², Simon Schenk¹³, Thorbjorn Akerstrom¹⁴, Meghan Kelly¹⁴, Bente K Pedersen¹⁴, Sylvia C Hewitt¹⁵, Kenneth S Korach¹⁵, Andrea L Hevener¹⁶

Affiliations

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.

PMID: 27075628
PMCID: PMC4934679
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

Vicent Ribas et al. Sci Transl Med. 2016.

. 2016 Apr 13;8(334):334ra54.

doi: 10.1126/scitranslmed.aad3815.

Authors

Affiliations

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.

PMID: 27075628
PMCID: PMC4934679
DOI: 10.1126/scitranslmed.aad3815

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.

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Figures

**Fig. 1. Skeletal muscle ERαexpression correlates with metabolic health in females**
(A and B) Inverse relationship between Esr1 (natural variation in expression) versus adiposity and fasting insulin in women (n = 42; •, premenopausal n = 29, postmenopausal n = 13). AU, arbitrary units. (C and D) In 10 strains of female mice (•, n = 4 mice per indicated strain; age, 16 weeks), detected by Pearson’s correlation test, *P < 0.05 (Ppia, peptidylprolyl isomerase A housekeeping gene, for comparison]. (E) Muscle ESR1 expression in premenopausal women with (MetSyn) and without (Healthy) the MetSyn (n = 18 to 21 per group). (F and G) *Esr1* expression and representative immunoblots of ERα protein in skeletal muscle (quadriceps) from lean and *Lep^Ob* female mice (n = 6 per genotype; age, 12 weeks). Values are expressed as means ± SEM. All expression values were normalized to 1.0. Mean differences were detected by Student’s t test or analysis of variance (ANOVA); *P < 0.05, between-group comparison.

**Fig. 2. Muscle-specific ERαdeletion impairs glucose tolerance and muscle insulin action**
(A) ERα protein in muscle, liver, and adipose tissue from Control f/f and MERKO female mice (representative immunoblot, n = 3 per genotype). (B) *Esr1* expression in muscles [quadriceps, gastrocnemius, tibialis, soleus, and extensor digitorum longus (EDL)] from female MERKO and Control f/f (n = 8 mice per genotype) assessed by quantitative polymerase chain reaction (qPCR). WAT, white adipose tissue. (C) Relative comparison of *Esr2* and *Gper* (ER G protein– coupled receptor) expression in quadriceps from Control f/f and MERKO mice (n = 8 per genotype). P > 0.05. (D) Glucose tolerance [glucose tolerance test (GTT), 1000 mg/kg] in Control f/f and MERKO female mice (n = 6 to 8 per genotype; age, 24 to 26 weeks). *P < 0.05 detected by Student’s t test for AUC. (E) Skeletal muscle and hepatic insulin sensitivity (IS-GDR, insulin-stimulated glucose disposal rate; HGP, hepatic glucose production) assessed by glucose clamp for Control f/f and MERKO mice (n = 6 to 8 mice per genotype; age, 28 weeks). P < 0.05. (F) Ex vivo soleus muscle glucose uptake (fold change from basal; n = 6 mice per genotype). Values for insulin sensitivity are expressed as means ± SEM; *P < 0.05 detected by ANOVA. (G and H) GLUT4 transcript and protein levels in basal 6-hour–fasted quadriceps muscle from Control f/f and MERKO mice (n = 5 to 8 mice per genotype). (I and J) Representative immunoblots and densitometry of insulin signaling (IRS-1–associated p85 and p-Akt) in quadriceps and soleus muscle from glucose clamp and ex vivo glucose uptake studies, respectively, in Control f/f and MERKO mice (n = 6 mice per genotype per condition). P < 0.05. IP, immunoprecipitation; IB, immunoblot. (K to M) *Esr1* expression (K), ERα protein levels (L), and insulin signaling (M) (IRS-1^pY–and IRS-1–associated p85) in control (Scr) and Esr1-KD C2C12 myotubes (0 to 100 nM insulin; studies performed in triplicate). Densitometric analyses are expressed as means±SEM in arbitrary units normalized to 1.0; *P < 0.05, between-group differences; ^#P < 0.05, within-group treatment comparison, detected by Student’s t test and ANOVA.

**Fig. 3. Esr1 deletion promotes mitochondrial dysfunction, ROS production, and increased muscle inflammation**
(A) Heightened proinflammatory signaling (p-IKKβ and p-JNK 1/2) (fold change over baseline normalized to 1.0) in female MERKO muscle (n = 6 per genotype; left panel) and myotubes (n = 4 per condition; right panel), respectively. P < 0.05. (B) Bioactive lipid intermediates (TAG, triacylglycerol; ceramides) in quadriceps muscle from female Control f/f and MERKO mice (n = 6 muscles pergenotype). P < 0.05. (C and D) Palmitate oxidation and esterification as well as basal and maximal (stimulated using carbonylcyanide p-trifluoromethoxyphenylhydrazone, FCCP) oxygen consumption and ATP synthesis in control (Scr) versus Esr1-KDmyotubes (n = 6). (E) Citrate synthase activity in muscle harvested from Control f/f versus MERKO mice (n = 6 per genotype). (F) Quantitative reverse transcription PCR (RT-PCR) analyses of muscle from Control f/f versus MERKO mice (n = 6 per genotype). (G) Immunoblots and corresponding densitometry of mitochondrial electron transport complexes versus actin loading control in muscle from Control f/f versus MERKO mice (n = 6 per genotype). (H and I) H₂O₂ and O₂⁻ production in control (Scr) versus Esr1- KD C2C12 myocytes. (J) Gpx3 expression and protein in Control f/f versus MERKO muscle (n = 6 per genotype). (K) Oxidative stress–induced protein carbonylation in quadriceps muscle from Control f/f versus MERKO mice (n = 8 per genotype). (L) Calcium buffering capacity/mPTP opening in mitochondria isolated from Control f/f versus MERKO mice (n = 5 per genotype). All values are expressed as means ± SEM. Mean differences detected by Student’s t test and ANOVA where appropriate; *P < 0.05.

**Fig. 4. Impaired mtDNA replication and altered mitochondrial morphology in MERKO muscle**
(A) Muscle mtDNA content, expressed as a ratio of mtDNA/nuclear (nuc) DNA (n = 8 per group). (B) Muscle polymerase γ1 (Polγ1), Polγ2, and Polrmt expression. (C) mtDNA replication as measured by ²H₂O incorporation into newly synthesized mtDNA (deoxynucleosides, dG and dC) from Control f/f and MERKO mice (n = 6 per genotype). (D) Representative electron micrographs of soleus muscle from female Control f/f and MERKO mice, low- and high-magnification inset (IM, intramyofibrillar; SS, subsarcolemmal; scale bar, 1 µm). (E) Skeletal muscle intermyofibrillar mitochondrial area (n = 3 mice per genotype). (F) mtDNA mutation load was detected by random mutation capture (RMC) at basal (no treatment), after H₂O₂ treatment, and during recovery from H₂O₂ treatment. (G) mtDNA copy number at basal, after H₂O₂ treatment [in the presence of chloramphenicol (Chl) plus cycloheximide (Chx), and during recovery (in the presence of bafilomycin A₁ (BafA₁)]. All values are expressed as means ± SEM. Mean differences detected by Student’s t test and ANOVA where appropriate; *P < 0.05, between-genotype difference; ^#P < 0.05, within-genotype between treatment difference.

**Fig. 5**
Altered fission-fusion dynamics signaling in muscle from MERKO versus Control f/f mice. (A and B) DRP1^Ser637 phosphorylation (A) and DRP1 protein abundance (B) in enriched mitochondrial fractions from female Control f/f and MERKO quadriceps muscle (n = 4; representative immunoblots). Porin, control. (C) Protein-protein association between DRP1 and the phosphatase calcineurin (CnA) (above; n = 3 to 6 per genotype) in muscle from Control f/f and MERKO mice. (D and E) Calcineurin and PKA activity in quadriceps muscle from Control f/f and MERKO mice (n = 6 to 10 per genotype). (F to H) FIS1, OPA1, and MFN2 protein expression in muscle from Control f/f and MERKO mice relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression (control) (n = 6 per genotype). (I) Expression of Fis1, Mfn2, and Opa1 proteins in quadriceps muscle from female Control f/f and MERKO mice relative to Ppia expression (housekeeping gene control) (n = 6 per genotype). All values are expressed as means ± SEM. Mean differences detected by Student’s t test or ANOVA. *P < 0.05, difference between genotypes.

**Fig. 6. ERαdeficiency impairs mitophagic signaling in muscle**
(A to D) Expression of Park family members (Park2 and Park6) in muscle from female Control f/f and MERKO mice (n = 6 per genotype, A and B) and C2C12 myotubes (n = 6 per group, C and D). (E) CCCP-induced accumulation of full-length (63-kD) PINK1 protein in control (Scr) and Esr1-KD myotubes (n = 6 observations per condition). Veh, vehicle (control). (F) Densitometric analysis of LC3BII protein levels in muscle from fed and fasted (24 hours) female Control f/f versus MERKO mice relative to GAPDH expression (n = 6 mice per condition). (G and H) Confocal microscopy and flow cytometry analyses of dually labeled RFP-GFP-LC3B expressed in control (Scr) and Esr1-KD muscle cells during nutrient deprivation. (G) Reduced red punctae were observed in Esr1-KD muscle cells versus Scr-control, indicating diminished autolysosome formation (scale bar, 1 µm). (H) To more accurately quantify fluorescence signals in muscle cells, flow cytometry analyses were performed in triplicate during nutrient deprivation in the presence and absence of BafA¹ (10,000 live events quantified). Bars depicting quantification of dual signal represent autophagosome abundance (closed bars); a single RFP signal represents autolysosome abundance (gray bars); and cells showing loss of signal represent autophagosome degradation (hatched bars). (I to K) The impact of PKA inhibition (H89, 50 µM) on p62 protein levels and LC3B processing in ERα-replete myotubes in the absence or presence of CCCP (20 µM) to stimulate mitophagy (n = 3 per condition). (I) Representative immunoblots and (J and K) densitometric analyses. All values are expressed as means ± SEM. Mean differences detected by Student’s t test or ANOVA. *P < 0.05, difference between genotypes; ^#P < 0.05, within-group, between-treatment difference.

**Fig. 7. Impaired mitochondrial fission signaling through DRP1 impairs oxidative metabolism and induces insulin resistance**
(A) Insulin signaling (p-PDK1^S241, p-Akt^Ser473, and p-GSK3β) in C2C12 cells treated with the Drp1 selective inhibitor Mdivi-1 (50 µM) versus vehicle control (n = 6 per condition). (B) DRP1 protein levels in C2C12 myotubes relative to GAPDH expression, with Drp1-KD achieved by lentiviral delivery of shRNA (five clones tested, A to E). (C to E) Drp1-KD impaired insulin signaling in C2C12 myotubes (1, 10, and 100 nM insulin treatment). (F) Drp1-KD promoted accumulation of lipid in myotubes as determined by Oil Red O staining (n = 6 observations per genotype) (using two of the five shRNA lentiviral clones, C and D). Values are expressed as means ± SEM. Mean differences detected by Student’s t test or ANOVA. *P < 0.05, difference between genotypes.

**Fig. 8. Rcan1 is up-regulatedin ERα-deficient muscle and impairs insulin action**
(A and B) *Rcan1* gene expression is elevated in female MERKO muscle (n = 8 per genotype) and in human muscle from women with MetSyn (n = 8 per group) compared with respective controls. (C to E) Rcan1-1 and Rcan1-4 protein levels are elevated in MERKO muscle versus Control f/f (n = 8 per genotype). (F to J) Rcan1 overexpression by adenovirus (Ad) infection of C2C12 or primary myotubes impairs insulin action as shown by (G) reduced insulin–stimulated p-Akt^Ser473 (1, 10, and 100 nM insulin), (I) IRS-1–p85 association (50 nM insulin), and (J) 2-deoxyglucose uptake (n = 3 per condition in triplicate, 50 nM insulin). All values are expressed as means ± SEM. Mean differences detected by Student’s t test and ANOVA. *P < 0.05, difference between genotypes; ^#P<0.05 within-group, between-treatment difference. (K) Schematic overview of the MERKO phenotype. Skeletal muscle–specific ERα deletion reduced mtDNA replication and impaired muscle oxidative metabolism, despite maintenance of mtDNA copy number. Elevated Rcan1 and PKA reduced calcineurin activity levels, promoting elongated, hyperfused mitochondria in female MERKO muscle. The morphological changes coupled with an imbalanced PKA-calcineurin axis blunted mitochondrial fission signaling through DRP1 and impaired macroautophagy, processes critical for mitochondrial turnover, mitophagy. Unopposed fusion of the outer and inner mitochondrial membranes was permitted by increased expression of mitochondria-specific fusion proteins Mfn2 and OPA1. The retention of damaged mitochondria to the network was paralleled by increased ROS production, inflammation, and insulin resistance in skeletal muscle from female MERKO mice.

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

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

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