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The Impact of Skeletal Muscle Erα on Mitochondrial Function And Copyedited by: oup MINI REVIEW The Impact of Skeletal Muscle ERα on Mitochondrial Function and Metabolic Health Downloaded from https://academic.oup.com/endo/article-abstract/161/2/bqz017/5735479 by University of Southern California user on 19 February 2020 Andrea L. Hevener1,2, Vicent Ribas1, Timothy M. Moore1, and Zhenqi Zhou1 1David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes, and Hypertension, University of California, Los Angeles, California 90095; and 2Iris Cantor-UCLA Women’s Health Research Center, University of California, Los Angeles, California 90095 ORCiD numbers: 0000-0003-1508-4377 (A. L. Hevener). The incidence of chronic disease is elevated in women after menopause. Increased expression of ESR1 (the gene that encodes the estrogen receptor alpha, ERα) in muscle is highly associated with metabolic health and insulin sensitivity. Moreover, reduced muscle expression levels of ESR1 are observed in women, men, and animals presenting clinical features of the metabolic syndrome (MetSyn). Considering that metabolic dysfunction elevates chronic disease risk, including type 2 diabetes, heart disease, and certain cancers, treatment strategies to combat metabolic dysfunction and associated pathologies are desperately needed. This review will provide published work supporting a critical and protective role for skeletal muscle ERα in the regulation of mitochondrial function, metabolic homeostasis, and insulin action. We will provide evidence that muscle-selective targeting of ERα may be effective for the preservation of mitochondrial and metabolic health. Collectively published findings support a compelling role for ERα in the control of muscle metabolism via its regulation of mitochondrial function and quality control. Studies identifying ERα-regulated pathways essential for disease prevention will lay the important foundation for the design of novel therapeutics to improve metabolic health of women while limiting secondary complications that have historically plagued traditional hormone replacement interventions. (Endocrinology 161: 1–16, 2020) Key Words: estradiol action, estrogen receptor alpha, mitochondrial function, skeletal muscle metabolism, metabolic health or over 2 decades researchers have shown strong re- lationships between estrogen action and metabolic Abbreviations: AMP 5′, adenosine monophosphate; AMPK, 5′ adenosine F monophosphate-activated protein kinase; AF1, activation function 1; AF2, ac- health in women. Moreover, epidemiological reports in- tivation function 2; AP1, activation protein 1; COX1, mitochondrial cytochrome dicate that chronic disease incidence increases in women C oxidase 1; Cyp19, aromatase cytochrome p450; DBD, DNA binding domain; Drp1, dynamin related protein 1; E2, estradiol; ER, estrogen receptor; ERE, es- following menopause. Considering that menopause trogen response element; ERK, extracellular signal regulated kinase; Esr1, mouse occurs on average at age 51 (www.nia.nih.gov), and gene encoding the estrogen receptor alpha; FABP, fatty acid binding protein; FAT/ CD36, plasma membrane inducible long chain fatty acid translocase shown to that life expectancy has increased for white females to transport fatty acids to the mitochondria; Foxo, subgroup of the forkhead fam- ~81.1 years (National Vital Statistics Reports, 2019) (1), ily of transcription factors with a conserved forkhead box, DNA-binding domain; GPCR, G-protein coupled receptors; GPER, G protein-coupled estrogen receptor; women in the modern era are challenged with height- HRT, hormone replacement therapy; KD, knockdown; KO, knockout; LBD, lig- ened disease risk associated with increasing adiposity and binding domain; mt, mitochondrial; MAPK, mitogen-activated protein kin- ase; MEF2, myocyte enhancer factor 2; MERKO, muscle specific ERα knockout; and metabolic dysfunction for up to 3 decades of life. MetSyn, Metabolic Syndrome; Mfn, Mitochrondrial mitofusin; MNAR, modulator Although many researchers and clinicians have focused of nongenomic estrogen receptors; mt, mitochondrial; OPA1, optic atrophy 1; on the impact of replacement estrogens to ameliorate OVX, ovariectomized; PI3K, phosphoinositide 3-kinase; PKA, protein kinase A; PPAR, peroxisome proliferator activated receptor; PolG, heterodimeric enzyme polymerase gamma that controls mtDNA replication; Polg1, the gene that en- ISSN Online 1945-7170 codes the catalytic subunit of the mtDNA polymerase PolG; Rcan1, regulator of calcineurin 1, a phosphatase that (among many functions) controls Drp1 action Published by Oxford University Press on behalf of the Endocrine Society 2020. and mitochondrial fission; ROS, reactive oxygen species; RR, relative risk; SF1, Received 18 May 2019. Accepted 11 February 2020. steroidogenic factor 1; T2D, type 2 diabetes mellitus; TFAM, mitochondrial tran- First Published Online 13 February 2020. scription factor A; UCP, uncoupling protein Corrected and Typeset 13 February 2020. doi: 10.1210/endocr/bqz017 Endocrinology, February 2020, 161(2):1–16 https://academic.oup.com/endo 1 Copyedited by: oup 2 Hevener et al ERα on Mitochondrial Function and Metabolic Health Endocrinology, February 2020, 161(2):1–16 clinical symptoms and provide protective health benefit, that the ERα form, ERα (encoded by the gene ESR1), is an incomplete understanding of hormone action as an important target to combat metabolic dysfunction by well as estrogen receptor distribution and function has enhancing mitochondrial metabolism. contributed to our continued confusion and failure to advance therapeutic strategies to combat chronic Molecular Mechanisms of Estrogen Downloaded from https://academic.oup.com/endo/article-abstract/161/2/bqz017/5735479 by University of Southern California user on 19 February 2020 disease-associated pathologies for women. Receptor Action Regarding the benefits of exogenous hormone re- placement therapy (HRT) on diabetes risk after meno- Phylogenetic analysis of steroid receptors in basal verte- pause, large randomized clinical trials of postmenopausal brates and reconstruction of the sequences and functional estrogen-based HRT compared with placebo and pro- attributes of ancestral proteins led to the conclusion that spective cohort studies have shown reductions in fasting the primordial steroid receptor was an ER (9). Early glucose, insulin, and incidence of new-onset type 2 dia- studies in reproductive tissues investigating the actions betes (T2D) (2–7). Meta-analyses indicate a 30% lower of estradiol led to the paradigm of classical nuclear ERs relative risk (RR 0.7 [CI, 0.6–0.9]) of new-onset T2D in as ligand-activated transcription factors (10). ERs exist postmenopausal women following HRT compared with in two main forms, α and β, with multiple splice variants placebo (8). The mechanism by which HRT reduces T2D of unknown function. ERs exhibit tissue specificity in incidence in postmenopausal women is not yet known; expression and function, and determination of receptor however, molecular studies in rodents indicate that this specificity is an area of intense investigation (11). The protective effect may be achieved in part as a consequence classical, or genomic mechanism of ER action, describes of estrogen-induced insulin-sensitization. Considering a scenario whereby the ligand-activated ER dissociates that 75% to 85% of insulin-stimulated glucose disposal from its chaperone and binds as a dimer either directly is into skeletal muscle and since skeletal muscle typically to estrogen response elements (EREs) in target genes represents 30% to 40% of total body mass, we have fo- promoters or indirectly to AP-1 or SP-1 response elem- cused our efforts in understanding the effects of estradiol/ ents through protein tethering association with other estrogen receptor (ER) α action in this tissue. transcription factors to DNA (12) (Fig. 1). Overlap in Since insulin resistance and metabolic dysfunction are binding sites for E2-liganded ERα and ERβ is observed identified as major underpinnings in the pathobiology when receptors are expressed individually; however, of chronic diseases that plague our society, in this review when both ERs are present, few sites are shared. Each we will present studies related to the biological actions ER restricts the binding site occupancy of the other, of estradiol and estrogen receptors on mitochondrial with ERα typically dominating (13). Moreover, ligand- function in skeletal muscle, and the impact of these bio- activated ERs promote transcription in a cyclic fashion. logical actions exert on glucose homeostasis and insulin The repeated cycling of the receptor complex on and sensitivity. We will present basic research suggesting off target promoters in the presence of continuous E2 Figure 1. Molecular actions of ERα to activate or repress target genes by classical DNA binding, non-ERE genomic action, or non-genomic actions. ERE, estrogen response element in target gene promoters; P, phosphorylation; TF, transcription factor. Copyedited by: oup doi: 10.1210/endocr/bqz017 https://academic.oup.com/endo 3 stimulation may represent a mechanism of continuous sensing and adaptation to the external hormonal milieu to yield the appropriate transcriptional response (14). In addition to classical signaling, E2-ERα can act within seconds to minutes via extranuclear and Downloaded from https://academic.oup.com/endo/article-abstract/161/2/bqz017/5735479 by University of Southern California user on 19 February 2020 membrane-associated forms of the receptor (15) (Fig. 1). Membrane-associated
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