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

Vicent Ribas; Brian G Drew; Zhenqi Zhou; Jennifer Phun; Nareg Y Kalajian; Teo Soleymani; Pedram Daraei; Kevin Widjaja; Jonathan Wanagat; Thomas Q de Aguiar Vallim; Amy H Fluitt; Steven Bensinger; Thuc Le; Caius Radu; Julian P Whitelegge; Simon W Beaven; Peter Tontonoz; Aldons J Lusis; Brian W Parks; Laurent Vergnes; Karen Reue; Harpreet Singh; Jean C Bopassa; Ligia Toro; Enrico Stefani; Matthew J. Watt; Simon Schenk; Thorbjorn C A Akerstrom; Meghan Kelly; Bente Klarlund Pedersen; Sylvia C Hewitt; Kenneth S Korach; Andrea L Hevener

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, Brian G Drew, Zhenqi Zhou, Jennifer Phun, Nareg Y Kalajian, Teo Soleymani, Pedram Daraei, Kevin Widjaja, Jonathan Wanagat, Thomas Q de Aguiar Vallim, Amy H Fluitt, Steven Bensinger, Thuc Le, Caius Radu, Julian P Whitelegge, Simon W Beaven, Peter Tontonoz, Aldons J Lusis, Brian W Parks, Laurent VergnesKaren Reue, Harpreet Singh, Jean C Bopassa, Ligia Toro, Enrico Stefani, Matthew J. Watt, Simon Schenk, Thorbjorn C A Akerstrom, Meghan Kelly, Bente Klarlund Pedersen, Sylvia C Hewitt, Kenneth S Korach, Andrea L Hevener

Department of Clinical Medicine

99 Citations (Scopus)

Abstract

Impaired estrogen receptor a (ERa) 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 ERa expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERa 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, ERa deficiency diminished mtDNA turnover by a balanced reduction inmtDNAreplication and degradation.Our findings indicate the retention of dysfunctionalmitochondria inMERKO muscle and implicate ERa in the preservation ofmitochondrial health and insulin sensitivity as a defense against metabolic disease in women.

Original language	English
Article number	334ra54
Journal	Science Translational Medicine
Volume	8
Issue number	334
Number of pages	23
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.aad3815
Publication status	Published - 13 Apr 2016

Keywords

Animals
Autophagy
DNA Replication
DNA, Mitochondrial
Dynamins
Estrogen Receptor alpha
Female
Gene Deletion
Glucose
Homeostasis
Humans
Insulin
Intracellular Signaling Peptides and Proteins
Lipid Metabolism
Mice
Mice, Knockout
Mitochondria, Muscle
Mitochondrial Dynamics
Muscle Proteins
Muscle, Skeletal
Organ Specificity
Oxidation-Reduction
Oxidative Stress
Reactive Oxygen Species
Signal Transduction
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Ribas, V., Drew, B. G., Zhou, Z., Phun, J., Kalajian, N. Y., Soleymani, T., Daraei, P., Widjaja, K., Wanagat, J., de Aguiar Vallim, T. Q., Fluitt, A. H., Bensinger, S., Le, T., Radu, C., Whitelegge, J. P., Beaven, S. W., Tontonoz, P., Lusis, A. J., Parks, B. W., ... Hevener, A. L. (2016). Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Science Translational Medicine, 8(334), [334ra54]. https://doi.org/10.1126/scitranslmed.aad3815

Ribas, V, Drew, BG, Zhou, Z, Phun, J, Kalajian, NY, Soleymani, T, Daraei, P, Widjaja, K, Wanagat, J, de Aguiar Vallim, TQ, Fluitt, AH, Bensinger, S, Le, T, Radu, C, Whitelegge, JP, Beaven, SW, Tontonoz, P, Lusis, AJ, Parks, BW, Vergnes, L, Reue, K, Singh, H, Bopassa, JC, Toro, L, Stefani, E, Watt, MJ, Schenk, S, Akerstrom, TCA, Kelly, M, Pedersen, BK, Hewitt, SC, Korach, KS & Hevener, AL 2016, 'Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females', Science Translational Medicine, vol. 8, no. 334, 334ra54. https://doi.org/10.1126/scitranslmed.aad3815

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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 a (ERa) 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 ERa expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERa 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, ERa deficiency diminished mtDNA turnover by a balanced reduction inmtDNAreplication and degradation.Our findings indicate the retention of dysfunctionalmitochondria inMERKO muscle and implicate ERa in the preservation ofmitochondrial health and insulin sensitivity as a defense against metabolic disease in women.",

keywords = "Animals, Autophagy, DNA Replication, DNA, Mitochondrial, Dynamins, Estrogen Receptor alpha, Female, Gene Deletion, Glucose, Homeostasis, Humans, Insulin, Intracellular Signaling Peptides and Proteins, Lipid Metabolism, Mice, Mice, Knockout, Mitochondria, Muscle, Mitochondrial Dynamics, Muscle Proteins, Muscle, Skeletal, Organ Specificity, Oxidation-Reduction, Oxidative Stress, Reactive Oxygen Species, Signal Transduction, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.",

author = "Vicent Ribas and Drew, {Brian G} and Zhenqi Zhou and Jennifer Phun and Kalajian, {Nareg Y} and Teo Soleymani and Pedram Daraei and Kevin Widjaja and Jonathan Wanagat and {de Aguiar Vallim}, {Thomas Q} and Fluitt, {Amy H} and Steven Bensinger and Thuc Le and Caius Radu and Whitelegge, {Julian P} and Beaven, {Simon W} and Peter Tontonoz and Lusis, {Aldons J} and Parks, {Brian W} and Laurent Vergnes and Karen Reue and Harpreet Singh and Bopassa, {Jean C} and Ligia Toro and Enrico Stefani and Watt, {Matthew J.} and Simon Schenk and Akerstrom, {Thorbjorn C A} and Meghan Kelly and Pedersen, {Bente Klarlund} and Hewitt, {Sylvia C} and Korach, {Kenneth S} and Hevener, {Andrea L}",

note = "Copyright {\textcopyright} 2016, American Association for the Advancement of Science.",

year = "2016",

month = apr,

day = "13",

doi = "10.1126/scitranslmed.aad3815",

language = "English",

volume = "8",

journal = "Science Translational Medicine",

issn = "1946-6234",

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T1 - Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females

AU - Ribas, Vicent

AU - Drew, Brian G

AU - Zhou, Zhenqi

AU - Phun, Jennifer

AU - Kalajian, Nareg Y

AU - Soleymani, Teo

AU - Daraei, Pedram

AU - Widjaja, Kevin

AU - Wanagat, Jonathan

AU - de Aguiar Vallim, Thomas Q

AU - Fluitt, Amy H

AU - Bensinger, Steven

AU - Le, Thuc

AU - Radu, Caius

AU - Whitelegge, Julian P

AU - Beaven, Simon W

AU - Tontonoz, Peter

AU - Lusis, Aldons J

AU - Parks, Brian W

AU - Vergnes, Laurent

AU - Reue, Karen

AU - Singh, Harpreet

AU - Bopassa, Jean C

AU - Toro, Ligia

AU - Stefani, Enrico

AU - Watt, Matthew J.

AU - Schenk, Simon

AU - Akerstrom, Thorbjorn C A

AU - Kelly, Meghan

AU - Pedersen, Bente Klarlund

AU - Hewitt, Sylvia C

AU - Korach, Kenneth S

AU - Hevener, Andrea L

PY - 2016/4/13

Y1 - 2016/4/13

N2 - Impaired estrogen receptor a (ERa) 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 ERa expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERa 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, ERa deficiency diminished mtDNA turnover by a balanced reduction inmtDNAreplication and degradation.Our findings indicate the retention of dysfunctionalmitochondria inMERKO muscle and implicate ERa in the preservation ofmitochondrial health and insulin sensitivity as a defense against metabolic disease in women.

AB - Impaired estrogen receptor a (ERa) 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 ERa expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERa 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, ERa deficiency diminished mtDNA turnover by a balanced reduction inmtDNAreplication and degradation.Our findings indicate the retention of dysfunctionalmitochondria inMERKO muscle and implicate ERa in the preservation ofmitochondrial health and insulin sensitivity as a defense against metabolic disease in women.

KW - Animals

KW - Autophagy

KW - DNA Replication

KW - DNA, Mitochondrial

KW - Dynamins

KW - Estrogen Receptor alpha

KW - Female

KW - Gene Deletion

KW - Glucose

KW - Homeostasis

KW - Humans

KW - Insulin

KW - Intracellular Signaling Peptides and Proteins

KW - Lipid Metabolism

KW - Mice

KW - Mice, Knockout

KW - Mitochondria, Muscle

KW - Mitochondrial Dynamics

KW - Muscle Proteins

KW - Muscle, Skeletal

KW - Organ Specificity

KW - Oxidation-Reduction

KW - Oxidative Stress

KW - Reactive Oxygen Species

KW - Signal Transduction

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.1126/scitranslmed.aad3815

DO - 10.1126/scitranslmed.aad3815

M3 - Journal article

C2 - 27075628

SN - 1946-6234

VL - 8

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 334

M1 - 334ra54

ER -

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

Abstract

Keywords

UN SDGs

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