Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males

Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood, especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor α [ERα]) is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain-of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in the skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.

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Publication Details

Journal
Cell Reports Medicine
Published
2025-05-01
DOI
https://doi.org/10.1016/j.xcrm.2025.102116
Citations
6
Primary Topic
Mitochondrial Function and Pathology
Type
article
Field-Weighted Citation Impact
4.84

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article

Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males

Matteo Pellegrini, Andrea Lynn Hevener, Tamer Sallam, Karen Reue et al.
6 citations
Cell Reports Medicine
Mitochondrial Function and Pathology
4.84
article

Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males

Matteo Pellegrini, Andrea Lynn Hevener, Tamer Sallam, Karen Reue, Mark O. Goodarzi, Aldons Jake Lusis, Orian S. Shirihai, Frode Norheim, Cathy C. Lee, Joshua Hansen, Alexander R. Strumwasser, Marco Morselli, Vicent Ribas, James Sanford, Kenneth S. Korach, Jerome I. Rotter, Marcus Seldin, Thomas Q. de Aguiar Vallim, Brian W. Parks, Sushil K. Mahata, Zhenqi Zhou, Jonathan Wanagat, Rebeca Acín‐Pérez, Tyler J. Sagendorf, Bethan L. Clifford, Timothy M. Moore, Noelle Morrow, Joshua Adkins, Sylvia C. Hewitt, Zhengyi Zhang, Alice Ma, Peter Tran, Francesco J. DeMayo, Hirotaka Iwasaki, Mingqi Zhou, Ben Drucker
article en
6 citations

Abstract

Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood, especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor α [ERα]) is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain-of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in the skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.

Cell Reports MedicineVol. 6(5)
Cedars-Sinai Medical Center (US), Research Triangle Park Foundation (US), Pacific Northwest National Laboratory (US), University of California, Los Angeles (US), University of Oslo (NO), University of California, Irvine (US), UCLA Health (US), UCLA Medical Center (US), University of California San Diego (US), National Institute of Environmental Health Sciences (US), VA Greater Los Angeles Healthcare System (US)
UCSD-UCLA Diabetes Research Center, National Institutes of Health, University of California, San Diego, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, Clinical and Translational Science Institute, University of California, Los Angeles
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Openalex Percentile: Top 5%
Mitochondrial Function and Pathology
4.84
DOIOpen Access PDFOpenAlex
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