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

作者：Zhenqi Zhou, Timothy M. Moore, Alexander R. Strumwasser, Vicent Ribas, Hirotaka Iwasaki, Noelle Morrow, Alice Ma, Peter Tran, Jonathan Wanagat, Thomas Q. de Aguiar Vallim, Bethan L. Clifford, Zhengyi Zhang, Tamer Sallam, Brian W. Parks, Karen Reue, Orian S. Shirihai, Rebeca Acín‐Pérez, Marco Morselli, Matteo Pellegrini, Sushil K. Mahata, Frode Norheim, Mingqi Zhou, Marcus Seldin, Aldons J. Lusis, Cathy C. Lee, Mark O. Goodarzi, Jerome I. Rotter, Joshua Hansen, Ben Drucker, Tyler J. Sagendorf, Joshua Adkins, James Sanford, Francesco J. DeMayo, Sylvia C. Hewitt, Kenneth S. Korach, Andrea L. Hevener · 发表于：Cell Reports Medicine · 年份：2025 · DOI：10.1016/j.xcrm.2025.102116 · 被引用次数：7 · 研究领域：Mitochondrial Function and Pathology、RNA Research and Splicing、Adipose Tissue and Metabolism

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.