@article{3a3c8e4545c74a5f86b97c8b6f3bee82,
title = "Innately expressed estrogen-related receptors in the skeletal muscle are indispensable for exercise fitness",
abstract = "Transcriptional determinants in the skeletal muscle that govern exercise capacity, while poorly defined, could provide molecular insights into how exercise improves fitness. Here, we have elucidated the role of nuclear receptors, estrogen-related receptor alpha and gamma (ERRα/γ) in regulating myofibrillar composition, contractility, and exercise capacity in skeletal muscle. We used muscle-specific single or double (DKO) ERRα/γ knockout mice to investigate the effect of ERRα/γ deletion on muscle and exercise parameters. Individual knockout of ERRα/γ did not have a significant impact on the skeletal muscle. On the other hand, DKO mice exhibit pale muscles compared to wild-type (WT) littermates. RNA-seq analysis revealed a predominant decrease in expression of genes linked to mitochondrial and oxidative metabolism in DKO versus WT muscles. DKO muscles exhibit marked repression of oxidative enzymatic capacity, as well as mitochondrial number and size compared to WT muscles. Mitochondrial function is also impaired in single myofibers isolated from DKO versus WT muscles. In addition, mutant muscles exhibit reduced angiogenic gene expression and decreased capillarity. Consequently, DKO mice have a significantly reduced exercise capacity, further reflected in poor fatigue resistance of DKO mice in in vivo contraction assays. These results show that ERRα and ERRγ together are a critical link between muscle aerobic capacity and exercise tolerance. The ERRα/γ mutant mice could be valuable for understanding the long-term impact of impaired mitochondria and vascular supply on the pathogenesis of muscle-linked disorders.",
keywords = "angiogenesis, estrogen-related receptors, exercise, mitochondria, skeletal muscle",
author = "Sopariwala, {Danesh H.} and Rios, {Andrea S.} and Guangsheng Pei and Anirban Roy and {Tomaz da Silva}, Meiricris and {Thi Thu Nguyen}, Hao and Addison Saley and {Van Drunen}, Rachel and Anastasia Kralli and Kristin Mahan and Zhongming Zhao and Ashok Kumar and Narkar, {Vihang A.}",
note = "Funding Information: The ERRα floxed mice were kindly provided by Janice Huss (City of Hope). ERRγ floxed mice were obtained from ICS (Strasburg, France). Both ERRα and ERRγ floxed mice were originally generated at ICS (Strasburg, France), and were used in this study under the auspices of material transfer agreement between ICS and UTHealth. We would like to thank Dr. Zhengmei Mao in the UTHealth Institute of Molecular Medicine microscopy core facility for assistance with microscopy, imaging, and analysis. We would like to thank Mr. James P. Barrish at Department of Pathology, Texas Children's Hospital, Houston, TX for performing transmission electron microscopy of skeletal muscle samples. Funding Information: This research was supported in parts by NIH/NHLBI grants (R01HL152108, R01HL129191), American Heart Association transformational research award (20TPA35410038), and Hamman Foundation Endowment in Cardiovascular Research to V.A.N, as well as NIH/NIAMS grant (RO1AR059810) to Ashok Kumar. D.H.S. was supported by a post‐doctoral fellowship from American Heart Association (19POST34380771). Z.Z. was partially supported by the Cancer Prevention and Research Institute of Texas grants (CPRIT RP180734 and RP210045). The funders had no role in the study design, data collection, and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.",
year = "2023",
month = feb,
doi = "10.1096/fj.202201518R",
language = "English (US)",
volume = "37",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "2",
}