{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:00:00Z","timestamp":1785438000681,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,11]]},"group-title":"Physiology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01HL152108"],"award-info":[{"award-number":["R01HL152108"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["23CDA1054599"],"award-info":[{"award-number":["23CDA1054599"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01LM012806"],"award-info":[{"award-number":["R01LM012806"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U01AG079847"],"award-info":[{"award-number":["U01AG079847"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30CA016672"],"award-info":[{"award-number":["P30CA016672"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["RP240610"],"award-info":[{"award-number":["RP240610"]}],"id":[{"id":"https:\/\/ror.org\/0003xa228","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RP210045)"],"award-info":[{"award-number":["RP210045)"]}],"id":[{"id":"https:\/\/ror.org\/0003xa228","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01hg94g33","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Estrogen-related receptor gamma (ERR\u03b3) drives an exercise mimicking aerobic gene program in the skeletal muscle that could be beneficial in aging. We have investigated the effect of chronic ERR\u03b3 activation on minimizing sarcopenia.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Experiments were performed in muscle specific ERR\u03b3 transgenic (TG) mice and wild type (WT) littermates, at young (4-5 months) and old (24-26 months) age. In the skeletal muscle, global gene expression changes, as well as myofiber histological changes in fiber type, size, vascular supply and neuromuscular junction (NMJ), and mitochondrial content were measured. Functional analysis was performed using in vivo muscle contraction assay. Exercise fitness was measured using treadmill sprint and endurance test. Gene and protein expression was measured using QPCR and Westerns, respectively.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    ERR\u03b3 activates a pan-ERR aerobic program in the skeletal muscle to increase expression of 574 genes including ERR\u03b1, mitochondrial homeostasis (e.g. Mfn1, Opa1, Drp1, Fis1, and Tfam), vascularization (e.g. Vegfa, Angpt1, Fgf1), and neuromuscular junction (NMJ) (e.g. Nrp1, Aspa, Ptprm, Cxcr4), simultaneously suppressing the expression of atrophy related genes (e.g. Atrogin1, Traf6, Nedd4, Myd88, p21). ERR\u03b3 increases mitochondrial content [Mitochondrial area: old TG vs. WT, 2.00 fold; young TG vs. WT, 1.32 fold], oxidative capacity [NADH-TR activity: old TG vs. WT, 1.20 fold; young TG vs. WT, 1.22 fold] and myofiber type [2a: old TG (687\u00b1258) vs. WT (252\u00b171); young TG (797\u00b1168) vs. WT (440\u00b176); 2x: old TG 1348\u00b187 vs. WT 976\u00b1219; young TG 1131\u00b1135 vs. WT 936\u00b184; 2b: old TG (798\u00b1103) vs. WT (1628\u00b1148); young TG (967\u00b1133) vs. WT (1623\u00b1189)], and capillarity [capillary-to-myofiber ratio: old TG (3.25\u00b10.19) vs. WT (2.41\u00b10.16); young TG (3.41\u00b10.21) vs WT (2.59\u00b10.2)] and [NMJ number [old TG (67\u00b18) vs. WT (40\u00b19); young TG (77\u00b111) vs WT (77\u00b17)], mitigating age-related loss of NMJ and myofiber cross-sectional area [old TG (1570\u00b1147\u00b5m\n                    <jats:sup>2)<\/jats:sup>\n                    vs. WT (1692.5\u00b1208\u00b5m\n                    <jats:sup>2<\/jats:sup>\n                    ) WT; young TG (1828.15\u00b1132.8\u00b5m\n                    <jats:sup>2<\/jats:sup>\n                    ) vs. WT (2109.7\u00b1296.8\u00b5m\n                    <jats:sup>2<\/jats:sup>\n                    )]. ERR\u03b3 overexpression preserves muscle contractility with aging [Fatigue resistance: 22.72% reduction in force in old vs. young WT; 3.11% reduction in force between old vs. young TG]. Furthermore, ERR\u03b3 maintains exercise fitness in old mice [Running: old TG (2964.52\u00b1405m) vs. old WT (910.75\u00b16034m); young TG (2232.43\u00b1193.64m) vs. young WT (1366.76\u00b160.76m)].\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>ERR\u03b3 drives a pan-ERR and counter sarcopenic gene program enhancing oxidative myofiber type, mitochondrial content, vasculature, and NMJ in aging muscle. Consequently, ERR\u03b3 minimizes myofiber atrophy, preserves contractility, and improves exercise fitness in old mice. Therefore, ERRs are potential translational targets for combating sarcopenia.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.07.730739","type":"posted-content","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T14:40:21Z","timestamp":1781188821000},"source":"Crossref","is-referenced-by-count":0,"title":["Estrogen-related receptor signaling counters sarcopenia and preserves exercise fitness in naturally aged mice"],"prefix":"10.64898","author":[{"given":"DH","family":"Sopariwala","sequence":"first","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School, UTHealth, Houston, TX, 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"DeBruine","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School, UTHealth, Houston, TX, 77030"},{"name":"MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Poliakova","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School, UTHealth, Houston, TX, 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Mosa","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School, UTHealth, Houston, TX, 77030"},{"name":"MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Mann","sequence":"additional","affiliation":[{"name":"Department of Biology and Biochemistry, College of Natural Sciences and Mathematics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Citu","family":"Citu","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, McWilliams School of Biomedical Informatics, UTHealth, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, McWilliams School of Biomedical Informatics, UTHealth, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Kumar","sequence":"additional","affiliation":[{"name":"Institute of Muscle Biology & Cachexia, College of Pharmacy, University of Houston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"VA","family":"Narkar","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School, UTHealth, Houston, TX, 77030"},{"name":"MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061314100894000_2026.06.07.730739v1.1","unstructured":"Kirk, B. , et al., The Conceptual Definition of Sarcopenia: Delphi Consensus from the Global Leadership Initiative in Sarcopenia (GLIS). 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