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The alpha7 nicotinic acetylcholine receptor (\u03b17nAChR) is expressed in skeletal muscle, with an unknown role in muscle endurance. Here, we try to explore whether \u03b17nAChR could act as a potential therapeutic target for the treatment of muscle fatigue. Results showed that nicotine and PNU\u2010282987 (PNU), as nonspecific and specific agonists of \u03b17nAChR, respectively, could both significantly increase C57BL6\/J mice treadmill\u2010running time in a time\u2010 and dose\u2010dependent manner. The improvement effect of PNU on running time and ex vivo muscle fatigue index disappeared when \u03b17nAChR deletion. RNA sequencing revealed that the differential mRNAs affected by PNU were enriched in glycolysis\/gluconeogenesis signaling pathways. Further studies found that PNU treatment significantly elevates glycogen content and ATP level in the muscle tissues of \u03b17nAChR<jats:sup>+\/+<\/jats:sup> mice but not \u03b17nAChR<jats:sup>\u2010\/\u2010<\/jats:sup> mice. \u03b17nAChR activation specifically increased endogenous glycogen\u2010targeting protein orosomucoid (ORM) expression both in vivo skeletal muscle tissues and in vitro C2C12 skeletal muscle cells. In ORM1 deficient mice, the positive effects of PNU on running time, glycogen and ATP content, as well as muscle fatigue index, were abolished. Therefore, the activation of \u03b17nAChR could enhance muscle endurance via elevating endogenous anti\u2010fatigue protein ORM and might act as a promising therapeutic strategy for the treatment of muscle fatigue.<\/jats:p>","DOI":"10.1002\/jcb.30630","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T05:48:50Z","timestamp":1721195330000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Activation of \u03b17 Nicotinic Acetylcholine Receptor Improves Muscle Endurance by Upregulating Orosomucoid Expression and Glycogen Content in Mice"],"prefix":"10.1002","volume":"125","author":[{"given":"Fei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy, School of Pharmacy Second Military Medical University Shanghai 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