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Acid-sensing ion channels (ASICs) within muscle afferents are activated by H<jats:sup>+<\/jats:sup> and other chemicals and have been shown to play a role in various chronic muscle pain conditions. Here, we further defined the role of ASICs in IEIP, and also tested if ASIC3 is required for DOMS. After undergoing exhaustive treadmill exercise, exercise-induced muscle pain was assessed in wild-type (WT) and <jats:italic>ASIC3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice at baseline via muscle withdrawal threshold (MWT), immediately, and 24\u2005h after exercise. Locomotor movement, grip strength, and repeat exercise performance were tested at baseline and 24\u2005h after exercise to evaluate DOMS. We found that <jats:italic>ASIC3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> had similar baseline muscle pain, locomotor activity, grip strength, and exercise performance as WT mice. WT showed diminished MWT immediately after exercise indicating they developed IEIP, but <jats:italic>ASIC3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice did not. At 24\u2005h after baseline exercise, both <jats:italic>ASIC3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and WT had similarly lower MWT and grip strength, however, <jats:italic>ASIC3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> displayed significantly lower locomotor activity and repeat exercise performance at 24\u2005h time points compared to WT. In addition, <jats:italic>ASIC3<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice had higher muscle injury as measured by serum lactate dehydrogenase and creatine kinase levels at 24\u2005h after exercise. These results show that ASIC3 is required for IEIP, but not DOMS, and in fact might play a protective role to prevent muscle injury associated with strenuous exercise.<\/jats:p>","DOI":"10.3389\/fpain.2023.1215197","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T23:03:59Z","timestamp":1695164639000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["ASIC3 plays a protective role in delayed-onset muscle soreness (DOMS) through muscle acid sensation during exercise"],"prefix":"10.3389","volume":"4","author":[{"given":"Tahsin","family":"Khataei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Benson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,9,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1080\/14737175.2016.1179582","article-title":"Exercise-induced neuroprotective effects on neurodegenerative diseases: the key role of trophic factors","volume":"16","author":"Campos","year":"2016","journal-title":"Expert Rev Neurother"},{"key":"B2","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1161\/CIRCULATIONAHA.109.881888","article-title":"Exercise rehabilitation in peripheral artery disease: functional impact and mechanisms of benefits","volume":"123","author":"Hamburg","year":"2011","journal-title":"Circulation"},{"key":"B3","doi-asserted-by":"publisher","first-page":"3831972","DOI":"10.1155\/2017\/3831972","article-title":"Exercise modifies the gut microbiota with positive health effects","volume":"2017","author":"Monda","year":"2017","journal-title":"Oxid Med Cell Longev"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e0210418","DOI":"10.1371\/journal.pone.0210418","article-title":"Exercise-induced hypoalgesia: a meta-analysis of exercise dosing for the treatment of chronic pain","volume":"14","author":"Polaski","year":"2019","journal-title":"PLos One"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2132039","DOI":"10.1155\/2018\/2132039","article-title":"Effects of exercise training combined with increased physical activity to prevent chronic pain in community-dwelling older adults: a preliminary randomized controlled trial","volume":"2018","author":"Hirase","year":"2018","journal-title":"Pain Res Manag"},{"key":"B6","first-page":"203","article-title":"Exercise-induced muscle pain, soreness, and cramps","volume":"34","author":"Miles","year":"1994","journal-title":"J Sports Med Phys Fitness"},{"key":"B7","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1249\/00005768-198412000-00002","article-title":"Mechanisms of exercise-induced delayed onset muscular soreness: a brief review","volume":"16","author":"Armstrong","year":"1984","journal-title":"Med Sci Sports Exerc"},{"key":"B8","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1080\/02640419608727714","article-title":"Muscle tenderness and peak torque changes after downhill running following a prior bout of isokinetic eccentric exercise","volume":"14","author":"Eston","year":"1996","journal-title":"J Sports Sci"},{"key":"B9","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1007\/s11916-003-0060-y","article-title":"Induction and assessment of muscle pain, referred pain, and muscular hyperalgesia","volume":"7","author":"Graven-Nielsen","year":"2003","journal-title":"Curr Pain Headache Rep"},{"key":"B10","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1055\/a-0810-3516","article-title":"Advances in delayed-onset muscle soreness (DOMS) - 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