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Existing countermeasures have largely failed to preserve muscle size and function, underscoring the need for novel therapeutic strategies. We recently identified pipecolic acid and succinate (PAS) as microbial\u2010derived exerkines that prevent disuse\u2010induced atrophy and preserve muscle function in adult mice. Here, we tested whether PAS similarly protects aged muscle. Aged male and female mice received vehicle (VEH) or PAS via drinking water during 10\u2009days of unilateral hindlimb casting. PAS did not preserve soleus or plantaris mass, but casted gastrocnemius mass was greater in PAS\u2010 than VEH\u2010treated mice irrespective of sex. PAS attenuated the loss of soleus and plantaris fiber cross\u2010sectional area, with the largest effect in the female soleus. PAS enhanced soleus contractile function in a sex\u2010specific manner: females exhibited greater absolute force and rate of force development, and males greater fatigue resistance. Gastrocnemius citrate synthase activity was greater in PAS\u2010 than VEH\u2010treated females but not males, mirroring the female\u2010specific preservation of soleus fiber size and function. These sexually dimorphic responses highlight microbial\u2010derived metabolites as a novel therapeutic avenue for preserving muscle function during disuse in aging and underscore the importance of considering sex as a biological variable.<\/jats:p>","DOI":"10.14814\/phy2.71137","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:41:16Z","timestamp":1791268876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microbial\u2010derived Exerkines preserve muscle size and function during disuse in aged mice in a sex\u2010dependent manner"],"prefix":"10.14814","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2022-9859","authenticated-orcid":false,"given":"Jainil","family":"Daredia","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine University of Kentucky  Lexington Kentucky USA"},{"name":"Center for Muscle Biology, College of Health Sciences University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor R.","family":"Valentino","sequence":"additional","affiliation":[{"name":"Buck Institute for Research on Aging  Novato California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Ismaeel","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine Auburn University  Auburn Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine University of Kentucky  Lexington Kentucky USA"},{"name":"Center for Muscle Biology, College of Health Sciences University of Kentucky  Lexington Kentucky USA"},{"name":"Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"McCarthy","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine University of Kentucky  Lexington Kentucky USA"},{"name":"Center for Muscle Biology, College of Health Sciences University of Kentucky  Lexington Kentucky USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0228-1750","authenticated-orcid":false,"given":"Benjamin I.","family":"Burke","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine University of Kentucky  Lexington Kentucky USA"},{"name":"Center for Muscle Biology, College of Health Sciences University of Kentucky  Lexington Kentucky 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