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While skeletal muscle dysfunction is central to frailty, most preclinical models focus on basal function and place less emphasis on physiological stress responses. Here, we examined the influence of increased indices of frailty on skeletal muscle resistance and resilience using a physiologically relevant model of downhill running stress. Aged female C57BL\/6JN mice (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200947;\u2009&gt;\u200917\u00a0months) were stratified into Low (\u2264\u20091 frailty markers) or High (\u2265\u20092 frailty markers) groups based on their number of positive frailty markers. Mice were subsequently randomized to undergo two bouts of downhill running or remain cage sedentary. Twenty-four hours later, contractile function was assessed ex vivo in the extensor digitorum longus (EDL) and soleus muscles. RNA was extracted from the gastrocnemius of randomly selected samples and analyzed by RNA sequencing. Despite comparable specific tetanic force, High frailty marked mice exhibited greater fatiguability and impaired recovery kinetics in the EDL following running stress. RNA sequencing revealed divergent transcriptional signatures between mice in Low and High frailty marked groups in response to running, including upregulation of mitochondrial bioenergetic and complex assembly pathways in Low group mice and downregulation in High group mice. These data demonstrate that downhill running stress unmasks latent impairments with frailty in skeletal muscle, and that mitochondrial dysfunction and\/or redox imbalance may be potential contributors to reduced muscle resilience. Overall, our results emphasize the importance of incorporating physiological stress paradigms to uncover frailty-associated muscle impairments that are not apparent under basal conditions.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s11357-025-01856-7","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T03:46:06Z","timestamp":1757562366000},"page":"1665-1681","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Increasing indices of frailty in aged female mice are associated with impaired skeletal muscle resilience to downhill running stress"],"prefix":"10.1007","volume":"48","author":[{"given":"Grant R.","family":"Laskin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"La\u00eds R.","family":"Perazza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ted G.","family":"Graber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baylah R.","family":"Mazonson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhoung J.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Verdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6481-9029","authenticated-orcid":false,"given":"LaDora V.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"1856_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.maturitas.2020.05.018","volume":"139","author":"E Rudnicka","year":"2020","unstructured":"Rudnicka E, Napiera\u0142a P, Podfigurna A, M\u0119czekalski B, Smolarczyk R, Grymowicz M. 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