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This study aimed to elucidate whether the activation of the adenosine 5\u2019-monophosphate-activated protein kinase (AMPK)\/silent information regulator 1 (SIRT1) signaling pathway ameliorates sepsis-acquired weakness (SAW) via modulating the peroxisome proliferator-activated receptor \u03b3 coactivator-1\u03b1 (PGC-1\u03b1)\/peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) axis. A PGC-1\u03b1 knockout mouse model was established using the cecal ligation and puncture (CLP) method to induce sepsis and subsequent SAW. Multiple histological analyses were performed to evaluate tissue pathological lesions, mitochondrial morphological and structural abnormalities, myelin injury, and skeletal muscle alterations. ELISA was utilized to quantify the expression levels of pro-inflammatory factors and neurotransmitters. Western blotting and RT-qPCR were further employed to detect the expression of mitochondrial functional proteins and downstream molecules associated with the AMPK\/SIRT1 signaling pathway. Successful construction of the PGC-1\u03b1 knockout CLP mouse model was confirmed via systematic verification. Functional experiments validated that AMPK\/SIRT1 pathway activation exerts protective effects against SAW in CLP mice through targeting the PGC-1\u03b1\/PPAR\u03b3 signaling cascade. Mechanistically, AMPK\/SIRT1 activation further modulates the PGC-1\u03b1\/PPAR\u03b3 pathway, thereby alleviating the progression of SAW. Collectively, targeted regulation of PGC-1\u03b1 may serve as a promising and actionable therapeutic strategy for the clinical prevention and treatment of ICU-AW in septic patients.<\/jats:p>","DOI":"10.1038\/s41420-026-03212-w","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T03:45:02Z","timestamp":1782186302000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["AMPK\/ SIRT1 signaling pathway activation acts on PGC-1\u03b1\/ PPAR\u03b3 to alleviate sepsis-acquired weakness"],"prefix":"10.1038","volume":"12","author":[{"given":"Lu","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meirong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0388-6998","authenticated-orcid":false,"given":"Qi","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"3212_CR1","doi-asserted-by":"publisher","first-page":"520","DOI":"10.1038\/s41401-021-00676-7","volume":"43","author":"C Deng","year":"2022","unstructured":"Deng C, Zhao L, Yang Z, Shang JJ, Wang CY, Shen MZ, et al. 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