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Heat shock factor 1 (HSF1) is a transcription factor that orchestrates cellular responses to various stresses, while its role in sarcopenia remains unknown. Here,\n                    <jats:italic>HSF1<\/jats:italic>\n                    mRNA expression was decreased in muscles of aged mice and humans, correlating negatively with the atrophic gene and positively with the mitochondrial gene. Aged HSF1 muscle\u2010specific knockout mice exhibited severe muscle atrophy and reduced endurance capacity, partially due to smaller fast fibers and mitochondrial dysfunction in slow fibers, as well as impaired systemic metabolic performance. In contrast, HSF1 overexpression in skeletal muscle improved these functions. Mechanistically, via RNA sequencing (RNA\u2010seq) and chromatin immunoprecipitation sequencing\u00a0(ChIP\u2010seq), it is revealed that HSF1 transcriptionally activated Sirtuin3 (SIRT3) for the deacetylation of both\u00a0PGC1\u03b11 and PGC1\u03b14 isoforms of peroxisome proliferator\u2010activated receptor gamma coactivator 1\u2010alpha (PGC1\u03b1), in skeletal muscle, enhancing mitochondrial function and muscle hypertrophy in vivo and in vitro, and inducing fibronectin type III domain\u2010containing protein 5 (FNDC5)\/Irisin for tissue crosstalk. Thus, HSF1 regulates skeletal muscle functions and systemic energy homeostasis via the SIRT3\u2010PGC1\u03b1 axis, representing a potential therapeutic target for sarcopenia and metabolic disorders.\n                  <\/jats:p>","DOI":"10.1002\/advs.202510368","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T10:38:18Z","timestamp":1765881498000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Skeletal Muscle HSF1 Alleviates Age\u2010Associated Sarcopenia and Mitochondrial Function Decline via SIRT3\u2010PGC1\u03b1 Axis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1442-6347","authenticated-orcid":false,"given":"Jun","family":"Zhang","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University  Shanghai 200241 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