Skeletal Muscle HSF1 Alleviates Age‐Associated Sarcopenia and Mitochondrial Function Decline via SIRT3‐PGC1α Axis

Abstract Age‐related sarcopenia, characterized by progressive loss of skeletal muscle mass and strength, impacts metabolic health and quality of life in the elderly. Heat shock factor 1 (HSF1) is a transcription factor that orchestrates cellular responses to various stresses, while its role in sarcopenia remains unknown. Here, HSF1 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‐specific 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‐seq) and chromatin immunoprecipitation sequencing (ChIP‐seq), it is revealed that HSF1 transcriptionally activated Sirtuin3 (SIRT3) for the deacetylation of both PGC1α1 and PGC1α4 isoforms of peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α), in skeletal muscle, enhancing mitochondrial function and muscle hypertrophy in vivo and in vitro, and inducing fibronectin type III domain‐containing protein 5 (FNDC5)/Irisin for tissue crosstalk. Thus, HSF1 regulates skeletal muscle functions and systemic energy homeostasis via the SIRT3‐PGC1α axis, representing a potential therapeutic target for sarcopenia and metabolic disorders.