2. Academic Validation
  3. Skeletal Muscle HSF1 Alleviates Age-Associated Sarcopenia and Mitochondrial Function Decline via SIRT3-PGC1α Axis

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

  • Adv Sci (Weinh). 2025 Dec 16:e10368. doi: 10.1002/advs.202510368.
Jun Zhang 1,  Min Hu 1,  Xia Wu 1,  Mingwei Guo 1,  Ying Ma 1,  Jin Qiu 1,  Siqi Wang 2,  Yuxiang Cao 1,  Yinzhao Zhong 1,  Fangfang Chen 1,  Yiwen Wang 1,  Wei Wei 1,  Yan Lu 3 4,  Yong Zhang 5 6,  Junjie Xiao 2,  Zhenji Gan 7,  Cheng Hu 3 8,  Xinran Ma 1 8 9 10,  Lingyan Xu 1 9 10
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 2 Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai, 200444, China.
  • 3 Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
  • 4 Institute of Metabolism and Regenerative Medicine, Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
  • 5 State Key Laboratory for Complex, Severe, and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
  • 6 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, 510005, China.
  • 7 State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, Nanjing, 210093, China.
  • 8 Department of Endocrinology and Metabolism, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, 201499, China.
  • 9 Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 10 Institute for Aging, East China Normal University, Shanghai, 200241, China.
PMID: 41400028 DOI: 10.1002/advs.202510368
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.

Keywords

aging; mitochondria; muscle atrophy; oxidative function; sarcopenia.

Figures
Products