journal article·2026-02Open access

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

Jun Zhang, Min Hu, Xia Wu, Mingwei Guo, Ying Ma, Jin Qiu, Siqi Wang, Yuxiang Cao, Yinzhao Zhong, Fangfang Chen, Yiwen Wang, Wei Wei, Yan Lu, Yong Zhang, Junjie Xiao, Zhenji Gan, Cheng Hu, Xinran Ma, Lingyan Xu

Advanced Science· Volume 13· Issue 11

Abstract

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.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Heat shock proteins research · Adipose Tissue and Metabolism · Muscle Physiology and Disorders

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 China

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

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

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

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

Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory) Guangzhou 510005 China

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

Department of Endocrinology and Metabolism Fengxian Central Hospital Affiliated to Southern Medical University Shanghai 201499 China

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

Institute for Aging East China Normal University Shanghai 200241 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · China Postdoctoral Science Foundation · Science and Technology Commission of Shanghai Municipality

References (84)

Show source-provided references
1. 10.1016/j.cmet.2012.12.01210.1016/j.cmet.2012.12.012 ↗
2. 10.1111/apha.1401210.1111/apha.14012 ↗
3. 10.1038/s41422-018-0078-710.1038/s41422-018-0078-7 ↗
4. 10.1038/s41572-024-00550-w10.1038/s41572-024-00550-w ↗
5. 10.1016/j.arr.2020.10120010.1016/j.arr.2020.101200 ↗
6. 10.1038/s41467-019-13694-110.1038/s41467-019-13694-1 ↗
7. 10.1038/s42255-024-00997-x10.1038/s42255-024-00997-x ↗
8. 10.1016/j.celrep.2017.05.05410.1016/j.celrep.2017.05.054 ↗
9. 10.1038/nrm.2017.7310.1038/nrm.2017.73 ↗
10. 10.1016/j.cell.2022.02.00410.1016/j.cell.2022.02.004 ↗
11. 10.1083/jcb.20160709110.1083/jcb.201607091 ↗
12. 10.1016/j.cmet.2015.08.00510.1016/j.cmet.2015.08.005 ↗
13. 10.1152/japplphysiol.00471.201110.1152/japplphysiol.00471.2011 ↗
14. 10.1002/phy2.7110.1002/phy2.71 ↗
15. 10.1371/journal.pone.007778810.1371/journal.pone.0077788 ↗
16. 10.1038/cddis.2016.2210.1038/cddis.2016.22 ↗
17. 10.1016/j.cell.2012.06.03110.1016/j.cell.2012.06.031 ↗
18. 10.1007/s00125-015-3671-z10.1007/s00125-015-3671-z ↗
19. Lee S. J. · J. Clin. Invest. · 2021 · 131
20. 10.1016/j.cmet.2013.10.00110.1016/j.cmet.2013.10.001 ↗
21. 10.1111/acel.1396110.1111/acel.13961 ↗
22. 10.1128/MCB.9.8.339310.1128/MCB.9.8.3393 ↗
23. 10.1016/j.molmet.2017.10.01210.1016/j.molmet.2017.10.012 ↗
24. 10.7554/eLife.3461310.7554/eLife.34613 ↗
25. 10.1016/j.cmet.2007.11.00310.1016/j.cmet.2007.11.003 ↗
26. 10.1038/s41467-020-20123-110.1038/s41467-020-20123-1 ↗
27. 10.1016/j.nmd.2011.10.00510.1016/j.nmd.2011.10.005 ↗
28. 10.1111/acel.7016410.1111/acel.70164 ↗
29. 10.1038/s41586-020-2499-y10.1038/s41586-020-2499-y ↗
30. 10.3390/ijms2204212310.3390/ijms22042123 ↗
31. 10.1016/j.stem.2023.03.01610.1016/j.stem.2023.03.016 ↗
32. 10.1038/s43587-023-00382-510.1038/s43587-023-00382-5 ↗
33. 10.3389/fphar.2020.0014210.3389/fphar.2020.00142 ↗
34. 10.1016/j.cmet.2020.12.02010.1016/j.cmet.2020.12.020 ↗
35. 10.1021/acs.analchem.3c0187510.1021/acs.analchem.3c01875 ↗
36. 10.18632/aging.10007510.18632/aging.100075 ↗
37. 10.1038/nature0335410.1038/nature03354 ↗
38. 10.1101/gad.152730710.1101/gad.1527307 ↗
39. 10.7150/thno.4592210.7150/thno.45922 ↗
40. 10.1093/nar/gkab16110.1093/nar/gkab161 ↗
41. 10.1093/database/baae00710.1093/database/baae007 ↗
42. 10.1016/j.jshs.2024.10096810.1016/j.jshs.2024.100968 ↗
43. 10.1126/science.108370110.1126/science.1083701 ↗
44. 10.1038/emboj.2010.22510.1038/emboj.2010.225 ↗
45. 10.1007/s10522-023-10063-w10.1007/s10522-023-10063-w ↗
46. 10.1093/hmg/ddu07310.1093/hmg/ddu073 ↗
47. 10.1074/jbc.M112.39036910.1074/jbc.M112.390369 ↗
48. 10.1016/j.abb.2013.06.00610.1016/j.abb.2013.06.006 ↗
49. 10.4049/jimmunol.090257910.4049/jimmunol.0902579 ↗
50. 10.1038/s41586-024-07348-610.1038/s41586-024-07348-6 ↗
51. 10.1007/s40279-018-0876-610.1007/s40279-018-0876-6 ↗
52. 10.1152/japplphysiol.00989.201110.1152/japplphysiol.00989.2011 ↗
53. 10.2337/db12-165010.2337/db12-1650 ↗
54. 10.2337/db14-181010.2337/db14-1810 ↗
55. 10.1111/j.1474-9726.2012.00843.x10.1111/j.1474-9726.2012.00843.x ↗
56. 10.1111/acel.1226010.1111/acel.12260 ↗
57. 10.1111/j.1474-9726.2012.00844.x10.1111/j.1474-9726.2012.00844.x ↗
58. 10.1038/srep0042510.1038/srep00425 ↗
59. 10.1111/acel.1341910.1111/acel.13419 ↗
60. 10.1093/eurheartj/ehv29010.1093/eurheartj/ehv290 ↗
61. 10.1002/jcb.2253110.1002/jcb.22531 ↗
62. 10.1002/jcb.2279510.1002/jcb.22795 ↗
63. 10.1016/j.gene.2011.07.02910.1016/j.gene.2011.07.029 ↗
64. 10.1093/jb/mvab11910.1093/jb/mvab119 ↗
65. 10.1371/journal.pone.008563610.1371/journal.pone.0085636 ↗
66. He S. · J. Clin. Invest. · 2021 · 131
67. 10.1038/s41580-020-0230-310.1038/s41580-020-0230-3 ↗
68. 10.1073/pnas.070507010410.1073/pnas.0705070104 ↗
69. 10.1073/pnas.060779510310.1073/pnas.0607795103 ↗
70. 10.1096/fj.14-26661910.1096/fj.14-266619 ↗
71. 10.1172/JCI3178510.1172/JCI31785 ↗
72. 10.1172/JCI17742710.1172/JCI177427 ↗
73. 10.1038/nature1077710.1038/nature10777 ↗
74. 10.1002/advs.20241101510.1002/advs.202411015 ↗
75. 10.1038/s41419-021-04134-410.1038/s41419-021-04134-4 ↗
76. 10.1080/19768354.2019.170663410.1080/19768354.2019.1706634 ↗
77. 10.1002/jcsm.1314110.1002/jcsm.13141 ↗
78. 10.1016/j.cmet.2010.11.00810.1016/j.cmet.2010.11.008 ↗
79. 10.1002/advs.20240698610.1002/advs.202406986 ↗
80. 10.1172/jci.insight.14996910.1172/jci.insight.149969 ↗
81. 10.1161/CIRCULATIONAHA.120.05044610.1161/CIRCULATIONAHA.120.050446 ↗
82. 10.1038/s42255-021-00414-710.1038/s42255-021-00414-7 ↗
83. 10.1038/s41598-021-91191-610.1038/s41598-021-91191-6 ↗
84. 10.1038/s41467-022-29472-510.1038/s41467-022-29472-5 ↗