The role of hypoxia-inducible factor-1α in the pathogenesis of sarcopenia

doi:10.16352/j.issn.1001-6325.2025.08.1093

Abstract

Abstract: HIF-1α, a key transcription factor for cellular adaptation to hypoxia, plays a significant role in the development of sarcopenia. In the context of long-term chronic hypoxia, the expression level of HIF-1α is abnormal. It functions in the development of sarcopenia by regulating multiple signaling pathways, including iron metabolism, mitochondrial function, angiogenesis, remodeling of the extracellular matrix, and protein synthesis and metabolism. Moreover, the overactivation of HIF-1α may lead to dysfunction of satellite cells, thereby reducing the capacity for muscle regeneration and repair.

Key words: hypoxia inducible factor-1α, sarcopenia, pathogenesis

CLC Number:

R587.1

ZHU Qihai, ZHANG Yu. The role of hypoxia-inducible factor-1α in the pathogenesis of sarcopenia[J]. Basic & Clinical Medicine, 2025, 45(8): 1093-1097.

References

[1] Sayer AA, Cruz-Jentoft A. Sarcopenia definition, diagnosis and treatment: consensus is growing[J]. Age Ageing, 2022, 51:afac220. doi: 10.1093/ageing/afac220.
[2] Gielen E, Dupont J, Dejaeger M, et al. Sarcopenia, osteoporosis and frailty[J]. Metabolism, 2023, 145:155638. doi: 10.1016/j.metabol.2023.155638.
[3] Attaway AH, Bellar A, Mishra S, et al. Adaptive exhaustion during prolonged intermittent hypoxia causes dysregulated skeletal muscle protein homeostasis[J]. J Physiol, 2023, 601:567-606. doi: 10.1113/JP283700.
[4] Taylor CT, Scholz CC. The effect of HIF on metabolism and immunity[J]. Nat Rev Nephrol, 2022, 18:573-587. doi: 10.1038/s41581-022-00587-8.
[5] Cirillo F, Mangiavini L, La Rocca P, et al. Human sarcopenic myoblasts can be rescued by pharmacological reactivation of HIF-1α[J]. Int J Mol Sci, 2022, 23:7114. doi: 10.3390/ijms23137114.
[6] Kang JS, Kim D, Rhee J, et al. Baf155 regulates skeletal muscle metabolism via HIF-1a signaling[J]. PLoS Biol, 2023, 21:e3002192. doi: 10.1371/journal.pbio.3002192.
[7] Suh DK, Lee WY, Yeo WJ, et al. A novel muscle atrophy mechanism: myocyte degeneration due to intracellular iron deprivation[J]. Cells, 2022, 11:2853. doi: 10.3390/cells11182853.
[8] Vinke J, Gorter AR, Eisenga MF, et al. Iron deficiency is related to lower muscle mass in community-dwelling individuals and impairs myoblast proliferation[J]. J Cachexia Sarcopenia Muscle, 2023, 14:1865-1879. doi: 10.1002/jcsm.13277.
[9] Ding H, Chen S, Pan X, et al. Transferrin receptor 1 ablation in satellite cells impedes skeletal muscle regenera-tion through activation of ferroptosis[J]. J Cachexia Sarcopenia Muscle, 2021, 12:746-768. doi: 10.1002/jcsm.12700.
[10] Welch N, Mishra S, Bellar A, et al. Differential impact of sex on regulation of skeletal muscle mitochondrial function and protein homeostasis by hypoxia-inducible factor-1α in normoxia[J]. J Physiol, 2024, 602:2763-2806. doi: 10.1113/JP285339.
[11] Zheng X, Narayanan S, Xu C, et al. Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes[J]. Elife, 2022, 11:e70714. doi: 10.7554/eLife.70714.
[12] Germanova E, Khmil N, Pavlik L, et al. The role of mitochondrial enzymes, succinate-coupled signaling pathways and mitochondrial ultrastructure in the formation of urgent adaptation to acute hypoxia in the myocardium[J]. Int J Mol Sci, 2022, 23:14248. doi: 10.3390/ijms232214248.
[13] Ito A, Hashimoto M, Tanihata J, et al. Involvement of Parkin-mediated mitophagy in the pathogenesis of chronic obstructive pulmonary disease-related sarcopenia[J]. J Cachexia Sarcopenia Muscle, 2022, 13:1864-1882. doi: 10.1002/jcsm.12988.
[14] Favier FB, Britto FA, Freyssenet DG, et al. HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology[J]. Cell Mol Life Sci, 2015, 72:4681-4696. doi: 10.1007/s00018-015-2025-9.
[15] Grunewald M, Kumar S, Sharife H, et al. Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span[J]. Science, 2021, 373:eabc8479. doi: 10.1126/science.abc8479.
[16] Ling M, Lai X, Quan L, et al. Knockdown of VEGFB/VEGFR1 signaling promotes white adipose tissue browning and skeletal muscle development[J]. Int J Mol Sci, 2022, 23:7524. doi: 10.3390/ijms23147524.
[17] Chen WJ, Lin IH, Lee CW, et al. Aged skeletal muscle retains the ability to remodel extracellular matrix for degradation of collagen deposition after muscle injury[J]. Int J Mol Sci, 2021, 22:2123. doi: 10.3390/ijms22042123.
[18] Nakamura S, Sato Y, Kobayashi T, et al. Insulin-like growth factor-Ⅰ is required to maintain muscle volume in adult mice[J]. J Bone Miner Metab, 2019, 37:627-635. doi: 10.1007/s00774-018-0964-6.
[19] Feng L, Li B, Xi Y, et al. Aerobic exercise and resistance exercise alleviate skeletal muscle atrophy through IGF-1/IGF-1R-PI3K/Akt pathway in mice with myocardial infarction[J]. Am J Physiol Cell Physiol, 2022, 322:C164-C176. doi: 10.1152/ajpcell.00344.2021.
[20] Dong S, Liang S, Cheng Z, et al. ROS/PI3K/Akt and Wnt/β-catenin signalings activate HIF-1α-induced metabolic reprogramming to impart 5-fluorouracil resistance in colorectal cancer[J]. J Exp Clin Cancer Res, 2022, 41:15. doi: 10.1186/s13046-021-02229-6.
[21] Jung U, Kim M, Dowker-Key P, et al. Hypoxia promotes proliferation and inhibits myogenesis in broiler satellite cells[J]. Poult Sci, 2024, 103:103203. doi: 10.1016/j.psj.2023.103203.
[22] Nguyen TH, Paprzycki L, Legrand A, et al. Hypoxia enhances human myoblast differentiation: involvement of HIF1α and impact of DUX4, the FSHD causal gene[J]. Skelet Muscle, 2023, 13:21. doi: 10.1186/s13395-023-00330-2.