Xiong Xia, Li Wen, Yu Chunlin, Qiu Mohan, Zhang Zengrong, Hu Chenming, Zhu Shiliang, Yang Li, Pen Han, Song Xiaoyan, Chen Jialei, Xia Bo, Han Shunshun, Yang Chaowu
Animal Breeding and Genetics Key Laboratory of Sichuan Province, Sichuan Animal Science Academy, Chengdu 610066, China.
Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China.
Int J Mol Sci. 2025 Feb 6;26(3):1390. doi: 10.3390/ijms26031390.
Ferritin heavy chain 1 (FTH1) is pivotal in the storage, release, and utilization of iron, plays a crucial role in the ferroptosis pathway, and exerts significant impacts on various diseases. Iron influences skeletal muscle development and health by promoting cell growth, ensuring energy metabolism and ATP synthesis, maintaining oxygen supply, and facilitating protein synthesis. However, the precise molecular mechanisms underlying iron's regulation of skeletal muscle growth and development remain elusive. In this study, we demonstrated that the conditional knockout (cKO) of FTH1 in skeletal muscle results in muscle atrophy and impaired exercise endurance. In vitro studies using FTH1 cKO myoblasts revealed notable decreases in GSH concentrations, elevated levels of lipid peroxidation, and the substantial accumulation of Fe, collectively implying the induction of ferroptosis. Mechanistically, E3 ubiquitin-protein ligase SMURF1 (SMURF1) acts as an E3 ubiquitin ligase for FTH1, thereby facilitating the ubiquitination and subsequent degradation of FTH1. Consequently, this activation of the ferroptosis pathway by SMURF1 impedes myoblast differentiation into myotubes. This study identifies FTH1 as a novel regulator of muscle cell differentiation and skeletal muscle development, implicating its potential significance in maintaining skeletal muscle health through the regulation of iron homeostasis.
铁蛋白重链1（FTH1）在铁的储存、释放和利用中起关键作用，在铁死亡途径中发挥重要作用，并对多种疾病产生重大影响。铁通过促进细胞生长、确保能量代谢和ATP合成、维持氧气供应以及促进蛋白质合成来影响骨骼肌的发育和健康。然而，铁调节骨骼肌生长和发育的精确分子机制仍不清楚。在本研究中，我们证明骨骼肌中FTH1的条件性敲除（cKO）会导致肌肉萎缩和运动耐力受损。使用FTH1 cKO成肌细胞的体外研究显示，谷胱甘肽（GSH）浓度显著降低、脂质过氧化水平升高以及铁大量积累，这些共同表明铁死亡的诱导。从机制上讲，E3泛素蛋白连接酶SMURF1作为FTH1的E3泛素连接酶，从而促进FTH1的泛素化及随后的降解。因此，SMURF1对铁死亡途径的这种激活阻碍了成肌细胞分化为肌管。本研究确定FTH1是肌肉细胞分化和骨骼肌发育的新型调节因子，暗示其通过调节铁稳态对维持骨骼肌健康具有潜在意义。
