2. Academic Validation
  3. Muscle-derived small extracellular vesicles induce liver fibrosis during overtraining

Muscle-derived small extracellular vesicles induce liver fibrosis during overtraining

  • Cell Metab. 2025 Jan 22:S1550-4131(24)00488-1. doi: 10.1016/j.cmet.2024.12.005.
Ya Liu 1,  Rui Zhou 1,  Yifan Guo 1,  Biao Hu 1,  Lingqi Xie 1,  Yuze An 1,  Jie Wen 1,  Zheyu Liu 1,  Min Zhou 1,  Weihong Kuang 1,  Yao Xiao 1,  Min Wang 1,  Genqing Xie 2,  Haiyan Zhou 1,  Renbin Lu 3,  Hui Peng 4,  Yan Huang 5
Affiliations

Affiliations

  • 1 Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008 Changsha, Hunan, China.
  • 2 Department of Endocrinology, The First People's Hospital of Xiangtan City, 411100 Xiangtan, Hunan, China.
  • 3 Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008 Changsha, Hunan, China. Electronic address: lurenbin@sklmg.edu.cn.
  • 4 Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008 Changsha, Hunan, China. Electronic address: penghui11083@csu.edu.cn.
  • 5 Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital of Central South University, 410008 Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 410008 Changsha, Hunan, China; FuRong Laboratory, 410078 Changsha, Hunan, China. Electronic address: yanhuang1018@csu.edu.cn.
PMID: 39879982 DOI: 10.1016/j.cmet.2024.12.005
Abstract

The benefits of exercise for metabolic health occur in a dose-dependent manner. However, the adverse effects of overtraining and their underlying mechanisms remain unclear. Here, we show that overtraining induces hepatic fibrosis. Mechanistically, we find that excessive lactate accumulation in skeletal muscle leads to the lactylation of SH3 domain-containing 3 (SORBS3), triggering its liquid-liquid phase separation (LLPS). LLPS of SORBS3 enhances its interaction with flotillin 1 and selectively facilitates the sorting of F-box protein 2 (FBXO2) into small extracellular vesicles, referred to as "lactate bodies." Lactate bodies induce hepatocyte Apoptosis followed by hepatic stellate cell activation via myeloid cell leukemia sequence 1 (MCL1)-BAX/Bak signaling. Inhibition of SORBS3 lactylation or FBXO2 disrupts lactate bodies formation and alleviates overtraining-triggered liver fibrosis. Likewise, reduction of muscle lactate bodies formation by salidroside attenuates overtraining-induced liver fibrosis. Collectively, we identify a process by which overtraining induces hepatic fibrosis, highlighting a potential therapeutic target for liver health.

Keywords

LLPS; lactylation; liver fibrosis; overtraining; small extracellular vesicles.

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