Cited by 78Extracellular vesicles in diseaseLiver physiology and pathologyExercise and Physiological Responses

Muscle-derived small extracellular vesicles induce liver fibrosis during overtraining

Liu, Ya, Zhou, Rui, Guo, Yifan, Hu, Biao, Xie, Lingqi, An, Yuze, Wen, Jie, Liu, Zheyu +9 more·2025·Cell Metabolism

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.

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Crossref · 10.1016/j.cmet.2024.12.005

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Authors
Liu, Y., Zhou, R., Guo, Y., Hu, B., Xie, L., An, Y., Wen, J., Liu, Z., Zhou, M., Kuang, W., Xiao, Y., Wang, M., Xie, G., Zhou, H., Lu, R., Peng, H., & Huang, Y.
Affiliations
Central South University (CN)
Corresponding author
  • Lu, Renbin
  • Peng, Hui
  • Huang, Yan
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2025-04
Volume
37
Issue
4
Pages
824-841.e8
ISSN
1550-4131 (ISSN-L)
OpenAlex
W4406903631
Cited by
78
References
61
Citations by year
2026: 46 · 2025: 32
FWCI
23.45
Type
journal article
Language
en
Open access
closed
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (82370883, 81930022, 82120108009)
  • Natural Science Foundation of Hunan Province (92149306, 2023JJ30890)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
Keywords
overtraining, liver fibrosis, small extracellular vesicles, lactylation, liquid-liquid phase separation, flotillin-1, hepatocyte apoptosis, hepatic stellate cell activation, salidroside
MeSH terms
Extracellular Vesicles, Animals, Humans, Liver Cirrhosis, Male, Mice, Inbred C57BL, Physical Conditioning, Animal, Apoptosis, Muscle, Skeletal, Lactic Acid, Hepatocytes, F-Box Proteins, Mice, Hepatic Stellate Cells

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