Muscle-derived small extracellular vesicles induce liver fibrosis during overtraining
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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Overtraining caused excessive lactate accumulation in skeletal muscle and the subsequent formation of lactate bodies, thereby inducing hepatocyte apoptosis and liver fibrosis via the MCL1-BAX/BAK axis.
“Recent evidence demonstrated that overtraining caused excessive lactate accumulation in skeletal muscle and the subsequent formation of lactate bodies, thereby inducing hepatocyte apoptosis and liver fibrosis via the MCL1-BAX/BAK axis [401, 402].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [401]
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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
- ORCID
- 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
- Licence
- 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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