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.

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