Exercise is good for health, it prevents obesity, diabetes, and fatty liver disease. However, excess of anything is bad, this holds true for exercise too. In a recent article published in the Cell Metabolism journal, a group of scientists found that over-exercise led to liver fibrosis and they delineated its detailed molecular mechanism using transgenic mice and cells. They found that over-exercise increased lactate in muscle, which enriched a few proteins in the extracellular vesicles that migrated to the liver promoting liver cell apoptosis and fibrosis.
Clinical study
They extracted 1255 individuals’ training and liver phenotype data (2017-2020) from the NHANES (National Health and Nutrition Examination Survey), conducted by the CDC in the United States. The individuals were divided into quartiles based on their physical activity. They found that Q4 group with the highest physical activity had abnormal liver function parameters such as liver AST, ALT, and stiffness, compared to Q1-Q3. This was consistent among all ethnic groups, suggesting an increased risk for liver dysfunction in individuals with excessive physical activity.
Cellular mechanism
They confirmed these findings in mice and found that long-term over-training led to liver cell apoptosis and fibrosis compared to moderately trained or resting control groups. As lactate is known to increase in exercise, they found that lactate was increased in serum, muscle, liver, and kidney of overtrained mice compared to the control group. Moreover, they found that muscle was the main source of lactate, which caused the enrichment of specific proteins in small extracellular vesicles (SEVs) that traveled to the liver through circulation causing apoptosis and fibrosis. When treated with salidroside, a drug that suppresses lactate dehydrogenase activity, thereby decreasing lactate amount, decreased liver apoptosis and fibrosis were observed. Salidroside has been used in athletes to improve muscle function and prevent damage.
Molecular mechanism
At the molecular level, high lactate caused a post-translational modification- lactylation on K479 site of SORBS3 protein in mice, which corresponds to a highly conserved K415 site in humans and a known lactylation site. SORBS3 is a cytoskeletal protein that interacts with a scaffolding protein FLOT1 and a ubiquitin ligase protein FBXO2. FBXO2 was found to be increased in over-trained mice SEVs compared to control. Further, FBXO2 targeted MCL1 protein for degradation in hepatocytes, which increased BAX/BAK activation followed by caspase-9 and 3 activation, causing hepatocyte apoptosis and contributing to liver fibrosis.
Future studies
- Further studies are needed to determine the effect of over-training on individuals with pre-existing liver conditions with diverse genetic backgrounds.
- Although this study has determined the effect of lactate on liver fibrosis, other mediators can also contribute to liver fibrosis and need to be validated.
- Clinical studies are needed to confirm the effect of salidroside in preventing liver damage caused by over-exercise.
- Lastly, it would be interesting to investigate the effect of over-exercise on other health issues.
