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Short-term physical activity reduces metabolic-associated steatohepatitis by promoting the degradation of branched-chain amino acids in skeletal muscle

2025-07-10
(Press-News.org) Background and Aims Metabolic-associated steatohepatitis (MASH) is an advanced and progressive liver disease that potentially causes cirrhosis and hepatocellular carcinoma. Exercise is a crucial and effective intervention for ameliorating metabolic dysfunction-associated steatotic liver disease. This study aimed to provide a comprehensive understanding of the underlying mechanisms of MASH, which benefit a broad spectrum of MASH patients, including those who have difficulty engaging in physical activity.

Methods We established a mouse model of MASH and selectively knocked down L-type amino acid transporter 1 and alanine-serine-cysteine transporter 2. Mice were fed a high-fat high-cholesterol diet and subjected to either short- or long-term exercise regimens. We assessed the phosphorylation and activity of branched-chain alpha-keto acid dehydrogenase (BCKDH) as well as branched-chain amino acid (BCAA) content in skeletal muscle following exercise.

Results Short-term exercise significantly reduced hepatic steatosis and inflammation without causing notable changes in body weight. It also enhanced BCKDH activity in skeletal muscle and decreased hepatic BCAA accumulation. Muscle-specific overexpression of BCKDH further promoted BCAA catabolism and significantly attenuated hepatic steatosis and inflammation in high-fat high-cholesterol-fed mice. In contrast, muscle-specific L-type amino acid transporter 1 knockdown, which suppresses BCAA uptake, markedly abolished these beneficial effects. Interestingly, BCKDH overexpression in muscle increased glutamine levels in both the blood and liver. Hepatic alanine-serine-cysteine transporter 2 knockdown, which inhibited glutamine uptake, lessened the protective effect of exercise on MASH. Further in vitro study revealed that glutamine derived from myocytes improved redox homeostasis and inhibited lipid accumulation in hepatocytes.

Conclusions In our study, enhanced BCAA oxidation in skeletal muscle following short-term exercise increased glutamine production, which circulated to the liver and helped ameliorate MASH by promoting redox balance. This mechanism offers a novel perspective and a promising therapeutic target for MASH treatment, with significant implications for future clinical interventions and drug development.

 

Full text

https://www.xiahepublishing.com/2310-8819/JCTH-2025-00072

 

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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[Press-News.org] Short-term physical activity reduces metabolic-associated steatohepatitis by promoting the degradation of branched-chain amino acids in skeletal muscle