Methionine cycle dysregulation mediates REDD1 overexpression-induced muscle atrophy in cancer cachexia

Published: 19 September 2024| Version 1 | DOI: 10.17632/584h5mk8mp.1
Contributors:
, Lulu Wei, Zhiqiang Huang,

Description

The essential amino acid methionine plays a pivotal role in one-carbon metabolism, facilitating the production of S-adenosylmethionine (SAM), a critical supplier for DNA methylation and thereby a modulator of gene expression. Here, we report that the methionine cycle is disrupted in skeletal muscle during cancer cachexia, leading to ER stress and DNA hypomethylation-induced expression of Ddit4, encoding the REDD1 protein, a key inhibitor of AKT signaling. Targeting DNA methylation by depletion or pharmacological inhibition of DNMT3A can exacerbate cachexia. Restoring DNMT3A or REDD1 KO in mice alleviates cancer cachexia-induced skeletal muscle atrophy. Methionine supplementation restores DNA methylation of the Ddit4 promoter in a DNMT3A-dependent manner, thereby inhibiting ATF4-mediated Ddit4 transcription. Thus, with the identification of the methionine/SAM-DNMT3A/DNA hypomethylation-Ddit4/REDD1 axis, our study provides molecular insights into an epigenetic mechanism underlying cancer cachexia, and it suggests nutrient supplementation as a promising therapeutic strategy to prevent or reverse cachectic muscle atrophy.

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Institutions

Nanjing University

Categories

Cancer, Muscle, Metabolism, DNA Methylation, Protein Energy Wasting, Methionine

Funding

National Natural Science Foundation of China

82370899

National Natural Science Foundation of China

82070912

Fundamental Research Funds for the Central Universities

0214/14380538

Team building and scientific research start-up funds of Nanjing University

0214/14912217

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