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

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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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