Disrupted methionine cycle triggers muscle atrophy in cancer cachexia through epigenetic regulation of REDD1

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 endoplasmic reticulum stress and DNA hypomethylation-induced expression of the DNA damage inducible transcript 4 (Ddit4) gene, encoding the regulated in development and DNA damage response 1 (REDD1) protein. Targeting DNA methylation by depletion or pharmacological inhibition of DNA methyltransferase 3A (DNMT3A) exacerbates cachexia, while restoring DNMT3A expression or REDD1 knockout alleviates cancer cachexia-induced skeletal muscle atrophy in mice. Methionine supplementation restores DNA methylation of the Ddit4 promoter in a DNMT3A-dependent manner, thereby inhibiting activating transcription factor 4 (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.