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

ABSTRACT: The essential amino acid methionine plays a pivotal role in one-carbon metabolism, facilitating the production of S-adenosylmethionine (SAMe), a critical supplier for DNA methylation. Here we find the disruption of methionine metabolism by rapid SAMe depletion in skeletal muscle in cancer cachexia, leading to endoplasmic reticulum (ER) stress and the overexpression of regulated in development and DNA damage responses (REDD1). Targeting the DNA methylation process via DNA methyltransferases (DNMTs) and REDD1 knockout can alleviate cancer cachexia-induced skeletal muscle atrophy. Methionine supplementation maintains the DNA methylation of DNA damage-inducible transcript 4 (Ddit4) by DNMT3A, thereby inhibiting activating transcription factor 4 (ATF4)-mediated Ddit4 transcription. Our study suggests that methionine or SAMe supplementation can effectively reverse muscle atrophy in cancer cachexia, providing valuable mechanistic insights and a promising therapeutic strategy for clinical application.

ORGANISM(S): Mus musculus

PROVIDER: GSE275001 | GEO | 2024/10/11

REPOSITORIES: GEO

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Project description:Background Loss of skeletal muscle mass in advanced cancer is recognized as an independent predictor of mortality. Mechanisms involved in this wasting process and parameters for early diagnosis are still lacking. As skeletal muscle is considered as a secretory organ, the aim of this present experimental work was to characterize the changes in muscle proteome and secretome associated with cancer-induced cachexia to better understand cellular mechanisms involved in this wasting process and to identify secreted proteins which might reflect the ongoing muscle atrophy process. Methods We investigated first the changes in the muscle proteome associated with cancer-induced cachexia by using differential label-free proteomic analysis on muscle of the C26 mouse model. The differentially abundant proteins were submitted to sequential bioinformatic secretomic analysis in order to identify potentially secreted proteins. Selected reaction monitoring and Western blotting were used to verify the presence of candidate proteins at the circulating level. Their muscle source was demonstrated by assessing their gene expression in skeletal muscle and in cultured myotubes. Finally, we also investigated their regulation in muscle cells. Alterations in several molecular pathways potentially involved in muscle atrophy were highlighted using Gene ontology enrichment analyses. Results Our results revealed a dramatic increased production (2-to 25-fold) by the muscle of several acute phase reactants (APR: Haptoglobin, Serpina3n, Complement C3, Serum amyloid A1) which are also released in the circulation during C26 cancer cachexia. Their production was confirmed in other preclinical models of cancer cachexia as well as in cancer patients. The muscular origin of these APR was demonstrated by their increased expression in skeletal muscle and myotubes. Glucocorticoids and pro-inflammatory cytokines contribute directly to their increased expression in muscle cells in vitro, while the role of IL-6 in the muscular induction of these APR was demonstrated in vivo. Conclusions Cancer is associated with marked changes in muscle secretome during muscle wasting. Our study demonstrates a marked increased production of APR by skeletal muscle in pre-clinical models of cancer cachexia and in cancer patients. Further studies are required to unravel the potential role of these proteins in muscle atrophy and their interest as biomarkers of cancer cachexia.