Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia_2

Cancer cachexia syndrome is characterized by extreme weight loss resulting mainly from the depletion of skeletal muscle. Based on the upregulation of catabolism and downregulation of anabolism, we used in vitro the myotube differentiation model to screen oncometabolites as key cachectic mediators. D-2-hydroxyglutarate (D2HG) induced muscle atrophy and proteolysis through the activation of the ubiquitinated proteasome system. D2HG is an oncometabolite produced through IDH1 mutation. Clinical evidence showed that IDH1 mutation in cancer patients resulted in high levels of D2HG and poor survival. The gain of function of mutated IDH1 (R132H) in the murine cancer model resulted in high levels of D2HG, accelerated progression of cachexia, and skeletal muscle deterioration. Excessive D2HG could directly impair the differentiation of myotubes and induced proteolysis through NADPH-dependent metabolic pathways. D2ghdh encodes the mitochondrial enzyme D-2hydroxyglutarate dehydrogenase that can convert D2HG to 2-ketoglutarate. D2hgdh overexpression in well-differentiated myotubes could alleviate D2HG-induced proteolysis and myotube wasting through catalyzing the excess D2HG and rescue the exhaustion of NADPH. The IFH1 inhibitor ivosidenib in the animal experiment of cancer cachexia delayed the progression of cancer cachexia and improved muscle atrophy, and significantly improved the survival rate in IDH1(R132H) mutation mice. These results indicated the contribution of IDH1 mutation in mediating excessive D2HG accumulation in cancer cachexia progression and highlighted the possibility of individualized treatment for cancer cachexia with IDH1 mutation patients.