2-Deoxy-D-glucose Alleviates Cancer Cachexia-Induced Muscle Wasting by Enhancing Ketone Metabolism and Inhibiting the Cori Cycle

Abstract

Cachexia is characterized by progressive weight loss accompanied by the loss of specific skeletal muscle and adipose tissue. Increased lactate production, either due to the Warburg effect from tumors or accelerated glycolysis effects from cachectic muscle, is the most dangerous factor for cancer cachexia. This study aimed to explore the efficiency of 2-deoxy-D-glucose (2-DG) in blocking Cori cycle activity and its therapeutic effect on cachexia-associated muscle wasting. A C26 adenocarcinoma xenograft model was used to study cancer cachectic metabolic derangements. Tumor-free lean mass, hindlimb muscle morphology, and fiber-type composition were measured after in vivo 2-DG administration. Activation of the ubiquitin-dependent proteasome pathway (UPS) and autophagic–lysosomal pathway (ALP) was further assessed. The cachectic skeletal muscles of tumor-bearing mice exhibited altered glucose and lipid metabolism, decreased carbohydrate utilization, and increased lipid β-oxidation. Significantly increased gluconeogenesis and decreased ketogenesis were observed in cachectic mouse livers. 2-DG significantly ameliorated cancer cachexia-associated muscle wasting and decreased cachectic-associated lean mass levels and fiber cross-sectional areas. 2-DG inhibited protein degradation-associated UPS and ALP, increased ketogenesis in the liver, and promoted ketone metabolism in skeletal muscle, thus enhancing mitochondrial bioenergetic capacity. 2-DG effectively prevents muscle wasting by increasing ATP synthesis efficiency via the ketone metabolic pathway and blocking the abnormal Cori cycle.