Cancer cachexia is a multifactorial metabolic syndrome characterized by loss of skeletal muscle and adipose tissue, leading to reduced physical function, impaired treatment tolerance, and increased mortality. Cachexia is associated with a hypermetabolic state in which hepatic gluconeogenesis and Cori cycle activity are upregulated, increasing whole-body energy expenditure. Tumor-derived lactate is believed to be the main driver of the increase in Cori Cycle flux. Transforming growth factor-β (TGF-β) is a pluripotent cytokine involved in cancer progression and elevated in patients with cachexia. TGF-β induces modest atrophy in vitro and impairs muscle regeneration but its metabolic effects on skeletal muscle are unknown. The objective of the study was to explore the effect of TGF-β1 treatment on C2C12 myotube metabolism. Our hypothesis was that TGF-β1 induces a glycolytic shift in muscle cells through upregulation of the rate-limiting enzymes hexokinase and phosphofructokinase. We treated C2C12 myotubes with 10 ng/ml of TGF-β1 or vehicle for 24 hours. Glycolysis was assessed by glucose disappearance, lactate accumulation in the media, Seahorse assay, and metabolomics. RNA-sequencing was performed to identify potential mechanisms, which was confirmed by quantitative PCR. TGF-β treatment of C2C12 myotubes induced glycolysis, resulting in increased glucose disposal and lactate production. This was confirmed by a Seahorse glycolytic capacity assay which demonstrated TGF-b-treated myotubes had elevated glycolytic capacity in addition to increased basal glycolysis. Metabolomics confirmed reduced glucose and increased glycolytic metabolites in myotubes. This metabolic reprogramming is accompanied by a surprising decrease in Hexokinase 2 and phosphofructokinase expression. In conclusion, beyond its role in driving muscle atrophy, TGF-β can increase glycolysis in skeletal muscle cells, resulting in increased lactate production. Therefore, skeletal muscle is a previously overlooked organ that may contribute to circulating lactate in cachexia and should be investigated further as a potential contributor to the hypermetabolic state observed in cancer. Funded by American Cancer Society IRG 21-141-46. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Riwhie et al. (Fri,) studied this question.