Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure

Heart failure involves metabolic changes such as decreased fat and glucose oxidation and increased glycolysis. The mitochondrial pyruvate carrier (MPC) transports pyruvate into the mitochondrial matrix and previous studies have showed that heart failure decreases MPC protein expression and cardiac-specific MPC2-/- mice (csMpc2-/-) spontaneously develop heart failure. However, it is unknown why loss of the MPC results in heart failure. The objective of this study was to investigate the link between the loss of MPC and heart failure. Targeted metabolomics and isotope tracing was performed in fl/fl and csMpc2-/- hearts after i.p. injection of U- 13 C-glucose to measure cardiac 13 C enrichment into glucose metabolites by LC-MS/MS. Cardiac glycogen was assessed biochemically and by electron microscopy. Glucose uptake was measured in cardiac muscle fibers by 3 H-2-deoxyglucose. Glycogen regulating enzymes were measured by western blot. fl/fl and csMpc2-/- mice were fed low fat control, or ketogenic diet. WT mice were infused with AngII and fed low fat or ketogenic diet. From our metabolomic analyses, surprisingly the failing csMpc2-/- hearts contained normal levels of both ATP and phosphocreatine high-energy phosphate pools. The failing csMpc2-/- hearts displayed increased enrichment from 13 C-glucose throughout the glycolytic pathway, increased glycolytic metabolite pool size, and a ~6X increase in glycogen levels, despite enhanced inhibitory phosphorylation of glycogen synthase. csMpc2-/- hearts also displayed increased glucose uptake both basally, and with insulin stimulation. Glycolytic enrichment was also increased in non-failing csMpc2-/- hearts of young mice, yet glycogen levels remained unchanged compared to fl/fl. Two weeks of ketogenic diet completely normalized the cardiac glycogen and reversed the HF in both the csMpc2-/- and AngII models. Lastly, mice were treated twice daily for two weeks with 100 mg/kg MZ-101, a glycogen synthase-1 inhibitor, which significantly reduced the size of failing csMpc2-/- hearts. These results suggest the loss of MPC in the heart increases glycolytic metabolism and ultimately glycogen accumulation and heart failure. Thus, the loss of MPC in the heart results in a glycogen storage disease phenotype, causing heart failure. NIH R00 HL136658, SLU start up funds, Doisy Scholar Fellowship This abstract was presented at the American Physiology Summit 2025 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.