| Autor: |
McCommis KS; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. kyle.mccommis@health.slu.edu.; Department of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA. kyle.mccommis@health.slu.edu., Kovacs A; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Weinheimer CJ; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Shew TM; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA., Koves TR; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA., Ilkayeva OR; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA., Kamm DR; Department of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA., Pyles KD; Department of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA., King MT; Laboratory of Metabolic Control, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA., Veech RL; Laboratory of Metabolic Control, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA., DeBosch BJ; Departments of Pediatrics and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA., Muoio DM; Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA., Gross RW; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.; Department of Chemistry, Washington University, St. Louis, MO, USA., Finck BN; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. |
| Abstrakt: |
The myocardium is metabolically flexible; however, impaired flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) complex, composed of MPC1 and MPC2, is required for pyruvate import into the mitochondria. Here we show that MPC1 and MPC2 expression is downregulated in failing human and mouse hearts. Mice with cardiac-specific deletion of Mpc2 (CS-MPC2 -/- ) exhibited normal cardiac size and function at 6 weeks old, but progressively developed cardiac dilation and contractile dysfunction, which was completely reversed by a high-fat, low-carbohydrate ketogenic diet. Diets with higher fat content, but enough carbohydrate to limit ketosis, also improved heart failure, while direct ketone body provisioning provided only minor improvements in cardiac remodelling in CS-MPC2 -/- mice. An acute fast also improved cardiac remodelling. Together, our results reveal a critical role for mitochondrial pyruvate use in cardiac function, and highlight the potential of dietary interventions to enhance cardiac fat metabolism to prevent or reverse cardiac dysfunction and remodelling in the setting of MPC deficiency. |
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