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Nutritional Modulation of Heart Failure in Mitochondrial Pyruvate Carrier-Deficient Mice
- Source :
- Nat Metab
- Publication Year :
- 2020
-
Abstract
- 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. Impaired myocardial metabolic flexibility is associated with cardiac dysfunction in diabetes and heart failure. McCommis et al. reveal a critical role for mitochondrial pyruvate use in cardiac function, and use dietary interventions to enhance cardiac fat metabolism in dilated cardiomyopathy.
- Subjects :
- Cardiac function curve
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Anion Transport Proteins
Citric Acid Cycle
Down-Regulation
Ketone Bodies
Mitochondrion
Mitochondrial Membrane Transport Proteins
Article
Mitochondria, Heart
Mice
Physiology (medical)
Internal medicine
Pyruvic Acid
Internal Medicine
medicine
Animals
Humans
Metabolomics
Heart metabolism
Heart Failure
Mice, Knockout
business.industry
Myocardium
Dilated cardiomyopathy
Cell Biology
Fasting
medicine.disease
Lipid Metabolism
Myocardial Contraction
Mice, Inbred C57BL
Endocrinology
Heart failure
Ketone bodies
cardiovascular system
Ketosis
business
Diet, Ketogenic
Ketogenic diet
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Nat Metab
- Accession number :
- edsair.doi.dedup.....7af51cfcfd656fcb0072d8d617a575b2