Nutritional modulation of heart failure in mitochondrial pyruvate carrier-deficient mice

Nat Metab. 2020 Nov;2(11):1232-1247. doi: 10.1038/s42255-020-00296-1. Epub 2020 Oct 26.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anion Transport Proteins / genetics
  • Anion Transport Proteins / metabolism*
  • Citric Acid Cycle / genetics
  • Diet, Ketogenic
  • Down-Regulation
  • Fasting
  • Heart Failure / diagnostic imaging
  • Heart Failure / genetics*
  • Heart Failure / therapy*
  • Humans
  • Ketone Bodies / metabolism
  • Lipid Metabolism / genetics
  • Metabolomics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Heart / metabolism
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Myocardial Contraction
  • Myocardium / metabolism
  • Pyruvic Acid / metabolism

Substances

  • Anion Transport Proteins
  • Ketone Bodies
  • MPC2 pyruvate carrier protein, mouse
  • Mitochondrial Membrane Transport Proteins
  • Pyruvic Acid