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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • McCommis, KS; Kovacs, A; Weinheimer, CJ; Shew, TM; Koves, TR; Ilkayeva, OR; Kamm, DR; Pyles, KD; King, MT; Veech, RL; DeBosch, BJ; Muoio, DM; Gross, RW; Finck, BN

Published Date

  • November 2020

Published In

Volume / Issue

  • 2 / 11

Start / End Page

  • 1232 - 1247

PubMed ID

  • 33106690

Pubmed Central ID

  • PMC7957960

Electronic International Standard Serial Number (EISSN)

  • 2522-5812

Digital Object Identifier (DOI)

  • 10.1038/s42255-020-00296-1

Language

  • eng

Conference Location

  • Germany