McCommis 2020 Nat Metab

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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 (2020) Nutritional modulation of heart failure in mitochondrial pyruvate carrier-deficient mice. Nat Metab 2:1232-47.

» PMID: 33106690

McCommis Kyle S, Kovacs Attila, Weinheimer Carla J, Shew Trevor M, Koves Timothy R, Ilkayeva Olga R, Kamm Dakota R, Pyles Kelly D, King M Todd, Veech Richard L, DeBosch Brian J, Muoio Deborah M, Gross Richard W, Finck Brian (2020) Nat Metab

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.


Bioblast editor: Plangger M O2k-Network Lab: US NC Durham Koves TR, US MO St Louis Gross RW, US MO St Louis Finck B, US MO St Louis McCommis KS


Labels: MiParea: Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style  Pathology: Cardiovascular 

Organism: Mouse  Tissue;cell: Heart  Preparation: Permeabilized tissue, Isolated mitochondria 


Coupling state: LEAK, OXPHOS  Pathway: F, N, S, NS  HRR: Oxygraph-2k 

2020-11