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

被引：98

作者：

McCommis, Kyle S. ^{[1
,2
]}

Kovacs, Attila ^{[1
]}

Weinheimer, Carla J. ^{[1
]}

Shew, Trevor M. ^{[1
]}

Koves, Timothy R. ^{[3
]}

Ilkayeva, Olga R. ^{[3
]}

Kamm, Dakota R. ^{[2
]}

Pyles, Kelly D. ^{[2
]}

King, M. Todd ^{[4
]}

Veech, Richard L. ^{[4
]}

DeBosch, Brian J. ^{[5
,6
]}

Muoio, Deborah M. ^{[3
]}

Gross, Richard W. ^{[1
,7
]}

Finck, Brian N. ^{[1
]}

机构：

[1] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA

[2] St Louis Univ, Sch Med, Dept Biochem & Mol Biol, St Louis, MO 63104 USA

[3] Duke Univ, Duke Mol Physiol Inst, Sch Med, Durham, NC USA

[4] NIAAA, Lab Metab Control, NIH, Bethesda, MD USA

[5] Washington Univ, Dept Pediat & Cell Biol, Sch Med, St Louis, MO USA

[6] Washington Univ, Sch Med, Dept Physiol, St Louis, MO 63110 USA

[7] Washington Univ, Dept Chem, St Louis, MO USA

来源：

NATURE METABOLISM | 2020年 / 2卷 / 11期

关键词：

MYOCARDIAL SUBSTRATE METABOLISM; MALONYL-COA; CARDIAC-HYPERTROPHY; PRESSURE-OVERLOAD; KETONE-BODIES; MOUSE MODEL; RAT-HEART; EXPRESSION; MUSCLE; DEHYDROGENASE;

D O I：

10.1038/s42255-020-00296-1

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：1232 / +

页数：24