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

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.

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Fig. 1: MPCs are downregulated in human heart failure, and deletion of cardiac MPC2 results in TCA cycle dysfunction.
Fig. 2: CS-MPC2−/− mice develop dilated cardiomyopathy.
Fig. 3: KD can prevent heart failure in CS-MPC2−/− mice.
Fig. 4: KD downregulates cardiac ketone body catabolism.
Fig. 5: KD enhances cardiac fatty acid metabolism.
Fig. 6: HF diets also prevent cardiac remodelling and dysfunction in CS-MPC2−/− mice.
Fig. 7: Improved cardiac remodelling during fasting is associated with enhanced fat oxidation.
Fig. 8: KD can reverse heart failure in CS-Mpc2−/− mice.

Data availability

All data from these studies are contained within this manuscript, the figures, and extended/supplemental figures and tables. Data are also available from the corresponding author upon reasonable request. Source data are provided with this paper.

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Acknowledgements

We sadly note that, Richard (Bud) L. Veech passed away at the age of 84 during the preparation of this manuscript. We thank him for providing the ketone ester diet and his enthusiasm toward this project. This work was supported by core resources of the Nutrition Obesity Research Center (NORC) (P30 DK56341), Diabetes Research Center (DRC) (P30 DK020579), and Institute for Clinical and Translational Sciences (ICTS) (UL1 TR002345) at the Washington University School of Medicine. NIH grant nos. K99/R00 HL136658 (to K.S.M.), R01 HL133178 (to R.W.G.) and R01 HL119225 and R01 DK104735 (to B.N.F.) supported these studies.

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Authors

Contributions

K.S.M. and B.N.F. conceived the study. K.S.M., A.K., C.J.W., T.M.S., T.R.K., O.R.I., D.M.M. and B.N.F. designed the study. Acquisition and analysis were conducted by K.S.M., A.K., C.J.W., T.R.K., O.R.I., D.R.K. and K.D.P. The resources were obtained by M.T.K., R.L.V., B.J.D. and R.W.G. Writing and editing of the manuscript were done by K.S.M., A.K., C.J.W., T.M.S., T.R.K., O.R.I., D.M.M., D.R.K., K.D.P., M.T.K., B.J.D., R.W.G. and B.N.F.

Corresponding author

Correspondence to Kyle S. McCommis.

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Competing interests

K.S.M. previously received research support from Cirius Therapeutics, and B.N.F. is a stockholder and scientific advisory board member of Cirius Therapeutics. R.L.V. held patents on the synthesis and uses of ketone esters, and M.T.K. is a coinventor in the synthesis of ketone esters. All other authors have declared that no competing interests exist.

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Extended data

Extended Data Fig. 1 Human heart failure gene expression and characterization of 6-week old CS-MPC2−/− mice.

Gene expression from human non-failing, failing, and failing hearts after left ventricular assist device (LVAD) placement (n = 14, 9, and 6 for Non-failing, Failing, and Post-LVAD, respectively). c-d, MPC1 and MPC2 protein expression quantification from non-failing and failing human hearts normalized to either VDAC, complex I and II, complexes III and IV, or Tubulin (n = 5). e, Gene expression for Mpc1 and Mpc2 from wildtype C57BL6/J mouse hearts after sham or transverse aortic constriction plus myocardial infarction (TAC + MI) surgery (n = 9 sham, 12 TAC-MI). f, Mouse heart gene expression for Mpc1 and Mpc2 (n = 7, 5, 7 for fl/fl, +/−, −/− respectively). g, Blood lactate measured after a 4 h fast prior to sacrifice in 6-week old mice (n = 6). h-i, Heart weight and lung weight of 6-week old mice (n = 6). j, Mouse heart gene expression of heart failure, and hypertrophy genes from 6-week old mice (n = 7, 5, 7 for fl/fl, +/−, −/− respectively). Data are presented as mean ± s.e.m. within dot plot. Each data point represents one individual mouse or sample. Two-tailed unpaired Student’s t test.

Extended Data Fig. 2 Heart failure develops in CS-MPC2−/− mice, but not CS-MPC2 +/− or mice treated with the MPC inhibitor MSDC-0602K.

a-h, Serial echocardiography data of chow-fed mice at 6, 10, and 16 weeks of age. Left ventricular internal diameter at end diastole (LVIDd) and end systole (LVIDs), end systolic volume (ESV), fractional shortening (FS), relative wall thickness (RWT), stroke volume (SV), and cardiac output (CO) (n = 7, 10, and 9 for fl/fl, +/−, and −/−, respectively). i, Heart weights from WT mice fed low fat (LF) diet or a high trans-fat, fructose, cholesterol (HTF-C) diet +/− 330 ppm MSDC-0602, an insulin-sensitizing MPC inhibitor (n = 7, 9, and 9 for LF, HTF-C, and HTF-C + MSDC-0602K, respectively). j, Heart gene expression of hypertrophy gene markers from WT mice fed LF, HTF-C, or HTF-C + MSDC-0602 diets (n = 6 for all groups). k-l, Heart gene expression for fatty acid transport and oxidation genes and PPARα target genes from chow-fed 16-week old mice after a 4 h fast (n = 7, 5, and 7 for fl/fl, +/−, and −/−, respectively). Data are presented as mean ± s.e.m., or mean ± s.e.m. within dot plot. Each data point represents one individual mouse or sample. Two-tailed unpaired Student’s t test.

Extended Data Fig. 3 Ketogenic diet prevents heart failure in CS-MPC2−/− mice.

a, Body weights of mice fed low fat (LF) or ketogenic diet (KD) from 6-17 weeks of age (initial n = 19, 15, 21, and 14 for fl/fl LF, CS-Mpc2−/− LF, fl/fl KD, and CS-Mpc2−/− KD, respectively)(fl/fl LF vs KD p < 0.0001; CS-Mpc2−/− LF vs KD p < 0.0001). b-c, Blood glucose and plasma insulin measured after a 4 h fast (n = 19, 11, 20, and 14, respectively for glucose and 8, 5, 9, and 7, respectively for insulin). d-n, Echocardiography data at 10 and 16 weeks of age. Left ventricular internal diameter at end diastole (LVIDd) and end systole (LVIDs), fractional shortening (FS), relative wall thickness (RWT), end diastolic volume (EDV), end systolic volume (ESV), stroke volume (SV), ejection fraction (EF), and cardiac output (CO) (n = 9, 7, 12, and 9 for fl/fl LF, CS-Mpc2−/− LF, fl/fl KD, and CS-Mpc2−/− KD, respectively). o-q, % Fat mass, % lean mass, and % free water body composition measured by echoMRI (n = 19, 12, 20, and 14, respectively). r-s, Gonadal and inguinal white adipose tissue (WAT) weights normalized to body weight (n = 19, 12, 20, and 14, respectively). Data are presented as mean ± s.e.m. or mean ± s.e.m. within dot plot. Each data point in dot plot represents one individual mouse sample. Two-way ANOVA with Tukey’s multiple comparisons test. For d-n, black p values indicate LF-fed fl/fl vs. CS-Mpc2−/−, red p values indicate LF vs. KD for CS-Mpc2−/− for each echocardiography date.

Extended Data Fig. 4 Ketone body injection modestly reduces cardiac remodeling in CS-MPC2−/− mice.

a, Timeline for β-hydroxybutyrate (βHB) injection experiment in which CS-MPC2−/− mice were injected i.p. with saline vehicle or 10 mmol/kg βHB daily from 12 to 14 weeks of age. b-h, Echocardiography measurements before and after 2 weeks of daily i.p. injection of saline vehicle (Veh) or 10 mmol/kg β-hydroxybutyrate. Left ventricular (LV) mass index, end-diastolic volume (EDV), end-systolic volume (ESV), heart rate (HR), relative wall thickness (RWT), ejection fraction (EF), and cardiac output (CO) (n = 4 Veh, 5 βHB). i, Plasma total ketone body concentrations (n = 4 Veh, 5 βHB). j, Heart weight normalized to tibia length (n = 4 Veh, 5 βHB). k, Gene expression markers of hypertrophy, heart failure, and fibrosis from hearts after 2 weeks of daily vehicle or βHB treatment (n = 4 Veh, 5 βHB). Data presented either as PRE-POST, or mean ± s.e.m. shown within dot plot. Each symbol represents an individual sample. Two-tailed unpaired Student’s t test.

Extended Data Fig. 5 Ketone ester diet does not improve cardiac remodeling or function in CS-MPC2−/− mice.

a, Plasma ketone bodies measured from mice fed either control or ketone ester (KE)-supplemented diet (n = 10, 7, 4, and 8, respectively). b-e, Echocardiography measurements after 6 weeks of KE diet feeding. Left ventricular (LV) mass index, end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) (n = 10, 7, 4, and 8, respectively). f, Heart weight normalized to tibia length (n = 10, 7, 4, and 8, respectively). g-i, Cardiac gene expression markers of hypertrophy and heart failure (Nppa, Nppb, Acta1) (n = 10, 7, 4, and 8, respectively). Data presented as mean ± s.e.m. shown within dot plot. Each symbol represents an individual sample. Two-way ANOVA with Tukey’s multiple comparisons test.

Extended Data Fig. 6 High-fat diets also greatly improve cardiac remodeling and function of CS-MPC2−/− mice.

a-I, Echocardiography measurements taken at 16 weeks of age after 10 weeks of low fat (LF), medium chain triglyceride (MCT), or high-fat (HF) feeding. Left ventricular internal diameter at end diastole (LVIDd) and end systole (LVIDs), fractional shortening (FS), relative wall thickness (RWT), end diastolic volume (EDV), end systolic volume (ESV), stroke volume (SV), and cardiac output (CO) (n = 5, 4, 4, 8, 4, and 5, respectively). j-l, Cardiac gene expression for Ppara and it’s targets Acot1 and Hmgcs2 (n = 11, 6, 10, 8, 4, and 5, respectively). Data are presented as mean ± s.e.m. within dot plot. Each data point represents an individual mouse. Two-way ANOVA with Tukey’s multiple comparisons test.

Extended Data Fig. 7 A 24 hour fast improves cardiac remodeling by enhancing fat oxidation.

a, Blood lactate of fed or fasted mice just prior to euthanasia (n = 22, 15, 16, and 14, respectively). b, Cardiac glycogen concentrations in hearts of fed and fasted mice (n = 10, 14, 15, and 14, respectively). c, Plasma TAG from fed or fasted mice (n = 22, 15, 16, and 14, respectively). d-i, Cardiac gene expression for natriuretic peptides and PPARα-target and fatty acid metabolism genes (n = 8, 9, 7, and 6, respectively). Data are presented as mean ± s.e.m. within dot plot. Each symbol on dot plot represents an individual sample. Two-way ANOVA with Tukey’s multiple comparisons test.

Extended Data Fig. 8 Ketogenic diet reverses heart failure in CS-MPC2−/− mice.

a-h, Echocardiography measurements before and after 3 weeks of LF or KD feeding in 16-week-old CS-MPC2−/− mice with established heart failure (n = 3 LF, 5 KD). Data are presented as PRE-POST. Each data point represents an individual mouse. Paired two-tailed student’s t-test for PRE vs. POST. Unpaired two-tailed student’s t-test for LF vs. KD.

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Supplementary Video 1

Cardiac dysfunction and remodelling prevented by ketogenic diet.

Supplementary Video 2

Cardiac dysfunction improved by high-fat diets.

Supplementary Video 3

Three weeks of ketogenic diet reverses heart failure in CS-MPC2−/− mice.

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Unprocessed western blots.

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McCommis, K.S., Kovacs, A., Weinheimer, C.J. et al. Nutritional modulation of heart failure in mitochondrial pyruvate carrier–deficient mice. Nat Metab 2, 1232–1247 (2020). https://doi.org/10.1038/s42255-020-00296-1

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