Ketogenic Diet Prevents Heart Failure from Defective Mitochondrial Pyruvate Metabolism

Abstract

The myocardium is metabolically flexible and can use fatty acids, glucose, lactate/pyruvate, ketones, or amino acids to fuel mechanical work. However, impaired metabolic flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) is required for pyruvate metabolism and is composed of a hetero-oligomer of two proteins known as MPC1 and MPC2. Interestingly, MPC1 and MPC2 expression is downregulated in failing human hearts and in a mouse model of heart failure. Mice with cardiac-specific deletion of MPC2 (CS-MPC2-/-) exhibited loss of both MPC2 and MPC1 proteins and reduced pyruvate-stimulated mitochondrial respiration. CS-MPC2-/mice exhibited normal cardiac size and function at 6-weeks old, but progressively developed cardiac dilation and contractile dysfunction thereafter. Feeding CS-MPC2-/-mice a ketogenic diet (KD) completely prevented or reversed the cardiac remodeling and dysfunction. Other diets with higher fat content and enough carbohydrate to limit ketosis also improved heart failure in CS-MPC2-/-mice, but direct ketone body provisioning provided only minor improvements in cardiac remodeling. Finally, KD was also able to prevent further remodeling in an ischemic, pressure-overload mouse model of heart failure. In conclusion, loss of mitochondrial pyruvate utilization leads to dilated cardiomyopathy that can be corrected by a ketogenic diet.

Octanoate is differentially metabolized in liver and muscle and fails to rescue cardiomyopathy in CPT2 deficiency

“…Because both rapamycin and trichostatin A improve mitochondrial oxidative metabolism in normal hearts ( 48 , 49 , 50 , 51 , 52 , 53 ), our data suggested that restoration of cardiac fatty acid oxidation is required for the effectiveness of these therapies. In agreement, both high-fat diet and medium-chain ketogenic diet were shown to improve severe cardiac hypertrophy in models of impaired cardiac pyruvate oxidation ( 21 , 34 ). These results suggest that increased flux of either ketones or fatty acids through oxidative metabolism can compensate for the loss of carbohydrate-oxidative metabolism and restore cardiac structure.…”

“…Octanoate boluses and medium-chain ketogenic diets can increase circulating ketone bodies ( 33 ) because of stimulation of high rates of medium-chain mFAO flux in the liver. Importantly, medium-chain ketogenic diets can completely revert severe cardiac hypertrophy in models of impaired cardiac pyruvate oxidation ( 21 , 34 ). Thus, to test the ability of highly enriched medium-chain ketotic feeding to alleviate the cardiac phenotype in the absence of carnitine mediated-fatty acid oxidation, a diet was formulated with octanoate (OctD) as a majority of the diet.…”

“…Thus, both ketogenic diets attenuated mitochondrial metabolic stress-induced myomitokine expression profiles in Cpt2 M−/− hearts, whereas minimal changes were observed in control hearts. Because medium-chain ketogenic diet corrected hypertrophy in a model of impaired pyruvate metabolism ( 21 , 34 ), we next questioned the effect of the LCKD and OctD diets on regulators of pyruvate oxidation. Cpt2 M−/− hearts had increased pyruvate dehydrogenase kinase 4 mRNA abundance and PDH phosphorylation, and neither LCKD nor OctD altered these regulators of pyruvate oxidative metabolism in either genotype suggesting that the diets may not directly impact pyruvate oxidation ( Fig.…”

Targeting hepatocyte carbohydrate transport to mimic fasting and calorie restriction

“…Trehalose and LT reduced fructose‐induced hepatic steatosis and induced hepatocyte fasting response signals, PGC1α, TFEB, and FGF21. Extrahepatic cardiometabolic effects of these compounds are broad, including peripheral insulin sensitization [118], activating peripheral thermogenesis, reduced adipocyte hypertrophy [119,120], in addition to reduced atherosclerotic plaque lesion area [27,121] and pathological cardiac remodeling in response to injury [122,123], that mimicked ketogenic dietary effects on heart failure [37]. Treating liver‐specific GLUT8‐deficient mice with oral trehalose did not increase the efficacy of trehalose on diet‐induced hepatic steatosis, which implies some mechanistic overlap between GLUT8 deletion and trehalose action [9].…”

“…Moreover, in children with NAFLD, low‐glycemic index foods reduced systolic blood pressure, plasma ALT, and insulin resistance indices (HOMA‐IR) after 3‐ and 6‐month treatment [35]. In mice, ketogenic diets reduce circulating lipids, intrahepatic lipids, and insulin resistance markers [36], and improve cardiac function during heart failure [37]. In balance of these findings, low‐carbohydrate diets in some contexts do not outperform other forms of caloric restriction [38].…”