WeightControl.com Interview with:
Kyle S. McCommis, Ph.D.
Assistant Professor
Biochemistry & Molecular Biology
St. Louis University School of Medicine
WeightControl.com: What is the background for this study? What are the main findings?
Response: It is well established that the heart is normally very flexible in what substrates it can metabolize in order to quickly adapt to different physiological scenarios. However, in cardiomyopathies such as heart failure, this metabolic flexibility is lost and there is a decreased ability for the heart to perform oxidative metabolism. This has previously been attributed mainly to a decrease in fat oxidation by the heart, but some studies also indicate decreased glucose oxidation.
We therefore were interested to see if the mitochondrial pyruvate carrier (MPC), which transports pyruvate derived from glucose or lactate into the mitochondria, could be playing a role in heart failure.
We first identified lower expression of the MPC proteins in failing human hearts compared to non-failing control hearts. We then created a MPC2 knockout mouse, which spontaneously developed heart failure with age. These failing hearts of course could not metabolize pyruvate, but they also displayed lower expression of fat oxidation enzymes.
We hypothesized that the hearts may be improved if we provided the mice with a diet that provided nutrients the hearts were better able to use. When we switched the diet to a low carbohydrate, high fat “ketogenic” diet, these MPC2 knockout mice no longer showed any signs of heart failure. We also aged some mice to where they developed severe heart failure, then switched them to the ketogenic diet, and shockingly observed almost complete reversal of their cardiac dysfunction. This lead us to question how the diet was rescuing these hearts; was it due to improved ketone body metabolism by the hearts, or due to improved fat metabolism from the large amount of dietary fat.
Essentially all of our experiments suggested that these failing hearts we regaining the ability to oxidize fatty acids, and were actually shutting off ketone body metabolism. Feeding the mice a normal “high fat” diet which contains enough carbohydrate and protein to not be overly ketogenic, was also able to prevent the heart failure in these mice.