AUTHOR=Gopal Keshav , Almutairi Malak , Al Batran Rami , Eaton Farah , Gandhi Manoj , Ussher John Reyes 

TITLE=Cardiac-Specific Deletion of Pyruvate Dehydrogenase Impairs Glucose Oxidation Rates and Induces Diastolic Dysfunction

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=5

YEAR=2018

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2018.00017

DOI=10.3389/fcvm.2018.00017

ISSN=2297-055X

ABSTRACT=<p>Obesity and type 2 diabetes (T2D) increase the risk for cardiomyopathy, which is the presence of ventricular dysfunction in the absence of underlying coronary artery disease and/or hypertension. As myocardial energy metabolism is altered during obesity/T2D (increased fatty acid oxidation and decreased glucose oxidation), we hypothesized that restricting myocardial glucose oxidation in lean mice devoid of the perturbed metabolic milieu observed in obesity/T2D would produce a cardiomyopathy phenotype, characterized via diastolic dysfunction. We tested our hypothesis via producing mice with a cardiac-specific gene knockout for pyruvate dehydrogenase (PDH, gene name <italic>Pdha1</italic>), the rate-limiting enzyme for glucose oxidation. Cardiac-specific <italic>Pdha1</italic> deficient (<italic>Pdha1</italic><sup>Cardiac−/−</sup>) mice were generated via crossing a tamoxifen-inducible Cre expressing mouse under the control of the alpha-myosin heavy chain (αMHC-MerCreMer) promoter with a floxed <italic>Pdha1</italic> mouse. Energy metabolism and cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Tamoxifen administration produced an ~85% reduction in PDH protein expression in <italic>Pdha1</italic><sup>Cardiac−/−</sup> mice versus their control littermates, which resulted in a marked reduction in myocardial glucose oxidation and a corresponding increase in palmitate oxidation. This myocardial metabolism profile did not impair systolic function in <italic>Pdha1</italic><sup>Cardiac−/−</sup> mice, which had comparable left ventricular ejection fractions and fractional shortenings as their αMHC-MerCreMer control littermates, but did produce diastolic dysfunction as seen via the reduced mitral E/A ratio. Therefore, it does appear that forced restriction of glucose oxidation in the hearts of <italic>Pdha1</italic><sup>Cardiac−/−</sup> mice is sufficient to produce a cardiomyopathy-like phenotype, independent of the perturbed metabolic milieu observed in obesity and/or T2D.</p>