Abstract
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 Pdha1), the rate-limiting enzyme for glucose oxidation. Cardiac-specific Pdha1 deficient (Pdha1Cardiac−/−) 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 Pdha1 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 Pdha1Cardiac−/− 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 Pdha1Cardiac−/− 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 Pdha1Cardiac−/− mice is sufficient to produce a cardiomyopathy-like phenotype, independent of the perturbed metabolic milieu observed in obesity and/or T2D.
Highlights
The healthy heart is a metabolic omnivore that is dynamically flexible, constantly switching between carbohydrates and fatty acids as its primary fuel source between repeated periods of refeeding and fasting, respectively [1, 2]
Systolic function appeared normal in Pdha1Cardiac−/− mice, since left ventricular (LV) ejection fraction (LVEF), fractional shortening, and cardiac output were similar in Pdha1Cardiac−/− mice and their αMHC-MerCreMer control littermates (Figure 3A–C), indicating that impaired myocardial glucose oxidation rates do not adversely affect LV systolic function
Despite being a major fuel source for the heart, our observations demonstrate that a marked reduction in glucose oxidation in the heart secondary to cardiac-specific deletion of PDH does not adversely affect LV systolic function
Summary
The healthy heart is a metabolic omnivore that is dynamically flexible, constantly switching between carbohydrates (i.e., glucose) and fatty acids as its primary fuel source between repeated periods of refeeding and fasting, respectively [1, 2]. Studies from Abel and colleagues have demonstrated that both leptin deficient ob/ob and leptin receptor deficient db/db mice exhibit robust increases in myocardial fatty acid oxidation rates, which is associated with a marked reduction in glucose oxidation rates [4]. Short-term high fat feeding of C57BL/6J mice for 2 weeks produces significant increases in myocardial fatty acid oxidation rates and a corresponding decline in myocardial glucose oxidation rates [6]. Such observations have been recapitulated in humans, as PET imaging studies by Peterson et al have demonstrated a marked increase in fatty acid oxidation rates in the hearts of obese women, which positively correlated with overall insulin resistance [7]
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