| The vertebrate heart grows in response to increased contractile demands. However, as a largely post-mitotic cell type, cardiomyocytes are forced to grow in size, rather than replicate. This process is stimulated and maintained in two ways. First is in response to exercise and pregnancy, whereby cardiomyocytes undergo reversible hypertrophy in the absence of pathological gene expression and contractile dysfunction. Second is the pathological route to hypertrophy, which exposes the cardiomyocyte to metabolic stress and a strong risk for contractile dysfunction as well as death.;I have characterized mechanisms that induce physiological cardiac hypertrophy in the Burmese python following ingestion. In doing so, I found a subset of fatty acids that are elevated in the python plasma after a meal. These fatty acids are capable of inducing ventricular hypertrophy not only in the fasted python, but also in mice. This finding represents a potential supplement for exercise or therapeutic for diseases characterized by cardiomyocyte wasting or death, such as cachexia or dilated cardiomyopathy, respectively.;I also studied a genetic model of hypertrophic cardiomyopathy, which presents canonical features of heart disease and failure (e.g. fetal gene expression, ventricular dilation and contractile dysfunction). I found that the diseased heart displays profound metabolic deficiencies and a compensatory liver response. Rectifying cardiac metabolism (by reactivating metabolic regulators) or normalizing liver function (by inhibiting enhanced de novo glucose production) improves ventricular contractile function and architecture. By demonstrating that a complex metabolic network between organs significantly alters the progression of hypertrophic cardiomyopathy, this study may be helpful in guiding the development of alternative cardiac therapies. |
