Abstract 1477: Essential Roles of Atg7 in Starvation-induced and Constitutive Autophagy in the Hearts
Autophagy is an evolutionarily conserved dynamic process that involves the sequestration of intracellular constituents by membranes and subsequent delivery to lysosomes, where they are degradated or recycled. In this sense, autophagy is involved in maintaining cellular homeostasis in physiological conditions. However, autophagy is also implicated in execution of programmed cell death through excessive self-degradation of essential intracellular components. In fact, a growing body of evidence has suggested that autophagy is closely linked to several pathological conditions such as dilated cardiomyopathies, valvular heart diseases, and hypertensive heart diseases. To elucidate the pathophysioliogical roles of autophagy in postnatal hearts, we generated myocyte-specific knockout mice of Atg7 (autophagy-related 7), an essential gene for autophagosome formation, by crossing Atg7-floxed mice with MCK-Cre transgenic mice, which express Cre-recombinase under muscle creatinine kinase promoter. As expected, Atg7-deficiency caused impairment of starvation-induced autophagy in the hearts, as exemplified by the absence of Atg5*âϵ“Atg12 conjugate and autophagy-specific LC-3 type-II fragment in Western blot analysis. In addition, loss of autophagy resulted in progressive cardiac enlargement, which was associated with a significant increase in the heart-to-body weight ratios. Notably, immunohistochemical analysis using an anti-ubiquitin antibody revealed the presence of ubiquitin-containing inclusion bodies in autophagy-deficient hearts. These results suggest that Atg7 is essential for cardiac autophagy in response to starvation, and that constitutive autophagy is responsible for controlling quality of the intracellular proteins in the hearts even under nutrient-rich conditions.