Thrombospondin1-regulated atrophy in the heart

Abstract Like skeletal muscle myofibers, cardiomyocytes in the heart constantly adjust their size based on perceived workload or disease stimulation, in which hypertrophic versus atrophic pathways are in balance to achieve an appropriate equilibrium matched to real-time workloads. In a less appreciated process, both heart and skeletal muscle can reduce size through molecular regulatory pathways that cause tissue catabolism. This reduction in size is referred to as atrophy and this process can underlie tissue remodeling and responses to disease stimulation or loss of sufficient nutrients (such as starvation) in which both tissues can serve as metabolic reservoirs. Here we uncovered a novel function for thrombospondin1 as a regulator of both cardiac and skeletal muscle atrophy. We have previously shown that the thrombospondin gene family (Thbs1- 5) plays a critical role in membrane stability through effects on the ER stress response and secretory pathways, as well as controlling the integrin and dystrophin-glycoprotein complexes present with the sarcolemma. However, more recently we have discovered that Thbs1 is uniquely induced by disease stimuli associated with cardiac remodeling and caloric restriction, and that Thbs1 uniquely regulates cellular atrophy and autophagy through an intracellular pathway within the ER/SR that functions at 2 levels. 1) Thbs1 directly binds and regulates the ER stress factor PERK and eIF2α to mediate cardiomyocyte atrophy through the transcription factor ATF4, and 2) Thbs1 selectively expands lysosomes and the vesicular pathway of autophagy. Hence, we hypothesize that Thbs1 is an ER-dependent chaperone that mediates cardiomyocyte size reduction, in part, by driving the catabolic process through autophagy. To investigate this hypothesis, we will interrogate 2 specific aims: 1) To examine the mechanisms of cardiac atrophy and autophagy through PERK/eIF2α/ATF4 signaling mediated by Thbs1 within the ER compartment. 2) To examine a mechanism whereby cardiac autophagy is mediated by Thbs1- dependent formation of lysosomes and associated catabolic vesicular activity. The proposed course of investigation will be conducted in both cultured cardiomyocytes and in genetically modified mouse models so that both reductionist and mechanistic approaches can be taken, as well as in vivo assessment in a physiologically relevant context. The proposed application is innovative as it will define for the first time what appears to be a novel cell biology pathway through Thbs1 that controls striated muscle remodeling through atrophy and autophagy.