Mechanism by which fatty acid metabolism impacts muscle maintenance

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Project Summary Due to their essential roles in fundamental biological processes (e.g., energy production and membrane formation), the availability of fatty acids (FAs) profoundly impacts the initiation and progression of various cellular and developmental events in animals. In particular, fat or FA levels have long been proposed to promote reproductive development, as well as neuronal and muscle functions for foraging ability under fasting conditions. Extensive studies have also revealed a cause/effect relationship between abnormal FA metabolism and pathologic conditions, including age-related neurological and muscular diseases. However, mechanisms underlying the impact of FA levels on specific physiological functions, especially functions regulated by FA-sensing mechanisms in specific tissues, have been underexplored. Our recent study found that an acyl-coA synthetase and protein myristoylation act as a FA sensor in the germline to regulate the onset of oogenesis by modulating the sex-determination. Based on this finding, we propose to elucidate the mechanisms by which FA availability regulates muscle maintenance and provide insights into the pathogenesis of FA metabolism-related degenerative diseases. We have obtained extensive preliminary data for a hypothesis where myristoylation deficiency of two ARF GTPases, and other proteins in muscle, mediate the impact of FA deficiency on sarcomere integrity by inducing ER stress and unfolded protein responses (UPR) that are known to be involved in the genesis of major diseases. We proposed three specific research aims to further investigate this hypothesis and the underlying mechanism. In Aim 1, we will use both molecular and genetic approaches to determine the role of myristoylation in muscle to maintain sarcomere integrity. Myristoylation level and subcellular localization of specific regulatory factors will be examined for roles in mediating the effect of FA level change on muscle functions. In Aim 2, we will analyze the role of ER stress and UPR in mediating the impact of myristoylation deficiency on muscle maintenance. We will first characterize ER stress and changes in the 3 UPR pathways in responding to FA and myristoylation deficiency. We will then test if experimentally inducing ER stress causes muscle defects similar to that from myristoylation deficiency, and whether repressing ER stress can rescue the muscle functions under myristoylation deficiency. For Aim 3, we will turn our attention to understanding how myristoylation and ER stress impact muscle integrity. We will use two systematic approaches, one expression analysis-initiated and one based on a suppressor screen, to search for factors that act downstream of or in parallel to UPRER in FA/myristoylation deficiency-induced muscle defects. We have already started analyzing one promising candidate, UNC-97/PINCH, that appears to play a significant role in the process. The proposed research will make significant advances in our understanding of the impact of FA metabolism on muscle functions.