Characterization of the Insulin to Autophagy Pathway in Muscles

Harvard Medical School, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Autophagy plays important and diverse roles in muscle biology, including a role in glycogen metabolism and muscle homeostasis. In particular, several myopathies are associated with accumulation of autophagic and lysosomal vesicles containing glycogen, but for most of them it remains unclear how glycogen metabolism connects to the pathology of the diseases. In addition, the role of the autophagy-lysosome pathway in muscle wasting is not clear, especially whether it contributes to pathogenesis or serves a protective role. The overall goal of this project is to characterize the mechanisms underlying autophagy in Drosophila muscles and the role autophagy plays during muscle wasting. A high level of conservation with higher organisms makes the Drosophila muscle an attractive system to study the role of autophagy in vivo. We have established two Drosophila models that allow us to: 1) study glycogen autophagy in skeletal muscle and 2) study muscle degeneration. We have made the surprising finding that glycogen synthase (GlyS) is a critical regulator of glycogen autophagy, possibly acting as an autophagic cargo receptor for the glycogen particle, and linking glycogen metabolism to the lysosomal pathway. In Aim 1, we propose to determine if GlyS is a cargo receptor, identify sites or regions on GlyS that are required for binding (direct o indirect) to autophagosomes, determine what signaling pathways regulate glycophagy, and determine whether GlyS function is conserved in mammalian cells. In Aim 2, we will identify other factors involved in the transport of glycogen to lysosomes using proteomic approaches and will distinguish between factors involved specifically in selective glycogen autophagy, and factors involved in other types of autophagy that occur in muscles. In Aim 3, we will characterize, using our Drosophila wasting model, the role of the autophagy-lysosome pathway in degradation of muscle proteins. Altogether, these studies will provide fundamental insights into the role of autophagy in muscles and its regulation.