Characterization of the Insulin to Autophagy Pathway in Muscles

摘要/摘要

SUMMARY / ABSTRACT Understanding the molecular mechanisms underlying muscle growth and wasting is highly relevant to conditions such as anorexia, sarcopenia, and diseases such as cachexia. Muscle size is regulated by the coordinated balance between protein synthesis and degradation. The IGF1-AKT-mTOR axis is a central player in regulating increase in protein synthesis by stimulating the translational machinery while simultaneously blocking protein degradation pathways, the ubiquitin-proteasome system and the autophagy-lysosome pathway. Drosophila muscle is a well-established system to study the maintenance of muscle mass, TOR signaling and autophagy. We have recently identified two new RNA biogenesis signaling pathways that regulate autophagy and metabolism downstream of TOR. In Aim 1, we will characterize RNA biogenesis processes regulated by TOR signaling in muscles, focusing on the regulation of autophagy and metabolism. In addition, we have established the adult fly midgut as a model to study tumor-induced host wasting. This model has allowed us to precisely follow transcriptional changes and morphological events leading to muscle wasting. In Aim 2, we will characterize the role of REPTOR, a transcription factor downstream of TOR, that we hypothesize acts as a “master regulator of cachexia” and will characterize its regulation and target genes. We will also analyze the role of mitophagy in muscle wasting. Finally, we have identified three factors, ImPL2, PvF1, and Upd3, derived from gut tumors that contribute to muscle wasting. We will characterize the role of an additional pathway, the Branchless/FGF pathway. In addition, we will perform a proteomic screen using a novel proximity labeling method to identify additional factors derived from tumors that affect wasting. Altogether, our studies will reveal novel cell autonomous and non-autonomous molecular mechanisms involved in the regulation of muscle mass. Considering the high level of conservation between Drosophila and higher organisms our studies are likely to help in the long term to devise treatments of conditions such as anorexia, sarcopenia and cachexia.