Although studies on muscle wasting have focused predominantly on identifying components of the catabolic machinery, we have limited understanding of how inhibition of anabolic signaling pathways such as Insulin that occurs during fasting regulates these catabolic processes to accelerate the loss of muscle mass. A number of studies have shown that the Insulin Growth Factor Receptor/Insulin Receptor blocks muscle protein breakdown through Forkhead box O (FoxO)-dependent activation of the Ubiquitin-Proteasomal (UPS) and autophagy pathways that are activated in many muscular disorders and aging, however, the molecular links between these components remain poorly defined. To gain mechanistic insights into these processes, we have initiated a number of studies in Drosophila that will allow us to take a systematic genetic dissection of how Insulin regulates autophagy and UPS pathways. These studies will be performed in the context of muscle growth and aging as we have shown that: 1. in larval muscles Insulin signaling is both necessary and sufficient for muscle growth, and that a decrease in muscle mass is accompanied by induction of autophagy;and 2. that overexpression of foxo in aging fly muscles slows down the aging process as detected by reduced accumulation of protein aggregates. In this application we propose to build on these observations and take advantage of the powerful genetic tools available in Drosophila to:
Aim 1 : Characterize the Insulin to autophagy pathway. We will use larval muscles to determine the contribution of known autophagy pathway components to autophagy induced by foxo or Pten overexpression in larval muscle;characterize the role of the Insulin signaling pathway components and in particular of the transcription factor FOXO in this process;and identify autophagy (atg) genes that are regulated transcriptionally by FOXO in muscles.
Aim 2 : Identify novel components of the Insulin to autophagy pathway. We will perform genetic screens based on RNA interference (RNAi) methods in a primary muscle cell system, followed by in vivo validation, to identify genes involved in either the induction or suppression of autophagy. These studies, complemented by proteomic and transcriptional analyses, will allow us to define the structure of the Insulin to autophagy pathway during larval growth.
Aim 3 : Conduct functional studies in aging Drosophila muscles. We will address the role of the UPS and autophagy pathways during aging. In particular, we will determine the mechanism(s) by which FOXO prevents the accumulation of protein aggregates in aging muscles, and the role of Insulin signaling in this process. Altogether, results from these studies will provide important insights into the pivotal role of Insulin and FOXO in regulating anabolic and catabolic pathways during muscle growth and aging. Because of the evolutionary conservation of Insulin signaling and the basic cellular machinery involved in protein degradation, we expect that our studies will be directly relevant to the understanding of muscle wasting associated with muscular dystrophies, cachexia and sarcopenia.
Our studies will address the role of Insulin and FOXO in regulating anabolic and catabolic pathways during muscle growth and aging in Drosophila. Because of the evolutionary conservation of Insulin signaling and the basic cellular machinery involved in protein degradation, our findings in the Drosophila model will be directly relevant to the understanding of muscle wasting associated with muscular dystrophies, cachexia and sarcopenia.
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