# Characterization of the Insulin to Autophagy Pathway in Muscles

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2022 · $512,987

## Abstract

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.

## Key facts

- **NIH application ID:** 10426200
- **Project number:** 5R01AR057352-13
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** NORBERT PERRIMON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $512,987
- **Award type:** 5
- **Project period:** 2010-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426200

## Citation

> US National Institutes of Health, RePORTER application 10426200, Characterization of the Insulin to Autophagy Pathway in Muscles (5R01AR057352-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10426200. Licensed CC0.

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