# Regulation of Muscle Mitochondrial Protein Homeostasis by Insulin/IGF-1/FoxO Signaling

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2021 · —

## Abstract

Insulin resistance and uncontrolled diabetes are very common among Veterans and lead to decreased
muscle strength, contributing to impaired recovery from illness and other disease-related morbidity. Indeed,
patients with diabetes recover strength slower after major surgery than non-diabetic patients. These changes
are associated with decreased muscle mitochondrial energy production, but the signals that control
mitochondrial metabolism in muscle during diabetes remain incompletely understood. We recently showed
that insulin receptors (IR) and IGF-1 receptors (IGF1R) display overlapping roles in the control of muscle
protein turnover through cellular autophagy, or “self-eating”, to maintain muscle mass, and that this control is
dependent on FoxO transcription factors. Furthermore, our preliminary studies show that knockout of
IR/IGF1R both chronically and acutely lead to mitochondrial abnormalities that can be prevented by deletion of
FoxOs in muscle. The goal of this proposal is to investigate whether FoxO proteins control muscle
mitochondrial metabolism and mitochondrial-specific autophagy, or “mitophagy”, in the context of decreased IR
and IGF1R signaling. To accomplish the goals of this project we propose 2 aims: Aim 1 will quantify mitophagy
using mitoTIMER/LAMP1-YFP and Parkin-YFP mitophagy biosensors in muscle from muscle-specific inducible
IR knockout, both IR/IGF1R knockout, or IR/IGF1R with FoxO1/3/4 quintuple knockout mice in concert with
measurements of mitochondrial bioenergetics; Aim 2 will determine the regulation of transcriptional and
protein homeostatic mechanisms by which loss of IR/IGF1R and/or FoxOs signaling in muscle leads to
impairment of mitochondrial Complex I. Our long-term goals are to understand the impact of diabetes and
insulin resistance on mitochondrial protein turnover in muscle to gain insights into the metabolic and
mitochondrial changes that can contribute to decreased strength and other complications of diabetes, which
are a significant source of morbidity and disability in our Veteran population.

## Key facts

- **NIH application ID:** 10075111
- **Project number:** 5I01BX004468-02
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Brian Timothy O'Neill
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075111

## Citation

> US National Institutes of Health, RePORTER application 10075111, Regulation of Muscle Mitochondrial Protein Homeostasis by Insulin/IGF-1/FoxO Signaling (5I01BX004468-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10075111. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*