# Roles of FoxO interactions in diabetic and age-related muscle disease

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

Uncontrolled type 2 diabetes is more common among Veterans than the general population and leads
to decreased muscle strength and increased muscle fatigue, contributing to impaired recovery from illness and
disability. Many other veterans have Type 1 diabetes that contributes to muscle weakness even with
reasonable glycemic control. These changes are also seen in aging and both conditions are associated with
mitochondrial dysfunction in muscle, but the signals that control mitochondrial metabolism in muscle during
diabetes and aging remain incompletely understood. We recently reported that mouse models of
streptozotocin (STZ) diabetes or aging cause muscle atrophy and mitochondrial dysfunction, which both
depend on FoxO transcription factor activation. FoxO activation in STZ diabetic muscle represses nuclear-
encoded mitochondrial gene transcription, particularly OXPHOS complex I subunits, and can be prevented by
deletion of FoxOs in muscle. Since inhibition of FoxOs in non-muscle tissues can lead to cancer, defining the
muscle-specific FoxO protein interactions that lead to improved muscle mitochondrial function in diabetes or
aging are critical to improve the treatment of muscle weakness. We have preliminary data demonstrating that
FoxOs and Sin3a corepressors are co-localized on OXPHOS promoters and that FoxO or Sin3a
overexpression can repress many complex I subunit genes. The goal of this proposal is to investigate the role
of FoxO interacting proteins in muscle mitochondrial function and muscle fatigue in the context of uncontrolled
diabetes or aging. To accomplish the goals of this project we propose 2 aims: Aim 1 will determine the
contribution of FoxO-Sin3 interactions to repression of Complex I (CI) and mitochondrial dysfunction in
diabetes; Aim 2 will determine the molecular interactions with FoxOs that contribute to repression of
mitochondrial function and muscle fatigue in aging. Our long-term goals are to understand the role of FoxOs
and FoxO-target genes in diabetes-induced defects of mitochondrial energy production in muscle to gain
insights into the metabolic changes that can contribute to decreased strength, increased fatigue and ultimately
lead to disability which is so common in our Veteran population.

## Key facts

- **NIH application ID:** 10918617
- **Project number:** 2I01BX004468-05A1
- **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:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2020-01-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918617

## Citation

> US National Institutes of Health, RePORTER application 10918617, Roles of FoxO interactions in diabetic and age-related muscle disease (2I01BX004468-05A1). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10918617. Licensed CC0.

---

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