# Autocrine Action of Elevated FGF-21 Contributing to Skeletal Muscle Atrophy in Response to Mitochondrial Dysfunction

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $435,211

## Abstract

PROJECT SUMMARY
Skeletal muscle atrophy and muscle wasting is associated with both acute and chronic pathological conditions
such as traumatic spinal cord injury and inpatient bedrest. Decreases in muscle mass from the atrophy is
associated with power outcomes to other comorbidities, and increased susceptibility to obesity and diabetes.
Current pharmaceutical interventions to increase muscle mass have been limited in their effectiveness. This poor
efficacy is in part due to the limited understanding of the different mechanisms that contribute to decrease muscle
mass. Mitochondrial dysfunction has been proposed as one of the contributors to skeletal muscle atrophy.
However, the precise mechanisms that contribute to impaired mitochondrial functionality and the development
of skeletal muscle atrophy is unknown. Mitochondrial dynamics have emerged as key regulators of both
physiology and pathology in skeletal muscle. We have recently reported that induced adult skeletal muscle
deletion of both mitofusin 1 and 2 have a profound effect on exercise capacity. Furthermore, preliminary analysis
of these animals exhibit signs of decrease muscle mass and the induction of the unfolded protein response
(UPR) and atrophy genes. We also observed elevated levels of FGF21 in skeletal muscle and circulation. These
data suggest that adult skeletal muscle mitochondrial dysfunction and elevated muscle-derived FGF21
contributes to the development of muscle atrophy. Furthermore, utilizing a spinal cord injury (SCI) model, which
develops pathological skeletal muscle atrophy, we observe elevated levels of skeletal muscle Fgf21 mRNA. We
hypothesize that the observed elevated skeletal muscle derived FGF21 in circulation further contributes to the
observed atrophy. Therefore, the overall objective of this proposal is to understand the contribution of
mitochondrial dysfunction in skeletal muscle to the development of skeletal muscle atrophy. Using genetic
models and translatable therapeutic interventions we will attempt to address this very important question. Results
from this proposal have broad implications for our understanding of the molecular changes that contribute to the
development of skeletal muscle atrophy. The specific aims are to: 1.) Establish the requirement of FGF21
signaling for skeletal muscle atrophy in response to muscle mitochondrial dysfunction; 2.) Reveal the
contribution of elevated FGF21 in the development of skeletal muscle atrophy in response to a contusion spinal
cord injury (SCI); 3.) Determine whether pharmacologic inhibition of FGF21 signaling after spinal cord injury
(SCI) prevents skeletal muscle atrophy. This proposal will to provide much needed insights into our
understanding of molecular pathogenesis of skeletal muscle atrophy.

## Key facts

- **NIH application ID:** 10840264
- **Project number:** 5R01AG069906-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Glenn Cameron Rowe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $435,211
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840264

## Citation

> US National Institutes of Health, RePORTER application 10840264, Autocrine Action of Elevated FGF-21 Contributing to Skeletal Muscle Atrophy in Response to Mitochondrial Dysfunction (5R01AG069906-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10840264. Licensed CC0.

---

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