# TWEAK/Fn14/UPR Signaling in Skeletal Muscle Wasting

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2024 · $535,070

## Abstract

ABSTRACT
Skeletal muscle wasting/cachexia is a devastating complication of a number of chronic disease
states, such as cancer and in the elderly population. Muscle wasting involves an imbalance in
the rates of protein synthesis and degradation, functional denervation, metabolic abnormalities,
and loss of mitochondrial content and function. TWEAK is a proinflammatory cytokine that binds
to cell surface receptor Fn14 to activate multiple intracellular signaling pathways. We have
found that the expression of Fn14 is increased in skeletal muscle of mouse models of cancer
cachexia and in aged mice. Skeletal muscle-specific ablation of Fn14 inhibits muscle wasting in
a murine model of cancer cachexia. TWEAK represses the rate of protein synthesis in skeletal
muscle both in vivo and in vitro. Furthermore, the TWEAK-Fn14 system regulates ER stress-
induced unfolded protein response (UPR) in skeletal muscle of tumor-bearing mice. In addition,
our experiments demonstrate that targeted inhibition of the PERK and/or IRE1/XBP1 arms of
the UPR improves protein synthesis in skeletal muscle of mice. However, the role of the
TWEAK-Fn14 system and UPR pathways in the regulation of skeletal muscle mass and function
during cancer cachexia and aging remains completely unknown. In this project, we will
investigate the role of TWEAK/Fn14/UPR signaling axis in skeletal muscle atrophy and whether
targeted genetic ablation of Fn14 or components of the UPR attenuate muscle wasting in
preclinical mouse models of cancer cachexia and during aging. Based on our preliminary
results, we hypothesize that the TWEAK/Fn14 system causes skeletal muscle wasting through
the activation of the PERK and the IRE1α/XBP1 arms of the UPR during aging and cancer
cachexia. Our specific aims are to: (I) Investigate the role of the TWEAK/Fn14 system in
skeletal muscle wasting during aging and cancer cachexia, and (II) Investigate the mechanisms
by which TWEAK/Fn14-induced activation of the UPR pathways cause skeletal muscle wasting
during aging and cancer cachexia. Our proposed studies will identify key mechanisms
responsible for the loss of skeletal muscle mass. Successful completion of this project will
provide strong basis for the development of new therapies for sarcopenia and cancer cachexia.

## Key facts

- **NIH application ID:** 10814855
- **Project number:** 5R01AR081487-02
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** ASHOK KUMAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $535,070
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814855

## Citation

> US National Institutes of Health, RePORTER application 10814855, TWEAK/Fn14/UPR Signaling in Skeletal Muscle Wasting (5R01AR081487-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10814855. Licensed CC0.

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