# Targeting Muscle Fatigability During Cachexia

> **NIH NIH R01** · WEST VIRGINIA UNIVERSITY · 2022 · $334,400

## Abstract

PROJECT SUMMARY/ABSTRACT
Clinically, nearly all breast cancer patients at the time of diagnosis and prior to treatment have some degree of
muscle dysfunction resulting in fatigue that ranges from mild to debilitating and may worsen during and after
chemotherapy, radiation, and/or surgery. Adverse systemic effects of tumor growth can often result in treatment
cessation and greater mortality in late stages of disease. The long-term goal of my work is to identify potential
therapeutic targets for fatigue and a mechanism linking BC with systemic muscle fatigue. The specific goal of this
proposal is to utilize our murine model to characterize the molecular adaptations in muscle and identify targets
to attenuate fatigue in patients with breast cancer. The central research hypothesis is that regulation of
mitochondrial bioenergetics via a PPARγ-agonist will attenuate breast tumor-associated muscle fatigue. Three
Specific Aims have been proposed to test this hypothesis, using murine models of breast cancer and novel in vitro
models of PPAR-activity. In Specific Aim 1, we will test the working hypothesis that breast tumor growth impairs
mitochondrial bioenergetics resulting in ATP deficiency and subsequent muscle fatigue through aberrant function
of mitochondrial electron transport chain (ETC) complex V. In Specific Aim 2, we will test the working hypothesis
that breast tumor-derived miR-27a-3p interacts with regulatory components of PPARγ within skeletal muscle to
decrease its function as a transcription factor, thereby specifically inducing alterations in mitochondrial function.
In Specific Aim 3, will test the working hypothesis that pioglitazone will attenuate breast tumor-associated fatigue
by upregulating PPARγ transcriptional activity in skeletal muscle, thereby rescuing mitochondrial bioenergetics
and ATP production. BC-PDOX mice and controls treated with and without pioglitazone will be evaluated for
muscle fatigue, mitochondrial bioenergetics and ATP content. This project is conceptually innovative in its use
of a preclinical mouse model that phenotypically and transcriptionally mimics BC-associated muscle fatigue in
the absence of cachexia. Our approach is both unique and practical in that it seeks to lay the foundation for
repurposing an existing FDA-approved PPARγ-agonist for treatment of fatigue in patients with BC, directly
addressing a key knowledge gap in this field. The outcomes of this project will impact the treatment of cancer-
related fatigue, with the potential to offer early-stage BC-patients a treatment strategy targeting this debilitating
symptom before the onset of cachexia. The aims and objectives of this project reflect the goals of the NCI, as
described in their mission statement, by specifically conducting research that will advance scientific knowledge
and be applicable to a large population of patients as well as helping improve patients’ quality of life during and
following completion of cancer-associated therapy.

## Key facts

- **NIH application ID:** 10445436
- **Project number:** 1R01AR079445-01A1
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Emidio Edward Pistilli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $334,400
- **Award type:** 1
- **Project period:** 2022-06-03 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445436

## Citation

> US National Institutes of Health, RePORTER application 10445436, Targeting Muscle Fatigability During Cachexia (1R01AR079445-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10445436. Licensed CC0.

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