# (PQ 12) The Regulation of Physical Function and Skeletal Muscle Metabolic Signaling After Cessation of 5-Fluorouracil Treatment

> **NIH NIH R21** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $154,442

## Abstract

Central objectives for successful cancer treatment include increased survival and improved quality of life.
Increased fatigue and decreased physical function remain challenges for most colorectal cancer (CRC)
patients after the completion of treatment. CRC patients report functional decrements that cause an inability to
perform daily tasks related to shopping, engaging in physical activity, and holding a job. Skeletal muscle loss
and metabolic dysfunction play a critical role in these negative outcomes. Historically, the examination of
skeletal muscle with cancer has not accounted for the effect of chemotherapy treatment, which has strong
potential to alter the health and life quality of cancer survivors. Determining how chemotherapy impacts cancer
patients’ long–term health and quality of life after the cessation of treatment is a critically significant question.
This proposed study is aligned with Provocative Question 12, “What are the molecular and/or cellular
mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?” This
question seeks to improve the understanding of chemotherapy complications that extend beyond acute toxicity
but can have significant ramifications for patient health and life quality. We seek to understand how sex,
gonadal function, and exercise, all of which regulate skeletal muscle function, interact with chemotherapy. Our
study will mechanistically examine the effect of exercise dose on skeletal muscle’s response to chemotherapy.
Although exercise is widely prescribed, the mechanistic interaction between exercise and chemotherapy is
poorly understood. Our study’s focus is based on fundamental discoveries by our group and others who have
examined chemotherapy-induced disruptions to skeletal muscle function, and our compelling preliminary data
that establishes a novel preclinical paradigm to examine the effects of sex, gonadal function, and exercise
dose on skeletal muscle’s response to either Folfox or Folfiri chemotherapy. Our central hypothesis is that
either Folfox or Folfiri treatment cause lasting fatigue through the disruption of skeletal muscle mitochondrial
quality control in mice, which can be rescued by low dose treadmill exercise and is exacerbated by female
gonadal dysfunction. We expect that chemotherapy effects on skeletal muscle are sex dependent, since sex
and ovarian function can affect muscle metabolism, inflammation, and IL-6 sensitivity. Specific aim 1 will
determine the effect of exercise dose on Folfox or Folfiri regulation of skeletal muscle fatigue and mitochondria
quality control in male and female mice. Three treadmill exercise doses that are based on recommendations
for cancer survivors will be examined. Specific aim 2 will investigate hypogonadism’s regulation of skeletal
muscle fatigue and mitochondria quality control by Folfox or Folfiri treatments and determine if sex hormone
administration can modify these outcomes. Our study provides a critical initial exam...

## Key facts

- **NIH application ID:** 9927604
- **Project number:** 5R21CA231131-02
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** James A Carson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $154,442
- **Award type:** 5
- **Project period:** 2019-05-08 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927604

## Citation

> US National Institutes of Health, RePORTER application 9927604, (PQ 12) The Regulation of Physical Function and Skeletal Muscle Metabolic Signaling After Cessation of 5-Fluorouracil Treatment (5R21CA231131-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9927604. Licensed CC0.

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