# Gene-therapy-based rescue in rats selectively bred for low voluntary running distance phenotype

> **NIH NIH R21** · UNIVERSITY OF MISSOURI-COLUMBIA · 2020 · $232,500

## Abstract

The U.S. now ranks 26th out of 35 for overall life expectancy among other developed and developing countries.
PROBLEM: Sedentary lifestyle increases the risk of 40 chronic diseases. Most (97%) adults do not meet U.S.
guidelines for weekly physical activity, thereby increasing the onset of chronic disease, beginning at a younger
age. Understanding the biological proclivity for sedentary living could help identify interventions to increase
U.S. life expectancy. Growing evidence suggests that genetics plays a significant role in decreasing the
motivation to be physically active. For example, in 772 mono- and di-zygotic twins, data was published showing
sedentary behavior is moderately heritable in adults based upon between-twin variation in sedentary
behaviors. PRELIMINARY STUDIES: Rats were successfully bred for the phenotype of low voluntarily wheel-
running (LVR) motivation and potential gene candidates specific to the nucleus accumbens, a region integral to
motivated behaviors, were found. One candidate gene, protein kinase inhibitor alpha (Pkiα), was shown to be
lowly expressed in LVR compared to outbred, wild-type (WT) rats and was further addressed due to its key
position in modulating motivation-related signaling. Local overexpression of the Pkiα in the nucleus
accumbens of female LVR rats increased voluntary running distances 3.1-fold compared to pair-matched empty
vector controls. Amazingly, WT rats did not increase nightly running distance following Pkia overexpression
and appeared to show molecular resistance to Pkiα overexpression. OBJECTIVES: A better understanding of
mechanisms that control the lack of motivation for physical activity behavior can help facilitate the
development of potential drug therapies for sedentary individuals and combat age-related decreases in physical
activity over the lifespan. As such, the goal of this application is to expand upon these findings and help reverse
sedentary lifestyle. STRATEGY: Aim 1 will further test the ability of Pkiα overexpression in the nucleus
accumbens of wild-type (WT) and LVR rats at 15 and 24 weeks of age to increase voluntary running behavior
and the molecular responses in male and female rats. Two hypotheses are that Pkiα overexpression in nucleus
accumbens will increase voluntary running distance: 1) in young LVR rats, but not WT because of their
differences in molecular responses; and 2) in both LVR and WT 24-wk-old rats whose running started less than
their younger counterparts. Aim 2 will examine whether differences in either single-nucleotide polymorphisms,
methylation, and/or differentially bound transcription-factors exist in the promoter of LVR vs. WT rats in 15-
and 24-wk-old rats. The outcome could help to explain the differential expression of Pkiα in different rat
models that correlate with different voluntary activity behaviors. SIGNIFICANCE: This 2-yr R21 project will
advance our understanding of molecular mechanisms responsible for sedentary behavior associated wi...

## Key facts

- **NIH application ID:** 9843628
- **Project number:** 5R21AG061691-02
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** FRANK W BOOTH
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $232,500
- **Award type:** 5
- **Project period:** 2019-01-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843628

## Citation

> US National Institutes of Health, RePORTER application 9843628, Gene-therapy-based rescue in rats selectively bred for low voluntary running distance phenotype (5R21AG061691-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9843628. Licensed CC0.

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