# Role of skeletal muscle mitophagy in healthy aging

> **NIH NIH R00** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2020 · $225,327

## Abstract

Project Summary
Mitochondrial quality in skeletal muscle progressively declines with advancing age, leading to tissue dysfunction
and disease. Several lines of evidence suggest poor mitochondrial quality in skeletal muscle of old animals and
humans is due in large part to an impaired or insufficient capacity to degrade damaged/dysfunctional
mitochondria via mitophagy. Exercise promotes mitochondrial quality leading to healthy aging but the underlying
mechanisms and how they differ with age is not well defined, particularly in regards to mitophagy, restraining
development of effective interventions. Building upon my previous work demonstrating that exercise does indeed
promote mitophagy in skeletal muscle but only of a small fraction of the total mitochondrial reticulum, I show here
evidence of an Ampk-dependent mechanism that may distinguish damaged vs. healthy regions of the
mitochondrial reticulum that is lost with age. Additionally, I show that key downstream mitophagy-related factors
that are recruited to mitochondria in skeletal muscle with exercise are required for mitochondrial quality and
healthy aging in d. melanogaster. The proposed research tests the hypothesis that recognition of damaged
regions of the mitochondrial reticulum in response to exercise is impaired in skeletal muscle of old mice, blunting
local recruitment of key mitophagy proteins, leading to poor mitochondrial quality. These studies will provide
insight into novel regulation of skeletal muscle mitophagy in response to exercise and lay a foundation for the
development of targeted interventions to promote mitochondrial quality in skeletal muscle for improved tissue
function and healthy aging. During the mentored phase, I will employ state-of-the-art two-photon microscopy to
perform intravital and ex vivo fluorescent lifetime microscopy of Ampk activity on mitochondria in skeletal muscle
of young and old mice to determine the age-dependent, localized response of Ampk to sustained contraction
and mitochondrial damage. Also, I will continue my professional and scientific development in preparation for
the independent phase with continuous guidance from my mentoring committee. During the independent phase,
I will employ co-somatic gene transfer in skeletal muscle of young and old wild-type mice as well as skeletal
muscle-specific, conditional Ulk1 knock-out mice to determine the age-dependent regulation for the recruitment
of downstream mitophagy-related factors to mitochondria in skeletal muscle in response to exercise. Also, I will
develop novel phospho-mimetic constructs to constitutively activate or inhibit mitophagy-related factors Atg9 and
Atg2 in young and old mouse skeletal muscle and investigate their necessity and sufficiency for the breakdown
of mitochondrial proteins and maintenance of mitochondrial quality, via state-of-the-art high resolution proteomic
and confocal imaging approaches. Collectively, these studies and career development activities will foster my
c...

## Key facts

- **NIH application ID:** 10073683
- **Project number:** 4R00AG057825-03
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Josh C Drake
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $225,327
- **Award type:** 4N
- **Project period:** 2018-08-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073683

## Citation

> US National Institutes of Health, RePORTER application 10073683, Role of skeletal muscle mitophagy in healthy aging (4R00AG057825-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10073683. Licensed CC0.

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