# AMPK-Ulk1 in Exercise-Induced Mitophagy in Skeletal Muscle

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $486,805

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-communicable diseases, such as heart disease, stroke, cancer and diabetes, kill 38 million people
worldwide each year. These diseases are caused/exacerbated by an accumulation of damaged/dysfunctional
mitochondria in vital tissues/organs. Research in the PI's and many other laboratories show that regular
exercise improves mitochondrial function and is the most powerful intervention for the prevention and
treatment of non-communicable diseases. However, the molecular mechanisms underlying the benefits of
exercise remain largely unknown, hindering our ability to optimize exercise intervention and develop more
effective therapeutics. Autophagy, a conserved cellular degradation process for aggregated proteins and
damaged organelles is activated in skeletal muscle by exercise; however, the regulation and functional role of
mitophagy, a specific autophagic clearance process for mitochondria, in skeletal muscle by exercise training is
poorly understood. We developed a novel mitochondrial reporter gene, pMitoTimer, for quantification of
mitochondrial oxidative stress and mitophagy in vivo. Using this novel tool, we have recently shown that a
single bout of exercise induces mitochondrial oxidative stress and mitophagy in skeletal muscle, preceded by a
transient activation of the nutrient/energy sensor AMP-activated protein kinase (AMPK), autophagy protein
unc-51 like autophagy activating kinase 1 (Ulk1) and mitochondrial fission regulator dynamin-related protein 1
(Drp1), where both Ulk1 and Drp1 are known to be required for mitophagy. We further demonstrated in
muscle-specific dominant negative and constitutive active AMPK transgenic mice (dnAMPK and caAMPK,
respectively) that activation of Ulk1, but not that of Drp1, is caused by AMPK activation. These findings along
with previous findings of the role of AMPK-Ulk1 in non-muscle cells serve as scientific foundation for this
proposal. We hypothesize that exercise-induced activation of AMPK and Ulk1 along with Drp1-1 mediated
mitochondrial fission promotes mitophagy, hence improved mitochondrial quality, and contractile and metabolic
adaptations. To test this hypothesis, we propose the following specific aims:
1) To dissect the role of AMPK in exercise-induced mitophagy in skeletal muscle in vivo.
2) To ascertain the role of Ulk1 and Drp1 in exercise-induced mitophagy in skeletal muscle in vivo.
3) To define the functional role of mitophagy in exercise training-induced adaptations.
The proposed studies will address one of the most important questions in muscle biology and exercise
physiology. The results, whether accepting or refuting the hypothesis, will significantly improve our mechanistic
understanding of exercise training-induced mitochondrial quality control and functional adaptation in skeletal
muscle with great potential impact on future research of health benefits of exercise.

## Key facts

- **NIH application ID:** 9955205
- **Project number:** 5R01AR050429-14
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Zhen Yan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $486,805
- **Award type:** 5
- **Project period:** 2005-08-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955205

## Citation

> US National Institutes of Health, RePORTER application 9955205, AMPK-Ulk1 in Exercise-Induced Mitophagy in Skeletal Muscle (5R01AR050429-14). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9955205. Licensed CC0.

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