Cited by 529Autophagy in Disease and TherapyMetabolism, Diabetes, and CancerMuscle Physiology and Disorders

Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy

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Laker, Rhianna C., Drake, Joshua C., Wilson, Rebecca J., Lira, Vitor A., Lewellen, Bevan M., Ryall, Karen A., Fisher, Carleigh C., Zhang, Mei +4 more·2017·Nature Communications

Abstract

Mitochondrial health is critical for skeletal muscle function and is improved by exercise training through both mitochondrial biogenesis and removal of damaged/dysfunctional mitochondria via mitophagy. The mechanisms underlying exercise-induced mitophagy have not been fully elucidated. Here, we show that acute treadmill running in mice causes mitochondrial oxidative stress at 3-12 h and mitophagy at 6 h post-exercise in skeletal muscle. These changes were monitored using a novel fluorescent reporter gene, pMitoTimer, that allows assessment of mitochondrial oxidative stress and mitophagy in vivo, and were preceded by increased phosphorylation of AMP activated protein kinase (Ampk) at tyrosine 172 and of unc-51 like autophagy activating kinase 1 (Ulk1) at serine 555. Using mice expressing dominant negative and constitutively active Ampk in skeletal muscle, we demonstrate that Ulk1 activation is dependent on Ampk. Furthermore, exercise-induced metabolic adaptation requires Ulk1. These findings provide direct evidence of exercise-induced mitophagy and demonstrate the importance of Ampk-Ulk1 signaling in skeletal muscle.Exercise is associated with biogenesis and removal of dysfunctional mitochondria. Here the authors use a mitochondrial reporter gene to demonstrate the occurrence of mitophagy following exercise in mice, and show this is dependent on AMPK and ULK1 signaling.

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Authors
Laker, R. C., Drake, J. C., Wilson, R. J., Lira, V. A., Lewellen, B. M., Ryall, K. A., Fisher, C. C., Zhang, M., Saucerman, J. J., Goodyear, L. J., Kundu, M., & Yan, Z.
Affiliations
  • University of Virginia Medical Center (US)
  • University of Iowa (US)
  • University of Virginia (US)
  • Brigham and Women's Hospital (US)
  • St. Jude Children's Research Hospital (US)
Corresponding author
Yan, Zhen
Venue
Nature Communications
Published
2017-09-15
Volume
8
Issue
1
Pages
548-548
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2754409876
Cited by
529
References
76
Citations by year
2026: 71 · 2025: 53 · 2024: 64 · 2023: 82 · 2022: 65 · 2021: 66 · 2020: 54 · 2019: 38 · 2018: 30 · 2017: 6
FWCI
27.42
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • American Heart Association (14POST20450061, 114PRE20380254)
  • Joslin Diabetes Center (5P30 DK36836)
  • National Institutes of Health (HL007284, DK101043, DK 36836)
  • National Heart, Lung, and Blood Institute (R01HL114697, T32HL007284)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK101043, P30DK036836)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050429)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords
mitophagy, exercise training, AMPK, ULK1, mitochondrial oxidative stress, skeletal muscle, mitochondrial biogenesis, autophagy, metabolic adaptation, treadmill running
MeSH terms
Autophagy-Related Protein-1 Homolog, Animals, Humans, Lysosomes, Male, Mice, Inbred C57BL, Mitochondria, Phosphorylation, Exercise, Oxidative Stress, Muscle, Skeletal, Amino Acid Motifs, Mice, AMP-Activated Protein Kinases, Mitophagy

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