Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis
Open accessAbstract
Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.
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Exercise triggers autophagy by activating ULK1 and dissociating BCL2 from BECN1, thereby disinhibiting the initiation complex.
“Exercise triggers autophagy by activating ULK1 and dissociating BCL2 from BECN1, thereby disinhibiting the initiation complex [484,485].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [485]
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- Authors
- He, C., Bassik, M. C., Moresi, V., Sun, K., Wei, Y., Zou, Z., An, Z., Loh, J., Fisher, J., Sun, Q., Korsmeyer, S., Packer, M., May, H. I., Hill, J. A., Virgin, H. W., Gilpin, C., Xiao, G., Bassel-Duby, R., Scherer, P. E., & Levine, B.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Howard Hughes Medical Institute (US)
- Washington University in St. Louis (US)
- Corresponding author
- Levine, Beth
- ORCID
- Venue
- Nature
- Published
- 2012-01-18
- Volume
- 481
- Issue
- 7382
- Pages
- 511-515
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3518436
- OpenAlex
- W2082476985
- Cited by
- 1,136
- References
- 36
- Citations by year
- 2026: 40 · 2025: 47 · 2024: 49 · 2023: 55 · 2022: 64 · 2021: 90 · 2020: 93 · 2019: 76 · 2018: 93 · 2017: 99 · 2016: 94 · 2015: 112 · 2014: 82 · 2013: 80 · 2012: 61
- FWCI
- 79.93
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-11-06)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (R0I HL090842, R0I HL080244, R01HL090842)
- National Cancer Institute (R01CA112023, R01CA109618, P30CA142543)
- National Institute of Allergy and Infectious Diseases (R01AI084887, R0I AI084887)
- National Institute of Diabetes and Digestive and Kidney Diseases (RCI DK086629, R01DK055758, 1P01 DK0887761, RC1DK086629, P01DK088761)
- 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
- Bcl-2, Bcl-2 phosphorylation, skeletal muscle, myocardium, glucose metabolism, impaired glucose tolerance, high-fat diet, endurance, starvation-induced autophagy, exercise metabolism, diabetes protection
- MeSH terms
- Beclin-1, Animals, Autophagy, Cells, Cultured, Dietary Fats, Physical Exertion, Food Deprivation, Glucose, Glucose Tolerance Test, Homeostasis, Male, Mice, Transgenic, Mutation, Myocardium, Phosphorylation, Physical Conditioning, Animal, Physical Endurance, Protein Binding, Proto-Oncogene Proteins, Running, Glucose Intolerance, Muscle, Skeletal, Proto-Oncogene Proteins c-bcl-2, Leptin, Apoptosis Regulatory Proteins, Mice, Adiponectin, Gene Knock-In Techniques
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