Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle
Abstract
Data from transgenic animal models suggest that exercise-induced autophagy is critical for adaptation to physical training, and that Unc-51 like kinase-1 (ULK1) serves as an important regulator of autophagy. Phosphorylation of ULK1 at Ser 555 stimulates autophagy, whereas phosphorylation at Ser 757 is inhibitory. To determine whether exercise regulates ULK1 phosphorylation in humans in vivo in a nutrient-dependent manner, we examined skeletal muscle biopsies from healthy humans after 1-h cycling exercise at 50% maximal O 2 uptake on two occasions: 1) during a 36-h fast, and 2) during continuous glucose infusion at 0.2 kg/h. Physical exercise increased ULK1 phosphorylation at Ser 555 and decreased lipidation of light chain 3B. ULK1 phosphorylation at Ser 555 correlated positively with AMP-activated protein kinase-α Thr 172 phosphorylation and negatively with light chain 3B lipidation. ULK1 phosphorylation at Ser 757 was not affected by exercise. Fasting increased ULK1 and p62 protein expression, but did not affect exercise-induced ULK1 phosphorylation. These data demonstrate that autophagy signaling is activated in human skeletal muscle after 60 min of exercise, independently of nutritional status, and suggest that initiation of autophagy constitutes an important physiological response to exercise in humans.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [484]
Cites
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Kim, J., Kundu, M., Viollet, B., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2152 · Cited by 7,227 · see citing works
Guidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996 · see citing works
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941 · see citing works
The role of autophagy during the early neonatal starvation period
Kuma, A., Hatano, M., Matsui, M., Yamamoto, A., Nakaya, H., Yoshimori, T., Ohsumi, Y., Tokuhisa, T., & Mizushima, N. (2004) · Nature · doi:10.1038/nature03029 · Cited by 2,865 · see citing works
Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy
Egan, D. F., Shackelford, D. B., Mihaylova, M. M., Gelino, S., Kohnz, R. A., Mair, W., Vasquez, D. S., Joshi, A., Gwinn, D. M., Taylor, R., et al. (2011) · Science · doi:10.1126/science.1196371 · Cited by 2,600 · see citing works
How to Interpret LC3 Immunoblotting
Mizushima, N., & Yoshimori, T. (2007) · Autophagy · doi:10.4161/auto.4600 · Cited by 2,595 · cited 1× · see citing works
“LC3II itself is degraded when the autophagosome fuses with the lysosome (20), and our data could reflect increased presence of LC3BII in the lysosomal lumen and thus flux through the autophagy-lysosome Glucose infusion”
BackgroundMammalian autophagy: core molecular machinery and signaling regulation
Yang, Z., & Klionsky, D. J. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.11.014 · Cited by 1,956 · see citing works
Autophagy is required to maintain muscle mass.
Masiero, E., Agatea, L., Mammucari, C., Blaauw, B., Loro, E., Komatsu, M., Metzger, D., Reggiani, C., Schiaffino, S., & Sandri, M. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.10.008 · Cited by 1,282 · see citing works
Emerging regulation and functions of autophagy
Boya, P., Reggiori, F., & Codogno, P. (2013) · Nature Cell Biology · doi:10.1038/ncb2788 · Cited by 1,216 · see citing works
Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis
He, C., Bassik, M. C., Moresi, V., Sun, K., Wei, Y., Zou, Z., An, Z., Loh, J., Fisher, J., Sun, Q., et al. (2012) · Nature · doi:10.1038/nature10758 · Cited by 1,136 · see citing works
Grumati, P., Coletto, L., Sabatelli, P., Cescon, M., Angelin, A., Bertaggia, E., Blaauw, B., Urciuolo, A., Tiepolo, T., Merlini, L., et al. (2010) · Nature Medicine · doi:10.1038/nm.2247 · Cited by 540 · see citing works
Wong, P., Puente, C., Ganley, I. G., & Jiang, X. (2013) · Autophagy · doi:10.4161/auto.23323 · Cited by 497 · see citing works
Lira, V. A., Okutsu, M., Zhang, M., Greene, N. P., Laker, R. C., Breen, D. S., Hoehn, K. L., & Yan, Z. (2013) · The FASEB Journal · doi:10.1096/fj.13-228486 · Cited by 432 · see citing works
Stain-Free technology as a normalization tool in Western blot analysis
Gürtler, A., Kunz, N., Gomolka, M., Hornhardt, S., Friedl, A. A., McDonald, K., Kohn, J. E., & Posch, A. (2012) · Analytical Biochemistry · doi:10.1016/j.ab.2012.10.010 · Cited by 369 · see citing works
Sahani, M. H., Itakura, E., & Mizushima, N. (2014) · Autophagy · doi:10.4161/auto.27344 · Cited by 363 · see citing works
Grumati, P., Coletto, L., Schiavinato, A., Castagnaro, S., Bertaggia, E., Sandri, M., & Bonaldo, P. (2011) · Autophagy · doi:10.4161/auto.7.12.17877 · Cited by 267 · see citing works
Exercise induces autophagy in peripheral tissues and in the brain
He, C., Sumpter, R., & Levine, B. (2012) · Autophagy · doi:10.4161/auto.21327 · Cited by 259 · see citing works
The serine/threonine kinase ULK1 is a target of multiple phosphorylation events
Bach, M., Larance, M., James, D. E., & Ramm, G. (2011) · Biochemical Journal · doi:10.1042/bj20101894 · Cited by 253 · see citing works
Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis
Qiu, J., Tsien, C. D., Thapalaya, S., Narayanan, A. S., Weihl, C. C., Ching, J. K., Eghtesad, B., Singh, K., Fu, X., Dubyak, G., et al. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00183.2012 · Cited by 215 · see citing works
Frøsig, C., Jørgensen, S. B., Hardie, D. G., Richter, E. A., & Wojtaszewski, J. F. P. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00317.2003 · Cited by 161 · see citing works
Modulation of autophagy and ubiquitin-proteasome pathways during ultra-endurance running
Jamart, C., Francaux, M., Millet, G. Y., Deldicque, L., Frère, D., & Féasson, L. (2012) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00952.2011 · Cited by 157 · see citing works
Dissociation of AMPK activity and ACCβ phosphorylation in human muscle during prolonged exercise
Wojtaszewski, J. F. P., Mourtzakis, M., Hillig, T., Saltin, B., & Pilegaard, H. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02465-8 · Cited by 126 · see citing works
Vissing, K., McGee, S. L., Farup, J., Kjølhede, T., Vendelbo, M. H., & Jessen, N. (2013) · Scandinavian Journal of Medicine & Science in Sports · doi:10.1111/j.1600-0838.2011.01395.x · Cited by 111 · see citing works
Self-citationAutophagic response to exercise training in skeletal muscle with age
Kim, Y. A., Kim, Y. S., Oh, S. L., Kim, H.-J., & Song, W. (2013) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-013-0246-7 · Cited by 108 · see citing works
Autophagy and Protein Turnover Signaling in Slow-Twitch Muscle during Exercise
PAGANO, A. F., PY, G., BERNARDI, H., CANDAU, R. B., & SANCHEZ, A. M. J. (2014) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000000237 · Cited by 96 · see citing works
Vendelbo, M. H., Møller, A. B., Christensen, B., Nellemann, B., Clasen, B. F., Nair, K. S., Jørgensen, J. O. L., Jessen, N., & Møller, N. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102031 · Cited by 88 · see citing works
Self-citationVainshtein, A., Grumati, P., Sandri, M., & Bonaldo, P. (2014) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1096-z · Cited by 88 · see citing works
Fasting-related autophagic response in slow- and fast-twitch skeletal muscle
Ogata, T., Oishi, Y., Higuchi, M., & Muraoka, I. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.02.130 · Cited by 86 · see citing works
Exercise increases TBC1D1 phosphorylation in human skeletal muscle
Jessen, N., An, D., Lihn, A. S., Nygren, J., Hirshman, M. F., Thorell, A., & Goodyear, L. J. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00042.2011 · Cited by 67 · see citing works
Self-citationBach, E., Nielsen, R. R., Vendelbo, M. H., Møller, A. B., Jessen, N., Buhl, M. R., Krusenstjerna-Hafstrøm, T., Holm, L., Pedersen, S. B., Pilegaard, H., et al. (2013) · Diabetes · doi:10.2337/db13-0138 · Cited by 53 · see citing works
Self-citationAMP kinase in exercise adaptation of skeletal muscle
Jessen, N., Sundelin, E. I. O., & Møller, A. B. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.03.009 · Cited by 28 · see citing works
Self-citationMøller, A. B., Vendelbo, M. H., Rahbek, S. K., Clasen, B. F., Schjerling, P., Vissing, K., & Jessen, N. (2013) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-013-1318-9 · Cited by 25 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
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., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00520-9 · Cited by 529 · see citing works
Egan, B., & Sharples, A. P. (2023) · Physiological Reviews · doi:10.1152/physrev.00054.2021 · Cited by 278 · see citing works
Training-Induced Changes in Mitochondrial Content and Respiratory Function in Human Skeletal Muscle
Granata, C., Jamnick, N. A., & Bishop, D. J. (2018) · Sports Medicine · doi:10.1007/s40279-018-0936-y · Cited by 247 · see citing works
Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
Unravelling the mechanisms regulating muscle mitochondrial biogenesis
Hood, D. A., Tryon, L. D., Carter, H. N., Kim, Y., & Chen, C. C. W. (2016) · Biochemical Journal · doi:10.1042/bcj20160009 · Cited by 159 · see citing works
Exercise-induced skeletal muscle signaling pathways and human athletic performance
Camera, D. M., Smiles, W. J., & Hawley, J. A. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.02.007 · Cited by 128 · see citing works
Exercise and exercise training-induced increase in autophagy markers in human skeletal muscle
Brandt, N., Gunnarsson, T. P., Bangsbo, J., & Pilegaard, H. (2018) · Physiological Reports · doi:10.14814/phy2.13651 · Cited by 120 · see citing works
Impact of resistance training on the autophagy-inflammation-apoptosis crosstalk in elderly subjects
Mejías-Peña, Y., Estébanez, B., Rodriguez-Miguelez, P., Fernandez-Gonzalo, R., Almar, M., de Paz, J. A., González-Gallego, J., & Cuevas, M. J. (2017) · Aging · doi:10.18632/aging.101167 · Cited by 102 · see citing works
“However, the content of this protein is not always inversely correlated with autophagic activity [30]; although p62 is degraded in the process of autophagy and accumulates when this process is inhibited, it is possible that increased production of p62 equals the increment in p62 degradation during exercise.”
BackgroundEffects of aerobic training on markers of autophagy in the elderly
Mejías-Peña, Y., Rodriguez-Miguelez, P., Fernandez-Gonzalo, R., Martínez-Flórez, S., Almar, M., de Paz, J. A., Cuevas, M. J., & González-Gallego, J. (2016) · AGE · doi:10.1007/s11357-016-9897-y · Cited by 69 · see citing works
Sieljacks, P., Wang, J., Groennebaek, T., Rindom, E., Jakobsgaard, J. E., Herskind, J., Gravholt, A., Møller, A. B., Musci, R. V., de Paoli, F. V., et al. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00649 · Cited by 50 · see citing works
Self-citationEffects of skeletal muscle energy availability on protein turnover responses to exercise
Smiles, W. J., Hawley, J. A., & Camera, D. M. (2016) · Journal of Experimental Biology · doi:10.1242/jeb.125104 · Cited by 48 · see citing works
- Authors
- Møller, A. B., Vendelbo, M. H., Christensen, B., Clasen, B. F., Bak, A. M., Jørgensen, J. O. L., Møller, N., & Jessen, N.
- Affiliations
- Aarhus University (DK)
- Corresponding author
- Jessen, Niels
- ORCID
- Venue
- Journal of Applied Physiology
- Publisher
- American Physiological Society
- Published
- 2015-04-15
- Volume
- 118
- Issue
- 8
- Pages
- 971-979
- ISSN
- 0161-7567 (ISSN-L)
- 8750-7587
- 1522-1601
- OpenAlex
- W2024145500
- Cited by
- 109
- References
- 32
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 10 · 2023: 6 · 2022: 9 · 2021: 11 · 2020: 7 · 2019: 13 · 2018: 11 · 2017: 14 · 2016: 15 · 2015: 3
- FWCI
- 11.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Applied Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Danish Councin for Strategic Research
- Beckett Foundation
- The Danish PhD Schools for Metabolism and Endocrinology
- A.P. M�ller Foundation for the Advancement of Medical Science
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- ULK1, skeletal muscle, AMPK, fasting, glucose infusion, p62, autophagy initiation
- MeSH terms
- Autophagy-Related Protein-1 Homolog, Sequestosome-1 Protein, Adult, Autophagy, Blood Glucose, Fasting, Fatty Acids, Nonesterified, Humans, Male, Microtubule-Associated Proteins, Nutritional Status, Phosphorylation, Random Allocation, Exercise, Protein Serine-Threonine Kinases, Muscle, Skeletal, Cross-Over Studies, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, AMP-Activated Protein Kinases, Young Adult, Healthy Volunteers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review