Activation of γ2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury
Open accessAbstract
Rationale: AMPK (AMP-activated protein kinase) is a heterotrimeric protein that plays an important role in energy homeostasis and cardioprotection. Two isoforms of each subunit are expressed in the heart, but the isoform-specific function of AMPK remains unclear. Objective: We sought to determine the role of γ2-AMPK in cardiac stress response using bioengineered cell lines and mouse models containing either isoform of the γ-subunit in the heart. Methods and Results: We found that γ2 but not γ1 or γ3 subunit translocated into nucleus on AMPK activation. Nuclear accumulation of AMPK complexes containing γ2-subunit phosphorylated and inactivated RNA Pol I (polymerase I)–associated transcription factor TIF-IA at Ser-635, precluding the assembly of transcription initiation complexes for rDNA. The subsequent downregulation of pre-rRNA level led to attenuated endoplasmic reticulum (ER) stress and cell death. Deleting γ2-AMPK led to increases in pre-rRNA level, ER stress markers, and cell death during glucose deprivation, which could be rescued by inhibition of rRNA processing or ER stress. To study the function of γ2-AMPK in the heart, we generated a mouse model with cardiac-specific deletion of γ2-AMPK (cardiac knockout [cKO]). Although the total AMPK activity was unaltered in cKO hearts because of upregulation of γ1-AMPK, the lack of γ2-AMPK sensitizes the heart to myocardial ischemia/reperfusion injury. The cKO failed to suppress pre-rRNA level during ischemia/reperfusion and showed a greater infarct size. Conversely, cardiac-specific overexpression of γ2-AMPK decreased ribosome biosynthesis and ER stress during ischemia/reperfusion insult, and the infarct size was reduced. Conclusions: The γ2-AMPK translocates into the nucleus to suppress pre-rRNA transcription and ribosome biosynthesis during stress, thus ameliorating ER stress and cell death. Increased γ2-AMPK activity is required to protect against ischemia/reperfusion injury. Our study reveals an isoform-specific function of γ2-AMPK in modulating ribosome biosynthesis, cell survival, and cardioprotection.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
A reduction in ribosome biogenesis has been shown in COS7 and HEK293 cells and transgenic mice overexpressing γ2-AMPK.
“Others have also shown a reduction in ribosome biogenesis in COS7 and HEK293 cells and transgenic mice overexpressing γ2-AMPK (Cao et al., 2017).”
From Skeletal Muscle Ribosome and Mitochondrial Biogenesis in Response to Different Exercise Training Modalities (2021) · cites this paper as Cao et al., 2017
The Results section on pre-rRNA downregulation reports reduced nucleolar staining and pre-rRNA in γ2-overexpressing HEK293 cells under glucose deprivation or AMPK activation. The Methods and Results section reports reduced ribosome biosynthesis in mice with cardiac-specific γ2-AMPK overexpression during ischemia/reperfusion. The Results section on nuclear translocation describes γ2 expression and nuclear accumulation in COS7 cells, but does not show reduced ribosome biogenesis in those cells; the claim also omits the stress conditions for the reported reductions. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914 · see citing works
AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint
Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E., & Shaw, R. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.003 · Cited by 3,849 · see citing works
AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function
Hardie, D. G. (2011) · Genes & Development · doi:10.1101/gad.17420111 · Cited by 1,638 · see citing works
Scott, J. W., Hawley, S. A., Green, K. A., Anis, M., Stewart, G., Scullion, G. A., Norman, D. G., & Hardie, D. G. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19874 · Cited by 754 · see citing works
Russell, R. R., Li, J., Coven, D. L., Pypaert, M., Zechner, C., Palmeri, M., Giordano, F. J., Mu, J., Birnbaum, M. J., & Young, L. H. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19297 · Cited by 738 · see citing works
Mammalian AMP-activated protein kinase subfamily
Stapleton, D., Mitchelhill, K. I., Gao, G., Widmer, J., Michell, B. J., Teh, T., House, C. M., Fernandez, C. S., Cox, T., Witters, L. A., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.2.611 · Cited by 652 · see citing works
Characterization of AMP-activated protein kinase γ-subunit isoforms and their role in AMP binding
CHEUNG, P. C. F., SALT, I. P., DAVIES, S. P., HARDIE, D. G., & CARLING, D. (2000) · Biochemical Journal · doi:10.1042/bj3460659 · Cited by 637 · see citing works
AMPK is a direct adenylate charge-regulated protein kinase
Oakhill, J. S., Steel, R., Chen, Z.-P., Scott, J. W., Ling, N., Tam, S., & Kemp, B. E. (2011) · Science · doi:10.1126/science.1200094 · Cited by 612 · see citing works
Blair, E. M. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.11.1215 · Cited by 530 · see citing works
Arad, M., Benson, D. W., Pérez‐Atayde, A. R., McKenna, W. J., Sparks, E. A., Kanter, R. J., McGarry, K., Seidman, J. G., & Seidman, C. E. (2002) · Journal of Clinical Investigation · doi:10.1172/jci14571 · Cited by 460 · see citing works
Pyrko, P., Schönthal, A. H., Hofman, F. M., Chen, T. C., & Lee, A. S. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0625 · Cited by 453 · see citing works
Horman, S., Browne, G., Krause, U., Patel, J., Vertommen, D., Bertrand, L., Lavoinne, A., Hue, L., Proud, C. G., & Rider, M. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01077-1 · Cited by 440 · see citing works
Gundewar, S., Calvert, J. W., Jha, S. K., Toedt‐Pingel, I., Ji, S. Y., Nunez, D. J., Ramachandran, A., Anaya-Cisneros, M., Tian, R., & Lefer, D. J. (2008) · Circulation Research · doi:10.1161/circresaha.108.190918 · Cited by 422 · see citing works
Self-citationAMP-activated protein kinase: nature's energy sensor
Carling, D., Mayer, F. V., Sanders, M. J., & Gamblin, S. J. (2011) · Nature Chemical Biology · doi:10.1038/nchembio.610 · Cited by 412 · see citing works
Li, T., Zhang, Z., Kolwicz, S. C., Abell, L., Roe, N. D., Kim, M., Zhou, B., Cao, Y., Ritterhoff, J., Gu, H., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.11.005 · Cited by 405 · see citing works
Self-citationTerai, K., Hiramoto, Y., Masaki, M., Sugiyama, S., Kuroda, T., Hori, M., Kawase, I., & Hirota, H. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9554-9575.2005 · Cited by 351 · see citing works
Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation
Xie, Q., Khaoustov, V. I., Chung, C. C., Sohn, J., Krishnan, B., Lewis, D. E., & Yoffe, B. (2002) · Hepatology · doi:10.1053/jhep.2002.35441 · Cited by 339 · see citing works
Predominant α2/β2/γ3 AMPK activation during exercise in human skeletal muscle
Birk, J. B., & Wojtaszewski, J. F. P. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.120972 · Cited by 293 · see citing works
Gollob, M. H., Seger, J. J., Gollob, T. N., Tapscott, T., Gonzales, O., Bachinski, L. L., & Roberts, R. (2001) · Circulation · doi:10.1161/hc5001.102111 · Cited by 278 · see citing works
AMP-activated protein kinase adapts rRNA synthesis to cellular energy supply
Hoppe, S., Bierhoff, H., Cado, I., Weber, A., Tiebe, M., Grummt, I., & Voit, R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909873106 · Cited by 225 · see citing works
Xing, Y., Musi, N., FUJII, N. L., Zou, L., Luptak, I., Hirshman, M. F., Goodyear, L. J., & Tian, R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303521200 · Cited by 213 · see citing works
Self-citationA small molecule AMPK activator protects the heart against ischemia–reperfusion injury
Kim, A. S., Miller, E. J., Wright, T. M., Li, J., Qi, D., Atsina, K. B.-T., Zaha, V. G., Sakamoto, K., & Young, L. H. (2011) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2011.03.003 · Cited by 171 · see citing works
AMP-Activated Protein Kinase: A Key Stress Signaling Pathway in the Heart
Young, L. H., Li, J., Baron, S. J., & Russell, R. R. (2005) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2005.04.005 · Cited by 166 · see citing works
Exercise Increases Nuclear AMPK α2 in Human Skeletal Muscle
McGee, S. L., Howlett, K. F., Starkie, R. L., Cameron-Smith, D., Kemp, B. E., & Hargreaves, M. (2003) · Diabetes · doi:10.2337/diabetes.52.4.926 · Cited by 160 · see citing works
van Schadewijk, A. M., Wout, E. F. A. V. ’., Stolk, J. N., & Hiemstra, P. S. (2011) · Cell Stress and Chaperones · doi:10.1007/s12192-011-0306-2 · Cited by 158 · see citing works
Blair, E. M., Redwood, C. S., Ashrafian, H., Oliveira, S. M., Broxholme, J., Kerr, B. A., Salmon, A. P., Östman‐Smith, I., & Watkins, H. C. (2001) · Journal of Medical Genetics · Cited by 124 · see citing works
Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury
Paiva, M. S. A., Rutter‐Locher, Z., Gonçalves, L. M. M., Providência, L. A., Davidson, S. M., Yellon, D. M., & Mocanu, M. M. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00707.2010 · Cited by 122 · see citing works
AMP‐activated protein kinase isoenzyme family: subunit structure and chromosomal location
Stapleton, D., Woollatt, E., Mitchelhill, K. I., Nicholl, J. K., Fernández, C., Michell, B. J., Witters, L. A., Power, D. A., Sutherland, G. R., & Kemp, B. E. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00569-3 · Cited by 117 · see citing works
Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function
Yavari, A., Stocker, C. J., Ghaffari, S., Wargent, E. T., Steeples, V., Czibik, G., Pintér, K., Bellahcene, M., Woods, A., de Morentin, P. B. M., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.003 · Cited by 113 · see citing works
Luptak, I., Shen, M., He, H., Hirshman, M. F., Musi, N., Goodyear, L. J., Yan, J., Wakimoto, H., Morita, H., Arad, M., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30658 · Cited by 108 · see citing works
Self-citationSteinberg, G. R., Watt, M. J., McGee, S. L., Chan, S., Hargreaves, M., Febbraio, M. A., Stapleton, D., & Kemp, B. E. (2006) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h06-003 · Cited by 104 · see citing works
Day, P. M., Sharff, A., Parra, L. M., Cleasby, A., Williams, M. C., Hörer, S., Nar, H., Redemann, N. H., Tickle, I. J., & Yon, J. R. (2007) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444907009110 · Cited by 93 · see citing works
Zarrinpashneh, E., Carjaval, K., Beauloye, C., Ginion, A., Matéo, P., Pouleur, A., Horman, S., Vaulont, S., Hoerter, J. A., Viollet, B., et al. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01032.2005 · Cited by 92 · see citing works
Kim, M., Hunter, R. W., Garcia‐Menendez, L., Gong, G., Yang, Y.-Y., Kolwicz, S. C., Xu, J., Sakamoto, K., Wang, W., & Tian, R. (2014) · Circulation Research · doi:10.1161/circresaha.114.302364 · Cited by 84 · see citing works
Self-citationLi, Y., Zhu, W. M., Tao, J., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048115 · Cited by 75 · see citing works
AMPK isoform expression in the normal and failing hearts
Kim, M., Shen, M., Ngoy, S., Karamanlidis, G., Liao, R., & Tian, R. (2012) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2012.01.016 · Cited by 73 · see citing works
Self-citationZou, L., Shen, M., Arad, M., He, H., Løfgren, B., Ingwall, J. S., Seidman, C. E., Seidman, J. G., & Tian, R. (2005) · Circulation Research · doi:10.1161/01.res.0000179035.20319.c2 · Cited by 50 · see citing works
Self-citationPintér, K., Jefferson, A., Czibik, G., Watkins, H. C., & Redwood, C. S. (2012) · Cell Cycle · doi:10.4161/cc.11.5.19412 · Cited by 30 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases
Ren, J., Bi, Y., Sowers, J. R., Hetz, C., & Zhang, Y. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00511-w · Cited by 708 · see citing works
Mesquita, P. H. C., Vann, C. G., Phillips, S. M., McKendry, J., Young, K. C., Kavazis, A. N., & Roberts, M. D. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.725866 · Cited by 62 · see citing works
- Authors
- Cao, Y., Bojjireddy, N., Kim, M., Li, T., Zhai, P., Nagarajan, N., Sadoshima, J., Palmiter, R. D., & Tian, R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Cao, Yang
- Bojjireddy, Naveen
- ORCID
- Venue
- Circulation Research
- Published
- 2017-10-27
- Volume
- 121
- Issue
- 10
- Pages
- 1182-1191
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC5659937
- OpenAlex
- W2746333362
- Cited by
- 74
- References
- 38
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 10 · 2023: 9 · 2022: 7 · 2021: 13 · 2020: 6 · 2019: 7 · 2018: 2 · 2017: 2
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Washington
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL088634, R01HL129510, R01HL118989, R01HL067970)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- AMPK, ribosome biogenesis, myocardial ischemia-reperfusion injury, cardioprotection, pre-rRNA transcription, TIF-IA, RNA polymerase I, endoplasmic reticulum stress, cardiac cell death, glucose deprivation, nuclear translocation, infarct size
- MeSH terms
- Animals, Chlorocebus aethiops, Enzyme Activation, Humans, Mice, Transgenic, Ribosomes, Protein Biosynthesis, Myocardial Reperfusion Injury, Cell Death, Mice, Knockout, COS Cells, Active Transport, Cell Nucleus, Mice, AMP-Activated Protein Kinases, HEK293 Cells
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
