PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia
Open accessAbstract
Cachexia is frequently accompanied by severe metabolic derangements, although the mechanisms responsible for this debilitating condition remain unclear. Pyruvate dehydrogenase kinase (PDK)4, a critical regulator of cellular energetic metabolism, was found elevated in experimental models of cancer, starvation, diabetes, and sepsis. Here we aimed to investigate the link between PDK4 and the changes in muscle size in cancer cachexia. High PDK4 and abnormal energetic metabolism were found in the skeletal muscle of colon‐26 tumor hosts, as well as in mice fed a diet enriched in Pirinixic acid, previously shown to increase PDK4 levels. Viral‐mediated PDK4 over‐expression in myotube cultures was sufficient to promote myofiber shrinkage, consistent with enhanced protein catabolism and mitochondrial abnormalities. On the contrary, blockade of PDK4 was sufficient to restore myotube size in C2C12 cultures exposed to tumor media. Our data support, for the first time, a direct role for PDK4 in promoting cancer‐associated muscle metabolic alterations and skeletal muscle atrophy.—Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O'Connell, T. M., Bonetto, A. PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia. FASEB J. 33, 7778–7790 (2019). www.fasebj.org
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PDK4 is induced in cancer, starvation, diabetes, and sepsis.
“Finally, key enzymes in ATP production such as pyruvate dehydrogenase kinase (PDK)4 have been recently reported to be induced in cancer, starvation, diabetes, and sepsis, and its overexpression promotes myofiber shrinkage while its inhibition blunts atrophy84.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [84]
PDK4 inhibition blunts atrophy.
“Finally, key enzymes in ATP production such as pyruvate dehydrogenase kinase (PDK)4 have been recently reported to be induced in cancer, starvation, diabetes, and sepsis, and its overexpression promotes myofiber shrinkage while its inhibition blunts atrophy84.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [84]
PDK4 overexpression promotes myofiber shrinkage.
“Finally, key enzymes in ATP production such as pyruvate dehydrogenase kinase (PDK)4 have been recently reported to be induced in cancer, starvation, diabetes, and sepsis, and its overexpression promotes myofiber shrinkage while its inhibition blunts atrophy84.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [84]
Cites
1 retracted
Zhang, Y., Zhang, Y., Geng, L., Yi, H., Huo, W., Talmon, G. A., Kim, Y. C., Wang, S. M., & Wang, J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.713735 · Cited by 39 · see citing works
RetractedNIH Image to ImageJ: 25 years of image analysis
Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012) · Nature Methods · doi:10.1038/nmeth.2089 · Cited by 64,638 · see citing works
Warburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425 · see citing works
Definition and classification of cancer cachexia: an international consensus
Fearon, K., Strasser, F., Anker, S. D., Bosaeus, I. G., Bruera, E. D., Fainsinger, R. L., Jatoi, A., Loprinzi, C. L., Macdonald, N., Mantovani, G., et al. (2011) · The Lancet Oncology · doi:10.1016/s1470-2045(10)70218-7 · Cited by 5,800 · see citing works
Kim, J.-W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.002 · Cited by 3,905 · see citing works
Sandri, M., Sandri, C., Gilbert, A., Skurk, C., Calabria, E., Picard, A., Walsh, K., Schiaffino, S., Lecker, S. H., & Goldberg, A. L. (2004) · Cell · doi:10.1016/s0092-8674(04)00400-3 · Cited by 3,012 · see citing works
Koves, T. R., Ussher, J. R., Noland, R. C., Slentz, D., Mosedale, M., Ilkayeva, O., Bain, J., Stevens, R., Dyck, J. R. B., Newgard, C. B., et al. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.013 · Cited by 1,990 · see citing works
FoxO3 Controls Autophagy in Skeletal Muscle In Vivo
Mammucari, C., Milan, G., Romanello, V., Masiero, E., Rudolf, R., Del Piccolo, P., Burden, S. J., Di Lisi, R., Sandri, C., Zhao, J., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.11.001 · Cited by 1,953 · see citing works
Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression
Lecker, S. H., Jagoe, R. T., Gilbert, A., Gomes, M., Baracos, V., Bailey, J., Price, S. R., Mitch, W. E., & Goldberg, A. L. (2004) · The FASEB Journal · doi:10.1096/fj.03-0610com · Cited by 1,539 · see citing works
Cancer Cachexia: Mediators, Signaling, and Metabolic Pathways
Fearon, K. C. H., Glass, D. J., & D, D. C. G. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.06.011 · Cited by 1,203 · see citing works
Fuel selection in human skeletal muscle in insulin resistance: a reexamination.
Kelley, D. E., & Mandarino, L. J. (2000) · Diabetes · doi:10.2337/diabetes.49.5.677 · Cited by 1,017 · see citing works
Links between metabolism and cancerPreprint
Dang, C. V. (2012) · Genes & Development · doi:10.1101/gad.189365.112 · Cited by 991 · see citing works
Understanding the mechanisms and treatment options in cancer cachexia
Fearon, K. C. H., Arends, J., & Baracos, V. E. (2012) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2012.209 · Cited by 937 · see citing works
Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex
Bowker-Kinley, M. M., DAVIS, I. W., Wu, P., HARRIS, A. R., & POPOV, M. K. (1998) · Biochemical Journal · doi:10.1042/bj3290191 · Cited by 567 · see citing works
Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation
Holness, M. J., & Sugden, M. C. (2003) · Biochemical Society Transactions · doi:10.1042/bst0311143 · Cited by 479 · see citing works
Bonetto, A., Aydogdu, T., Jin, X., Zhang, Z., Zhan, R., Puzis, L., Koniaris, L. G., & Zimmers, T. A. (2012) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00039.2012 · Cited by 463 · see citing works
Self-citationRole of changes in cardiac metabolism in development of diabetic cardiomyopathy
An, D., & Rodrigues, B. B. (2006) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00278.2006 · Cited by 443 · see citing works
Mechanisms of metabolic dysfunction in cancer-associated cachexiaPreprint
Petruzzelli, M., & Wagner, E. F. (2016) · Genes & Development · doi:10.1101/gad.276733.115 · Cited by 341 · see citing works
Regulation of the activity of the pyruvate dehydrogenase complex
Harris, R. A., Bowker-Kinley, M. M., Huang, B., & Wu, P. (2002) · Advances in Enzyme Regulation · doi:10.1016/s0065-2571(01)00061-9 · Cited by 337 · see citing works
Self-citationFuruyama, T., Kitayama, K., Yamashita, H., & Mori, N. (2003) · Biochemical Journal · doi:10.1042/bj20030022 · Cited by 326 · see citing works
Wu, P., Inskeep, K., Bowker-Kinley, M. M., Popov, K. M., & Harris, R. A. (1999) · Diabetes · doi:10.2337/diabetes.48.8.1593 · Cited by 290 · see citing works
Self-citationDiversity of the Pyruvate Dehydrogenase Kinase Gene Family in Humans
Gudi, R., Bowker-Kinley, M. M., Kedishvili, N. Y., Zhao, Y., & Popov, K. M. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.48.28989 · Cited by 287 · see citing works
Sugden, M. C., & Holness, M. J. (2006) · Archives of Physiology and Biochemistry · doi:10.1080/13813450600935263 · Cited by 281 · see citing works
Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7
He, W. A., Calore, F., Londhe, P., Canella, A., D, D. C. G., & Croce, C. M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1402714111 · Cited by 251 · see citing works
Huang, B., Wu, P., Bowker-Kinley, M. M., & Harris, R. A. (2002) · Diabetes · doi:10.2337/diabetes.51.2.276 · Cited by 246 · see citing works
Self-citationPalamiuc, L., Schlagowski, A.-I., Ngo, S. T., Vernay, A., Dirrig‐Grosch, S., Henriques, A., Boutillier, A., Zoll, J., Echaniz‐Laguna, A., Loeffler, J., et al. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201404433 · Cited by 235 · see citing works
Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism
Pin, F., Barreto, R., Couch, M. E., Bonetto, A., & O’Connell, T. M. (2019) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12360 · Cited by 211 · see citing works
Self-citationWu, P., Peters, J. M., & Harris, R. A. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5608 · Cited by 206 · see citing works
Self-citationExcessive fatty acid oxidation induces muscle atrophy in cancer cachexia
Fukawa, T., Chua, B. Y.-J., Min‐Wen, J. C., Jun‐Hao, E. T., Huang, D. Y., Qian, C.-N., Ong, P., Li, Z., Chen, S., Mak, S. Y., et al. (2016) · Nature Medicine · doi:10.1038/nm.4093 · Cited by 206 · see citing works
Chen, J., Splenser, A. E., Guillory, B., Luo, J., Mendiratta, M., Belinova, B., Halder, T., Zhang, G., Li, Y., & Garcia, J. M. (2015) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12023 · Cited by 201 · see citing works
Watt, M. J., Heigenhauser, G. J. F., Dyck, D. J., & Spriet, L. L. (2002) · The Journal of Physiology · doi:10.1113/jphysiol.2002.018820 · Cited by 201 · see citing works
Barreto, R., Waning, D. L., Gao, H., Liu, Y., Zimmers, T. A., & Bonetto, A. (2016) · Oncotarget · doi:10.18632/oncotarget.9779 · Cited by 199 · see citing works
Self-citationPathophysiology of cancer cachexia: Much more than host–tumour interaction?
Skipworth, R. J. E., Stewart, G. D., Dejong, C. H. C., Preston, T., & Fearon, K. C. H. (2007) · Clinical Nutrition · doi:10.1016/j.clnu.2007.03.011 · Cited by 198 · see citing works
Johns, N., Stephens, N., & Fearon, K. (2013) · International Journal of Biochemistry and Cell Biology · doi:10.1016/j.biocel.2013.05.032 · Cited by 194 · see citing works
Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways
Barreto, R., Mandili, G., Witzmann, F. A., Novelli, F., Zimmers, T. A., & Bonetto, A. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00472 · Cited by 183 · see citing works
Self-citationIncreased muscle ubiquitin mRNA levels in gastric cancer patients.
Bossola, M., Muscaritoli, M., Costelli, P., Bellantone, R., Pacelli, F., Busquets, S., Argilès, J., López-Soriano, F., Civello, I. M., Baccino, F., et al. (2001) · American Journal of Physiology. Regulatory Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.280.5.r1518 · Cited by 164 · see citing works
Muscle oxidative capacity during IL-6-dependent cancer cachexia.
White, J. P., Baltgalvis, K. A., Puppa, M. J., Sato, S., Baynes, J., & Carson, J. (2011) · American Journal of Physiology. Regulatory Integrative and Comparative Physiology · doi:10.1152/ajpregu.00300.2010 · Cited by 162 · see citing works
Kwon, H., Huang, B., Unterman, T. G., & Harris, R. A. (2004) · Diabetes · doi:10.2337/diabetes.53.4.899 · Cited by 157 · see citing works
Self-citationAssessment of muscle mass and strength in mice
Bonetto, A., Andersson, D. C., & Waning, D. L. (2015) · BoneKEy Reports · doi:10.1038/bonekey.2015.101 · Cited by 152 · see citing works
Self-citationPiao, L. H., Sidhu, V. K., Fang, Y.-H., et al. (2012) · Journal of Molecular Medicine · doi:10.1007/s00109-012-0982-0 · Cited by 151 · see citing works
Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation
Jeoung, N. H., Wu, P., Joshi, M., Jaskiewicz, J. A., Bock, C. B., DePaoli-Roach, A. A., & Harris, R. A. (2006) · Biochemical Journal · doi:10.1042/bj20060125 · Cited by 143 · see citing works
Self-citationNahlé, Z., Hsieh, M., Pietka, T., Coburn, C. T., Grimaldi, P. A., Zhang, M. Q., Das, D., & Abumrad, N. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m706478200 · Cited by 122 · see citing works
Srivastava, N., Kollipara, R. K., Singh, D. K., Sudderth, J., Hu, Z., Nguyen, H. P., Wang, S., Humphries, C. G., Carstens, R. M., Huffman, K. E., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.08.003 · Cited by 122 · see citing works
Zhao, G., Jeoung, N. H., Burgess, S. C., Rosaaen-Stowe, K. A., Inagaki, T., Latif, S., Shelton, J. M., McAnally, J., Bassel‐Duby, R., Harris, R. A., et al. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00870.2007 · Cited by 120 · see citing works
Self-citationKim, Y. I., Lee, F. N., Choi, W. S., Lee, S., & Youn, J. H. (2006) · Diabetes · doi:10.2337/db05-1606 · Cited by 119 · see citing works
Oncogenic role of PDK4 in human colon cancer cells
Leclerc, D., Pham, D. N. T., Lévesque, N., Truongcao, M. M., Foulkes, W. D., Sapienza, C., & Rozen, R. R. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.38 · Cited by 115 · see citing works
Judge, S. M., Wu, C.-L., Beharry, A. W., Roberts, B. M., Ferreira, L. F., Kandarian, S. C., & Judge, A. R. (2014) · BMC Cancer · doi:10.1186/1471-2407-14-997 · Cited by 111 · see citing works
Fuel-sensing mechanisms integrating lipid and carbohydrate utilization
Sugden, M., Bulmer, K., & Holness, M. J. (2001) · Biochemical Society Transactions · doi:10.1042/bst0290272 · Cited by 103 · see citing works
Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting
Spriet, L. L., Tunstall, R. J., Watt, M. J., Carey, K. A., Hargreaves, M., & Cameron‐Smith, D. (2004) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01318.2003 · Cited by 102 · see citing works
Pin, F., Barreto, R., Kitase, Y., Mitra, S., Erne, C. E., Novinger, L. J., Zimmers, T. A., Couch, M. E., Bonewald, L. F., & Bonetto, A. (2018) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12311 · Cited by 100 · see citing works
Self-citationSkeletal muscle mitochondrial uncoupling in a murine cancer cachexia model
Tzika, A. A., de Oliveira, C. C. F., Shestov, A. A., Constantinou, C., Psychogios, N., Righi, V., Mintzopoulos, D., Busquets, S., López-Soriano, F. J., Milot, S. M., et al. (2013) · International Journal of Oncology · doi:10.3892/ijo.2013.1998 · Cited by 96 · see citing works
Combination of exercise training and erythropoietin prevents cancer-induced muscle alterations
Pin, F., Busquets, S., Toledo, M., Camperi, A., López-Soriano, F. J., Costelli, P., Argilés, J. M. A., & Penna, F. (2015) · Oncotarget · doi:10.18632/oncotarget.6439 · Cited by 95 · see citing works
Self-citationDegenhardt, T., Saramäki, A., Malinen, M., Rieck, M., Vaïsänen, S., Huotari, A., Herzig, K., Müller, R., & Carlberg, C. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.06.091 · Cited by 92 · see citing works
Liu, Z., Chen, X., Wang, Y., Peng, H., Wang, Y., Jing, Y., & Zhang, H. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.584821 · Cited by 83 · see citing works
Araki, M., Nakagawa, Y., Oishi, A., Han, S., Wang, Y., Kumagai, K., Ohno, H., Mizunoe, Y., IWASAKI, H. O., Sekiya, M., et al. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19072148 · Cited by 79 · see citing works
Constantin‐Teodosiu, D., Constantin, D., Stephens, F. B., Laithwaite, D., & Greenhaff, P. L. (2012) · Diabetes · doi:10.2337/db11-0799 · Cited by 65 · see citing works
Fuster, G., Busquets, S., Ametller, E., Oliván, M., Almendro, V., de Oliveira, C. C. F., Figueras, M., López-Soriano, F. J., & Argilés, J. M. A. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0231 · Cited by 46 · see citing works
Asp, M. L., Tian, M., Kliewer, K., & Belury, M. A. (2011) · Cancer Biology & Therapy · doi:10.4161/cbt.12.11.18134 · Cited by 43 · see citing works
Mallinson, J. E., Constantin‐Teodosiu, D., Glaves, P. D., Martin, E. A., Davies, W. J., Westwood, F. R., Sidaway, J. E., & Greenhaff, P. L. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.238022 · Cited by 40 · see citing works
Regulation of PDH activity and isoform expression: diet and exercise
Peters, S. J. (2003) · Biochemical Society Transactions · doi:10.1042/bst0311274 · Cited by 34 · see citing works
Fuel-sensing mechanisms integrating lipid and carbohydrate utilization
Sugden, M. C., Bulmer, K., & Holness, M. J. (2001) · Biochemical Society Transactions · doi:10.1042/0300-5127:0290272 · Cited by 34 · see citing works
Physiological characterization of a mouse model of cachexia in colorectal liver metastases.
Murphy, K., Struk, A., Malcontenti‐Wilson, C., Christophi, C., & Lynch, G. (2013) · American Journal of Physiology. Regulatory Integrative and Comparative Physiology · doi:10.1152/ajpregu.00057.2013 · Cited by 18 · see citing works
Crossland, H., Constantin‐Teodosiu, D., Gardiner, S. M., & Greenhaff, P. L. (2017) · Clinical Science · doi:10.1042/cs20170958 · Cited by 16 · see citing works
Shrivastav, S., Zhang, L., Okamoto, K., et al. (2013) · Molecular Endocrinology · doi:10.1210/me.2012-1370 · Cited by 14 · see citing works
Muscle interleukin-6 and fasting-induced PDH regulation in mouse skeletal muscle
Gudiksen, A., Bertholdt, L., Vingborg, M. B., Hansen, H. W., Ringholm, S., & Pilegaard, H. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00291.2016 · Cited by 13 · see citing works
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Mechanisms of muscle atrophy and hypertrophy: implications in health and disease
Sartori, R., Romanello, V., & Sandri, M. (2021) · Nature Communications · doi:10.1038/s41467-020-20123-1 · Cited by 940 · see citing works
- Authors
- Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O'Connell, T. M., & Bonetto, A.
- Affiliations
- Indiana University Indianapolis (US)
- Indiana University School of Medicine (US)
- Indiana University-Purdue University Indianapolis Center for Cachexia Research, Innovation, and Therapy Indiana University School of Medicine Indianapolis Indiana USA
- Corresponding author
- Bonetto, Andrea
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2019-03-20
- Volume
- 33
- Issue
- 6
- Pages
- 7778-7790
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC6529344
- OpenAlex
- W2925166956
- Cited by
- 81
- References
- 65
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 10 · 2023: 12 · 2022: 16 · 2021: 10 · 2020: 8 · 2019: 3
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nd)
- Funders
- Melvin and Bren Simon Cancer Center, Indiana University (P30CA082709)
- Indiana University
- V Foundation for Cancer Research (V2017-021)
- American Cancer Society (132013-RSG-l8-010-01-CCG)
- Indiana Clinical and Translational Sciences Institute
- Ralph W. and Grace M. Showalter Research Trust Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- PDK4, pyruvate dehydrogenase kinase, cancer cachexia, skeletal muscle atrophy, protein degradation, mitochondrial abnormalities, colon 26 tumor, tumor microenvironment
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Animals, Cachexia, Cell Line, Male, Mitochondria, Muscle, Muscular Atrophy, Neoplasms, Oxidation-Reduction, Muscle, Skeletal, Mice
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