Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways
Open accessAbstract
Cachexia represents one of the primary complications of colorectal cancer due to its effects on depletion of muscle and fat. Evidence suggests that chemotherapeutic regimens, such as Folfiri, contribute to cachexia-related symptoms. The purpose of the present study was to investigate the cachexia signature in different conditions associated with severe muscle wasting, namely Colon-26 (C26) and Folfiri-associated cachexia. Using a quantitative LC-MS/MS approach, we identified significant changes in 386 proteins in the quadriceps muscle of Folfiri-treated mice, and 269 proteins differentially expressed in the C26 hosts (p<0.05; -1.5 ≥ fold change ≥ +1.5). Comparative analysis isolated 240 proteins that were modulated in common, with a large majority (218) that were down-regulated in both experimental settings. Interestingly, metabolic (47.08%) and structural (21.25%) proteins were the most represented. Pathway analysis revealed mitochondrial dysfunctions in both experimental conditions, also consistent with reduced expression of mediators of mitochondrial fusion (OPA-1, mitofusin-2), fission (DRP-1) and biogenesis (Cytochrome C, PGC-1α). Alterations of oxidative phosphorylation within the TCA cycle, fatty acid metabolism, and Ca2+ signaling were also detected. Overall, the proteomic signature in the presence of both chemotherapy and cancer suggests the activation of mechanisms associated with movement disorders, necrosis, muscle cell death, muscle weakness and muscle damage. Conversely, this is consistent with the inhibition of pathways that regulate nucleotide and fatty acid metabolism, synthesis of ATP, muscle and heart function, as well as ROS scavenging. Interestingly, strong up-regulation of pro-inflammatory acute-phase proteins and a more coordinated modulation of mitochondrial and lipidic metabolisms were observed in the muscle of the C26 hosts that were different from the Folfiri-treated animals. In conclusion, our results suggest that both cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. These data support the undertaking of combination strategies that aim to both counteract tumor growth and reduce chemotherapy side effects.
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Muscle loss in aging sarcopenia, cancer cachexia, chemotherapy-induced cachexia, and in a model of myasthenia gravis is characterized by the decline of both fusion and fission machinery.
“Muscle loss in aging sarcopenia [185, 187, 215], cancer cachexia, chemotherapy-induced cachexia [157–159], and in a model of myasthenia gravis [216], is characterized by the decline of both fusion and fission machinery.”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [157]
The concomitant decrease of Opa1 and Drp1 also occurs in cancer cachexia and chemotherapy-induced cachexia as well as a model of myasthenia gravis.
“Moreover, the concomitant decrease of Opa1 and Drp1 also occurs in cancer cachexia and chemotherapy-induced cachexia [15,16,17] as well as a model of myasthenia gravis [18].”
From Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles (2019) · cites this paper as [15]
Both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting.
“However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting.”
From Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles (2019) · cites this paper as [15]
Muscle loss in aging sarcopenia, cancer cachexia, and myasthenia gravis is characterized by the decline of both fusion machinery and fission machinery.
“However, muscle loss in aging sarcopenia, cancer cachexia, and myasthenia gravis are characterized by the decline of both fusion machinery and fission machinery [6,11,12,15,16,17,18].”
From Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles (2019) · cites this paper as [15]
In skeletal muscle, mitochondrial fission proteins are reduced in ageing sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting.
“In skeletal muscle the mitochondrial fission proteins are reduced in different physiopathological conditions including ageing sarcopenia, cancer cachexia and chemotherapy-induced muscle wasting.”
From DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass (2019) · cites this paper as [16]
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Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302 · see citing works
Siegel, R. L., Miller, K. D., & Jemal, A. (2015) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21254 · Cited by 11,854 · see citing works
A statistical model for identifying proteins by tandem mass spectrometry.
Nesvizhskii, A., Keller, A., Kolker, E., & Aebersold, R. (2003) · Analytical Chemistry · doi:10.1021/ac0341261 · Cited by 4,902 · see citing works
Elias, J. E., & Gygi, S. P. (2007) · Nature Methods · doi:10.1038/nmeth1019 · Cited by 3,925 · 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
Pernas, L. F., & Scorrano, L. (2015) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105011 · Cited by 814 · 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-citationCancer cachexia, mechanism and treatment
Aoyagi, T., Terracina, K. P., Raza, A., Matsubara, H., & Takabe, K. (2015) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v7.i4.17 · Cited by 439 · see citing works
Antoun, S., Baracos, V. E., Birdsell, L., Escudier, B. J., & Sawyer, M. B. (2010) · Annals of Oncology · doi:10.1093/annonc/mdp605 · Cited by 420 · see citing works
Excess TGF-β mediates muscle weakness associated with bone metastases in mice
Waning, D. L., Mohammad, K. S., Reiken, S. R., Xie, W., Andersson, D. C., John, S. K., Chiechi, A., Wright, L. E., Umanskaya, A., Niewolna, M., et al. (2015) · Nature Medicine · doi:10.1038/nm.3961 · Cited by 380 · see citing works
Self-citationBonetto, A., Aydogdu, T., Kunzevitzky, N., Guttridge, D. C., Khuri, S., Koniaris, L. G., & Zimmers, T. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022538 · Cited by 348 · see citing works
Self-citationIbebunjo, C., Chick, J. M., Kendall, T., Eash, J. K., Li, C., Zhang, Y., Vickers, C., Wu, Z., Clarke, B. A., Shi, J., et al. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01036-12 · Cited by 267 · see citing works
Klimek, M. B., Aydogdu, T., Link, M., Pons, M., Koniaris, L. G., & Zimmers, T. A. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.12.123 · Cited by 229 · see citing works
Self-citationJung, H., Kim, J. W., Kim, S. W., Kim, S.-W., Yang, H. K., Lee, J. W., Lee, K. W., Kim, D., Kang, S., Kim, K., et al. (2014) · Supportive Care in Cancer · doi:10.1007/s00520-014-2418-6 · Cited by 217 · see citing works
Changes in skeletal muscle mass during palliative chemotherapy in patients with advanced lung cancer
Stene, G. B., Helbostad, J. L., Amundsen, T., Sørhaug, S., Hjelde, H. H., Kaasa, S., & Grønberg, B. H. (2014) · Acta Oncologica · doi:10.3109/0284186x.2014.953259 · Cited by 208 · see citing works
Monroe, M. E., Shaw, J. L., Daly, D. S., Adkins, J., & Smith, R. D. (2008) · Computational Biology and Chemistry · doi:10.1016/j.compbiolchem.2008.02.006 · Cited by 202 · 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-citationThoresen, L., Frykholm, G. J., Lydersen, S., Ulveland, H., Baracos, V. E., Prado, C. M. M., Birdsell, L., & Falkmer, S. (2012) · Clinical Nutrition · doi:10.1016/j.clnu.2012.05.009 · Cited by 187 · see citing works
Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action
Dutt, V., Gupta, S. K., Dabur, R., Injeti, E. R., & Mittal, A. (2015) · Pharmacological Research · doi:10.1016/j.phrs.2015.05.010 · Cited by 174 · see citing works
Chemotherapy-induced muscle wasting: association with NF-κB and cancer cachexia
Damrauer, J. S., Stadler, M., Acharyya, S., Baldwin, A. S., Couch, M. E., & D, D. C. G. (2018) · European Journal of Translational Myology · doi:10.4081/ejtm.2018.7590 · Cited by 165 · see citing works
Increased 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
Inflammation Based Regulation of Cancer Cachexia
Onesti, J. K., & D, D. C. G. (2014) · BioMed Research International · doi:10.1155/2014/168407 · Cited by 157 · see citing works
A statistical model-building perspective to identification of MS/MS spectra with PeptideProphet
Ma, K., Olga Vitek, A., & Nesvizhskii, A. I. (2012) · BMC Bioinformatics · doi:10.1186/1471-2105-13-s16-s1 · Cited by 139 · see citing works
Prado, C. M. M., Antoun, S., Sawyer, M. B., & Baracos, V. E. (2011) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e3283455d45 · Cited by 136 · see citing works
Chemotherapy-Related Neurotoxicity
Taillibert, S., Rhun, É. L., & Chamberlain, M. C. (2016) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-016-0686-x · Cited by 129 · see citing works
Cancer Cachexia, Malnutrition, and Tissue Protein Turnover in Experimental Animals
Tessitore, L., Costelli, P., Bonetti, G., & Baccino, F. M. (1993) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1993.1479 · Cited by 126 · see citing works
Ghrelin Prevents Cisplatin-Induced Mechanical Hyperalgesia and Cachexia
Garcia, J. M., Cata, J. P., Dougherty, P. M., & Smith, R. G. (2007) · Endocrinology · doi:10.1210/en.2007-0828 · Cited by 120 · see citing works
Inhibition of Cisplatin-Induced Lipid Catabolism and Weight Loss by Ghrelin in Male Mice
Garcia, J. M., Scherer, T., Chen, J.-A., Guillory, B., Nassif, A., Papusha, V. Z., Smiechowska, J., Asnicar, M., Buettner, C., & Smith, R. G. (2013) · Endocrinology · doi:10.1210/en.2013-1179 · Cited by 119 · see citing works
Carson, J. A., Hardee, J. P., & VanderVeen, B. N. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.11.005 · Cited by 104 · see citing works
de Oliveira, C. C. F., Busquets, S., Toledo, M., Penna, F., Aylwin, M. P., Sirisi, S., Ventura‐Silva, A. P., Orpí, M., García, A., Sette, A., et al. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.11.009 · Cited by 101 · 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
Costelli, P., & Baccino, F. M. (2003) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/01.mco.0000078984.18774.02 · Cited by 77 · see citing works
Argilés, J. M. A., López-Soriano, F. J., & Busquets, S. (2015) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000164 · Cited by 70 · see citing works
Bonetto, A., Penna, F., Minero, V. G., Reffo, P., Bonelli, G., Baccino, F. M., & Costelli, P. (2009) · Current Cancer Drug Targets · doi:10.2174/156800909789057015 · Cited by 69 · see citing works
Self-citationLai, X., Wang, L., Tang, H., & Witzmann, F. A. (2011) · Journal of Proteome Research · doi:10.1021/pr2005633 · Cited by 58 · see citing works
Self-citationMontagnani, F., Chiriatti, A., Turrisi, G., Francini, G., & Fiorentini, G. (2010) · Colorectal Disease · doi:10.1111/j.1463-1318.2010.02206.x · Cited by 53 · see citing works
Cordier, P., Nau, A., Ciccolini, J., et al. (2011) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-011-1666-0 · Cited by 44 · see citing works
Contribution of anorexia to tissue wasting in cachexia
Molfino, A., Laviano, A., & Fanelli, F. R. (2010) · Current Opinion in Supportive and Palliative Care · doi:10.1097/spc.0b013e32833e4aa5 · Cited by 39 · see citing works
How Relevant Are Cytokines in Colorectal Cancer Wasting?
Ravasco, P., Grillo, I. M., & Camilo, M. (2007) · The Cancer Journal · doi:10.1097/ppo.0b013e3181594940 · Cited by 38 · see citing works
Isaac, S. T., Tan, T. C., & Polly, P. (2016) · Current Drug Targets · doi:10.2174/1389450116666150416115721 · Cited by 19 · see citing works
Understanding Weight Loss in Patients With Colorectal Cancer: A Human Response to Illness
Bapuji, S. B., & Sawatzky, J. V. (2010) · Oncology nursing forum · doi:10.1188/10.onf.303-310 · Cited by 18 · see citing works
Proteomic analysis of media from lung cancer cells reveals role of 14-3-3 proteins in cachexia
McLean, J. B., Moylan, J. S., Horrell, E. M. W., & Andrade, F. H. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00136 · Cited by 12 · see citing works
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DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass
Favaro, G., Romanello, V., Varanita, T., Andrea Desbats, M., Morbidoni, V., Tezze, C., Albiero, M., Canato, M., Gherardi, G., De Stefani, D., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10226-9 · Cited by 398 · see citing works
Romanello, V., & Sandri, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03662-0 · Cited by 197 · see citing works
Dulac, M., Leduc‐Gaudet, J., Reynaud, O., Ayoub, M., Guérin, A., Finkelchtein, M., Hussain, S. N., & Gouspillou, G. (2020) · The Journal of Physiology · doi:10.1113/jp279802 · Cited by 90 · see citing works
Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles
Romanello, V., Scalabrin, M., Albiero, M., Blaauw, B., Scorrano, L., & Sandri, M. (2019) · Cells · doi:10.3390/cells8060597 · Cited by 91 · see citing works
Mitochondrial dynamics in cancer-induced cachexia
van der Ende, M., Grefte, S., Plas, R., Meijerink, J., Witkamp, R. F., Keijer, J., & van Norren, K. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.07.008 · Cited by 87 · see citing works
PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia
Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O'Connell, T. M., & Bonetto, A. (2019) · The FASEB Journal · doi:10.1096/fj.201802799r · Cited by 81 · see citing works
Self-citationRe Cecconi, A. D., Forti, M., Chiappa, M., Zhu, Z., Zingman, L. V., Cervo, L., Beltrame, L., Marchini, S., & Piccirillo, R. (2019) · Cancers · doi:10.3390/cancers11101541 · Cited by 66 · see citing works
Martin-Cantero, A., Reijnierse, E. M., Gill, B. M. T., & Maier, A. B. (2021) · Nutrition Reviews · doi:10.1093/nutrit/nuaa064 · Cited by 58 · see citing works
Fairman, C. M., Kendall, K. L., Hart, N. H., Taaffe, D. R., Galvão, D. A., & Newton, R. U. (2019) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2018.11.003 · Cited by 43 · see citing works
Chaillou, T., & Montiel-Rojas, D. (2023) · Frontiers in Aging · doi:10.3389/fragi.2023.1171850 · Cited by 10 · see citing works
- Authors
- Barreto, R., Mandili, G., Witzmann, F. A., Novelli, F., Zimmers, T. A., & Bonetto, A.
- Affiliations
- Indiana University Indianapolis (US)
- University of Turin (IT)
- Indiana University School of Medicine (US)
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center (US)
- Corresponding author
- Bonetto, Andrea
- Venue
- Frontiers in Physiology
- Publisher
- Frontiers Media SA
- Published
- 2016-10-19
- Volume
- 7
- Pages
- 472-472
- ISSN
- 1664-042X (ISSN-L)
- PMC
- PMC5070123
- OpenAlex
- W2534399581
- Cited by
- 183
- References
- 43
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 20 · 2023: 15 · 2022: 22 · 2021: 33 · 2020: 23 · 2019: 23 · 2018: 13 · 2017: 10
- FWCI
- 7.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Physiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by)
- Publisher
- Funders
- National Cancer Institute (R21CA190028, R01CA122596, R01CA194593)
- Lustgarten Foundation
- Associazione Italiana per la Ricerca sul Cancro (5xmille 12182, IG15257, IG15232)
- 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 › Cell Biology › Muscle metabolism and nutrition
- Keywords
- cancer cachexia, colorectal cancer, FOLFIRI, mitochondrial dysfunction, mitochondrial fission and fusion, oxidative phosphorylation, fatty acid metabolism, calcium signaling, acute phase proteins, muscle proteomics
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