{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:24:36Z","timestamp":1780446276045,"version":"3.54.1"},"reference-count":44,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T00:00:00Z","timestamp":1658880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cancer cachexia is one of the leading causes of mortality for late-stage cancer patients. One of its key characteristics is abnormal metabolism and loss of metabolic flexibility, i.e., loss of ability to switch between use of fats and carbohydrates as needed. Here, it is hypothesized that late-stage systemic cancer creates a chronic resource drain on the body that may result in the same metabolic adaptations that occur during intense endurance exercise, activating some of the same mechanisms of nutrient consumption that are supposed to be transient during strenuous physical activity. This hypothesis is evaluated by creating a mathematical model that characterizes the relationships between increased exercise intensity and carbohydrate and fat oxidation. The model is parametrized using published data on these characteristics for a group of professional athletes, moderately active individuals, and individuals with metabolic syndrome. Transitions between different zones of relative nutrient consumption as a function of increased effort are captured through explicitly modeling ventilatory thresholds, particularly VT1 and VT2, where fat is primarily used below VT1, both carbohydrates and fats are used between VT1 and VT2, and where carbohydrates become the primary source of fuel above VT2. A simulation is conducted of projected patterns of nutrient consumption when simulated \u201ceffort\u201d remains between VT1 and VT2, or above VT2, and it is proposed that it is the scenario when the simulated effort is maintained primarily above VT2 that most closely resembles metabolic patterns characteristic of cachexia. A discussion of a broader framework for understanding cachectic metabolism using insights from exercise physiology, including potential intervention strategies, concludes this paper.<\/jats:p>","DOI":"10.3390\/cells11152317","type":"journal-article","created":{"date-parts":[[2022,7,27]],"date-time":"2022-07-27T21:11:05Z","timestamp":1658956265000},"page":"2317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Understanding Metabolic Alterations in Cancer Cachexia through the Lens of Exercise Physiology"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1100-6806","authenticated-orcid":false,"given":"Irina","family":"Kareva","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Northeastern University, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.critrevonc.2018.05.006","article-title":"Cancer cachexia: Diagnosis, assessment, and treatment","volume":"127","author":"Sadeghi","year":"2018","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1200\/JCO.20.00611","article-title":"Management of cancer cachexia: ASCO guideline","volume":"38","author":"Roeland","year":"2020","journal-title":"Am. Soc. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1097\/CCO.0000000000000517","article-title":"Cancer cachexia, a clinical challenge","volume":"31","author":"Busquets","year":"2019","journal-title":"Curr. Opin. Oncol. LWW"},{"key":"ref_4","first-page":"2944","article-title":"Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes","volume":"51","author":"Kelley","year":"2002","journal-title":"Diabetes. Am. Diabetes Assoc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1093\/ajcn\/45.6.1420","article-title":"Comparison of indirect calorimetric measurements of resting energy expenditure with a ventilated hood, face mask, and mouthpiece","volume":"45","author":"Segal","year":"1987","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/0026-0495(88)90110-2","article-title":"The theoretical bases of indirect calorimetry: A review","volume":"37","author":"Ferrannini","year":"1988","journal-title":"Metabolism"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1152\/jappl.1983.55.2.628","article-title":"Calculation of substrate oxidation rates in vivo from gaseous exchange","volume":"55","author":"Frayn","year":"1983","journal-title":"J. Appl. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s40279-017-0751-x","article-title":"Assessment of metabolic flexibility by means of measuring blood lactate, fat, and carbohydrate oxidation responses to exercise in professional endurance athletes and less-fit individuals","volume":"48","author":"Brooks","year":"2018","journal-title":"Sports Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1242\/dmm.001180","article-title":"A comprehensive definition for metabolic syndrome","volume":"2","author":"Huang","year":"2009","journal-title":"Dis. Models Mech."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.2337\/dc12-0336","article-title":"Metabolic syndrome and risk of cancer: A systematic review and meta-analysis","volume":"35","author":"Esposito","year":"2012","journal-title":"Diabetes Care. Am. Diabetes Assoc."},{"key":"ref_11","first-page":"1","article-title":"Ventilation can exclusively be used to predict ventilatory thresholds: A retrospective analysis","volume":"16","author":"Gouw","year":"2021","journal-title":"Int. J. Res. Ex. Phys."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1111\/sms.14007","article-title":"The importance of ventilatory thresholds to define aerobic exercise intensity in cardiac patients and healthy subjects","volume":"31","author":"Anselmi","year":"2021","journal-title":"Scand. J. Med. Sci. Sports"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1159\/000194758","article-title":"Ventilatory Thresholds during a Graded Exercise Test","volume":"47","author":"Bhambhani","year":"1985","journal-title":"Respiration"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1249\/01.mss.0000218141.90442.6c","article-title":"Simplified strategy for the estimation of the exercise ventilatory thresholds","volume":"38","author":"Neder","year":"2006","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1177\/193229680700100414","article-title":"Blood lactate measurements and analysis during exercise: A guide for clinicians","volume":"1","author":"Goodwin","year":"2007","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_16","first-page":"CCRPM-S449","article-title":"The respiratory exchange ratio is associated with fitness indicators both in trained and untrained men: A possible application for people with reduced exercise tolerance","volume":"2","author":"Mascher","year":"2008","journal-title":"Clin. Med. Circ. Respir. Pulm. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1002\/jcsm.12630","article-title":"Diverging metabolic programmes and behaviours during states of starvation, protein malnutrition, and cachexia","volume":"11","author":"Olson","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1002\/jcsm.12225","article-title":"Establishment and characterization of a novel murine model of pancreatic cancer cachexia","volume":"8","author":"Michaelis","year":"2017","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kareva, I., Abou-Slaybi, A., Dodd, O., Dashevsky, O., and Klement, G.L. (2016). Normal wound healing and tumor angiogenesis as a game of competitive inhibition. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166655"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1056\/NEJM198612253152606","article-title":"Tumors: Wounds that do not heal","volume":"315","author":"Dvorak","year":"1986","journal-title":"N. Engl. J. Med. Mass Med. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kareva, I. (2017). Cancer as a disease of homeostasis: An angiogenesis perspective. Ecology and Evolution of Cancer, Elsevier.","DOI":"10.1016\/B978-0-12-804310-3.00019-3"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Holtan, S.G., Creedon, D.J., Haluska, P., and Markovic, S.N. (2009). Cancer and pregnancy: Parallels in growth, invasion, and immune modulation and implications for cancer therapeutic agents. Mayo Clinic Proceedings, Elsevier.","DOI":"10.4065\/84.11.985"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10In0759","DOI":"10.1016\/j.tranon.2020.100759","article-title":"Immune suppression in pregnancy and cancer: Parallels and insights","volume":"13","author":"Kareva","year":"2020","journal-title":"Transl. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Marshall, S., and Agarwal, E. (2017). Comparing characteristics of malnutrition, starvation, sarcopenia and cachexia in older adults. Handbook of Famine, Starvation, and Nutrient Deprivation: From Biology to Policy, Springer.","DOI":"10.1007\/978-3-319-40007-5_50-1"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/S0749-0690(02)00032-0","article-title":"Distinguishing starvation from cachexia","volume":"18","author":"Thomas","year":"2002","journal-title":"Clin. Geriatr. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.cmet.2017.04.004","article-title":"Autophagy and tumor metabolism","volume":"25","author":"Kimmelman","year":"2017","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1101\/gad.325514.119","article-title":"Role of tumor and host autophagy in cancer metabolism","volume":"33","author":"White","year":"2019","journal-title":"Genes Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1079\/PNS2004349","article-title":"Metabolic flexibility","volume":"63","author":"Storlien","year":"2004","journal-title":"Proc. Nutr. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"677","DOI":"10.2337\/diabetes.49.5.677","article-title":"Fuel selection in human skeletal muscle in insulin resistance: A reexamination","volume":"49","author":"Kelley","year":"2000","journal-title":"Diabetes"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1002\/jcsm.12554","article-title":"Ketone bodies attenuate wasting in models of atrophy","volume":"11","author":"Koutnik","year":"2020","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_31","unstructured":"Hutchinson, A., and Gladwell, M. (2018). Endure: Mind, Body, and the Curiously Elastic Limits of Human Performance, HarperCollins."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1001\/jama.289.1.76","article-title":"Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001","volume":"289","author":"Mokdad","year":"2003","journal-title":"JAMA Am. Med. Assoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1126\/science.1241244","article-title":"The health risk of obesity\u2014Better metrics imperative","volume":"341","author":"Ahima","year":"2013","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1073\/pnas.44.6.619","article-title":"The relation between longevity and obesity in human beings","volume":"44","author":"Pauling","year":"1958","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1249\/MSS.0000000000001074","article-title":"Effects of weight loss on lean mass, strength, bone, and aerobic capacity","volume":"49","author":"Weiss","year":"2017","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/1550-2783-12-S1-P58","article-title":"Differential effects of rapid or slow body weight loss on muscle weight and protein degradation pathways in rat skeletal muscle","volume":"12","author":"Nonaka","year":"2015","journal-title":"J. Int. Soc. Sports Nutr."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"999","DOI":"10.3945\/ajcn.113.071399","article-title":"Obesity paradox in cancer: New insights provided by body composition","volume":"99","author":"Gonzalez","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/jcsm.12267","article-title":"Loss of skeletal muscle during systemic chemotherapy is prognostic of poor survival in patients with foregut cancer","volume":"9","author":"Daly","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1478-7954-12-6","article-title":"Using maximum weight to redefine body mass index categories in studies of the mortality risks of obesity","volume":"12","author":"Stokes","year":"2014","journal-title":"Popul. Health Metr."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Martini, A.D., Dalleck, L.C., Mejuto, G., Larwood, T., Weatherwax, R.M., and Ramos, J.S. (2022). Changes in the Second Ventilatory Threshold Following Individualised versus Standardised Exercise Prescription among Physically Inactive Adults: A Randomised Trial. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19073962"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"25371","DOI":"10.2196\/25371","article-title":"A handheld metabolic device (lumen) to measure fuel utilization in healthy young adults: Device validation study","volume":"10","author":"Lorenz","year":"2021","journal-title":"Interact. J. Med. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"886","DOI":"10.4161\/15384047.2014.987075","article-title":"Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice","volume":"16","author":"Kliewer","year":"2015","journal-title":"Cancer Biol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Wolpern, A.E., Burgos, D.J., Janot, J.M., and Dalleck, L.C. (2015). Is a threshold-based model a superior method to the relative percent concept for establishing individual exercise intensity? A randomized controlled trial. BMC Sports Sci. Med. Rehabil., 7.","DOI":"10.1186\/s13102-015-0011-z"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1249\/01.mss.0000560956.86272.00","article-title":"The Use of Individualized Exercise Prescription to Target Oxidative Metabolism in A Stage Iv Colorectal, Metastatic Cancer Patient: 581 May 29 1: 20 PM\u20131: 40 PM","volume":"51","year":"2019","journal-title":"Med. Sci. Sports Exerc. 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