High-intensity interval training slows down tumor progression in mice bearing Lewis lung carcinoma

Christiano R R Alves, Willian das Neves, Gabriel C Tobias, Ney R Almeida, Raphael F Barreto, Camila M Melo, Camila G Carneiro, Alexandre T Garcez, Daniele P Faria, Roger  Chammas, Patricia C Brum


Background: The effects of high-intensity interval training (HIIT) in cancer progression are still unknown. Here, we aimed to evaluate whether a short-term HIIT protocol would counteract tumor progression in an experimental model of lung cancer. Methods: Mice were injected subcutaneously with Lewis Lung Carcinoma (LLC) cells and then randomly assigned into two groups: sedentary mice (LLC group) or mice submitted to HIIT (LLC + HIIT group). Results: LLC + HIIT group had lower tumor mass than LLC group (-52% after 18 days), even though no differences were found for tumor morphology or glycolytic capacity. HIIT increased Cd274 (PD-L1) mRNA levels by ~6 fold and tended to increase Tnfa and Il6 mRNA levels in LLC tumors. Moreover, HIIT increased Vegfa mRNA levels by 2.5 fold and tended to increase Pparg1a mRNA levels, suggesting that HIIT stimulates local inflammation and angiogenesis in LLC tumors. Additionally, HIIT improved running capacity and skeletal muscle contractile function in LLC tumor-bearing mice. Conclusions: HIIT attenuates tumor growth and increases the mRNA levels of genes involved in inflammation and angiogenesis in LLC tumor-bearing mice. Additionally, HIIT improves running capacity and skeletal muscle function in LLC tumor-bearing mice. Therefore, this study provides pre-clinical evidence that HIIT may be a beneficial co-therapy for lung cancer.

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Gulati M, Pandey DK, Arnsdorf MF, et al (2003) Exercise capacity and the risk of death in women. Circulation 108:1554–1559. doi: 10.1161/01.CIR.0000091080.57509.E9

Kokkinos P, Myers J, Kokkinos JP, et al (2008) Exercise capacity and mortality in black and white men. Circulation 117:614–622. doi: 10.1161/CIRCULATIONAHA.107.734764

Koch LG, Kemi OJ, Qi N, et al (2011) Intrinsic aerobic capacity sets a divide for aging and longevity. Circ Res 109:1162–1172. doi: 10.1161/CIRCRESAHA.111.253807

Booth FW, Roberts CK, Laye MJ (2012) Lack of exercise is a major cause of chronic diseases. Compr Physiol 2:1143–1211. doi: 10.1002/cphy.c110025.Lack

C F-L (2013) Exercise is the real polypill. Physiol 28: 330-358.

Hillman CH, Erickson KI, Kramer AF (2008) Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci 9:58–65. doi: 10.1038/nrn2298

Egan B, Zierath JR (2013) Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab 17:162–184. doi: 10.1016/j.cmet.2012.12.012

Alves CRR, da Cunha TF, da Paixão NA, Brum PC (2014) Aerobic exercise training (AET) as therapy for cardiac and cancer cachexia. Life Sci. doi: 10.1016/j.lfs.2014.11.029

Brum PC, Bacurau A V., Cunha TF, et al (2014) Skeletal myopathy in heart failure: effects of aerobic exercise training. Exp Physiol 99:616–620. doi: 10.1113/expphysiol.2013.076844

Brum PC, Bacurau AVN, Medeiros A, et al (2011) Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle function. Braz J Med Biol Res 44:827–835. doi: 10.1590/S0100-879X2011007500075

Gielen S, Laughlin MH, O’Conner C, Duncker DJ (2015) Exercise Training in Patients with Heart Disease: Review of Beneficial Effects and Clinical Recommendations. Prog Cardiovasc Dis 57:347–355. doi: 10.1016/j.pcad.2014.10.001

Meka N, Katragadda S, Cherian B, Arora RR (2008) Endurance exercise and resistance training in cardiovascular disease. Ther Adv Cardiovasc Dis 2:115–21. doi: 10.1177/1753944708089701

Pedersen BK, Saltin B (2015) Exercise as medicine - Evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand J Med Sci Sport 25:1–72. doi: 10.1111/sms.12581

Nobre TS, Antunes-Correa LM, Groehs R V, et al (2016) Exercise Training Improves Neurovascular Control and Calcium Cycling Gene Expression in Heart Failure Patients with Cardiac Resynchronization Therapy. Am J Physiol Hear Circ Physiol ajpheart 00275 2016. doi: 10.1152/ajpheart.00275.2016

Antunes-Correa LM, Kanamura BY, Melo RC, et al (2012) Exercise training improves neurovascular control and functional capacity in heart failure patients regardless of age. Eur J Prev Cardiol 19:822–829. doi: 10.1177/1741826711414626

Wisloff U, Stoylen A, Loennechen JP, et al (2007) Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation 115:3086–3094. doi: 10.1161/CIRCULATIONAHA.106.675041

Warburton DER, Nicol CW, Bredin SSD (2006) Health benefits of physical activity: the evidence. CMAJ 174:801–9. doi: 10.1503/cmaj.051351

Stanford KI, Goodyear LJ (2014) Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle. Adv Physiol Educ 38:308–314. doi: 10.1152/advan.00080.2014

Colberg SR, Sigal RJ, Fernhall B, et al (2010) Exercise and type 2 diabetes: The American College of Sports Medicine and the American Diabetes Association: Joint position statement. Diabetes Care. doi: 10.2337/dc10-9990

Zanuso S, Jimenez A, Pugliese G, et al (2010) Exercise for the management of type 2 diabetes: A review of the evidence. Acta Diabetol 47:15–22. doi: 10.1007/s00592-009-0126-3

Gualano B, Sá Pinto AL, Perondi B, et al (2010) Evidence for prescribing exercise as treatment in pediatric rheumatic diseases. Autoimmun Rev 9:569–573. doi: 10.1016/j.autrev.2010.04.001

Benatti FB, Pedersen BK (2014) Exercise as an anti-inflammatory therapy for rheumatic diseases—myokine regulation. Nat Rev Rheumatol 11:86–97. doi: 10.1038/nrrheum.2014.193

Perandini LA, Sales-de-Oliveira D, Mello SB V., et al (2014) Exercise training can attenuate the inflammatory milieu in women with systemic lupus erythematosus. J Appl Physiol 117:639–647. doi: 10.1152/japplphysiol.00486.2014

Becofsky KM, Sui X, Lee DC, et al (2015) A prospective study of fitness, fatness, and depressive symptoms. Am J Epidemiol 181:311–320. doi: 10.1093/aje/kwu330

Forbes D, Forbes SC, Blake CM, et al (2015) Exercise programs for people with dementia. Cochrane database Syst Rev 4:CD006489. doi: 10.1002/14651858.CD006489.pub4

Kemoun G, Thibaud M, Roumagne N, et al (2010) Effects of a physical training programme on cognitive function and walking efficiency in elderly persons with dementia. Dement GeriatrCogn Disord 29:109–114. doi: 10.1159/000272435

Jones, LW, Eves, ND, Scott J (2017) Bench-to-Bedside Approaches for Personalized Exercise Therapy in Cancer. Am Soc Clin Oncol Educ Book 37:684–694. doi: 10.14694/EDBK_173836

Speck RM, Courneya KS, Mâsse LC, et al (2010) An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. J Cancer Surviv 4:87–100. doi: 10.1007/s11764-009-0110-5

Rock CL, Doyle C, Demark-Wahnefried W, et al (2012) Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin 62:243–274. doi: 10.3322/caac.21142

Miller KD, Siegel RL, Lin CC, et al (2016) Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 66:271–289. doi: 10.3322/caac.21349

Didkowska J, Wojciechowska U, Mańczuk M, Łobaszewski J (2016) Lung cancer epidemiology: contemporary and future challenges worldwide. Ann Transl Med 4:150–150. doi: 10.21037/atm.2016.03.11

Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30. doi: 10.3322/caac.21332

Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011. CA Cancer J Clin 61:212–236. doi: 10.3322/caac.20121

Fearon K, Strasser F, Anker SD, et al (2011) Definition and classification of cancer cachexia: An international consensus. Lancet Oncol 12:489–495. doi: 10.1016/S1470-2045(10)70218-7

Fearon K, Arends J, Baracos V (2013) Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol 10:90–9. doi: 10.1038/nrclinonc.2012.209

Baracos VE, Reiman T, Mourtzakis M, et al (2010) Body composition in patients with non-small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis. Am J ClinNutr 91:1133S–1137S.

A.V. K, B.-S. P, D.-H. K, et al (2016) Aerobic and resistance training dependent skeletal muscle plasticity in the colon-26 murine model of cancer cachexia. Metabolism 65:685–698.

Pedersen L, Idorn M, Olofsson GH, et al (2016) Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab 23:554–562. doi: 10.1016/j.cmet.2016.01.011

Bacurau AVN, Belmonte MA, Navarro F, et al (2007) Effect of a High-Intensity Exercise Training on the Metabolism and Function of Macrophages and Lymphocytes of Walker 256 Tumor-Bearing Rats. Exp Biol Med 232:1289–1299. doi: 10.3181/0704-RM-93

Seelaender MCL, DoNascimento CMO, Curi R, Williams JF (1996) Studies on the lipid metabolism of Walker 256 tumour-bearing rats during the development of cancer cachexia. Biochem Mol Biol Int 39:1037–1047.

Deuster PA, Morrison SD, Ahrens RA (1985) Endurance exercise modifies cachexia of tumor growth in rats. Med Sci Sport Exerc 17:385–392.

Lira FS, Tavares FL, Yamashita AS, et al (2008) Effect of endurance training upon lipid metabolism in the liver of cachectic tumour-bearing rats. Cell Biochem Funct 26:701–708. doi: 10.1002/cbf.1495

Penna F, Busquets S, Pin F, et al (2011) Combined approach to counteract experimental cancer cachexia: Eicosapentaenoic acid and training exercise. J Cachexia Sarcopenia Muscle 2:95–104. doi: 10.1007/s13539-011-0028-4

Pin F, Busquets S, Toledo M, et al (2015) Combination of exercise training and erythropoietin prevents cancer-induced muscle alterations. Oncotarget 6:43202–15. doi: 10.18632/oncotarget.6439

Moreira JBN, Bechara LRG, Bozi LHM, et al (2013) High- versus moderate-intensity aerobic exercise training effects on skeletal muscle of infarcted rats. J Appl Physiol 114:1029–41. doi: 10.1152/japplphysiol.00760.2012

Moholdt T, Aamot IL, Granøien I, et al (2012) Aerobic interval training increases peak oxygen uptake more than usual care exercise training in myocardial infarction patients: a randomized controlled study. Clin Rehabil 26:33–44. doi: 10.1177/0269215511405229

Hwang C-L, Wu Y-T, Chou C-H (2011) Effect of aerobic interval training on exercise capacity and metabolic risk factors in people with cardiometabolic disorders: a meta-analysis. J Cardiopulm Rehabil Prev 31:378–85. doi: 10.1097/HCR.0b013e31822f16cb

Gibala MJ, Little JP, Macdonald MJ, Hawley J a (2012) Physiological adaptations to low-volume, high-intensity interval training in health and disease. J Physiol 590:1077–1084. doi: 10.1113/jphysiol.2011.224725

Gibala MJ, Little JP, van Essen M, et al (2006) Short-term sprint interval versus traditional endurance training: similar initial adaptations in human skeletal muscle and exercise performance. J Physiol 575:901–911. doi: 10.1113/jphysiol.2006.112094

Kong Z, Fan X, Sun S, et al (2016) Comparison of high-intensity interval training and moderate-to-vigorous continuous training for cardiometabolic health and exercise enjoyment in obese young women: A randomized controlled trial. PLoS One. doi: 10.1371/journal.pone.0158589

Fisher G, Brown AW, Brown MMB, et al (2015) High Intensity Interval- vs Moderate Intensity-Training for Improving Cardiometabolic Health in Overweight or Obese Males: A Randomized Controlled Trial. PLoS One. doi: 10.1371/journal.pone.0138853

Bowen TS, Rolim NPL, Fischer T, et al (2015) Heart failure with preserved ejection fraction induces molecular, mitochondrial, histological, and functional alterations in rat respiratory and limb skeletal muscle. Eur J Heart Fail 17:263–272. doi: 10.1002/ejhf.239

Guiraud T, Nigam A, Gremeaux V, et al (2012) High-intensity interval training in cardiac rehabilitation. Sports Med 42:587–605. doi: http://dx.doi.org/10.2165/11631910-000000000-00000

Gulati M, Pandey DK, Arnsdorf MF, et al (2003) Exercise capacity and the risk of death in women: The St. James Women Take Heart Project. Circulation 108:1554–1559. doi: 10.1161/01.CIR.0000091080.57509.E9

Jelleyman C, Yates T, O’Donovan G, et al (2015) The effects of high-intensity interval training on glucose regulation and insulin resistance: A meta-analysis. Obes Rev 16:942–961. doi: 10.1111/obr.12317

Tj??nna AE, Lee SJ, Rognmo ??ivind, et al (2008) Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: A pilot study. Circulation 118:346–354. doi: 10.1161/CIRCULATIONAHA.108.772822

Moreira JBN, Bechara LRG, Bozi LHM, et al (2013) High- versus moderate-intensity aerobic exercise training effects on skeletal muscle of infarcted rats. J Appl Physiol 114:1029–1041. doi: 10.1152/japplphysiol.00760.2012

Kir S, Komaba H, Garcia AP, et al (2016) PTH/PTHrP receptor mediates cachexia in models of kidney failure and cancer. Cell Metab 23:315–323. doi: 10.1016/j.cmet.2015.11.003

Kir S, White JP, Kleiner S, et al (2014) Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 1:1–19. doi: 10.1038/nature13528

Puppa MJ, Gao S, Narsale AA, Carson JA (2014) Skeletal muscle glycoprotein 130’s role in Lewis lung carcinoma-induced cachexia. FASEB J 28:998–1009. doi: 10.1096/fj.13-240580

Ruas JL, White JP, Rao RR, et al (2012) A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 151:1319–1331. doi: 10.1016/j.cell.2012.10.050

Kerr KM, Nicolson MC (2016) Non–Small Cell Lung Cancer, PD-L1, and the Pathologist. Arch Pathol Lab Med 140:249–254. doi: 10.5858/arpa.2015-0303-SA

Al-Chaqmaqchi H, Sadeghi B, Abedi-Valugerdi M, et al (2013) The Role of Programmed Cell Death Ligand-1 (PD-L1/CD274) in the Development of Graft versus Host Disease. PLoS One. doi: 10.1371/journal.pone.0060367

Johnston AJ, Murphy KT, Jenkinson L, et al (2015) Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival. Cell 162:1365–1378. doi: 10.1016/j.cell.2015.08.031

Johns N, Stephens NA, Fearon KCH (2013) Muscle wasting in cancer. Int J Biochem Cell Biol 45:2215–2229. doi: 10.1016/j.biocel.2013.05.032

Argilés (2014) Cancer cachexia: understanding the molecular basis. Nat Rev cancer 14: 754-62.

K F (2012) Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab 16: 153-166.

Culp PA, Choi D, Zhang Y, et al (2010) Antibodies to TWEAK receptor inhibit human tumor growth through dual mechanisms. Clin Cancer Res 16:497–508. doi: 10.1158/1078-0432.CCR-09-1929

Chinsomboon J, Ruas J, Gupta RK, et al (2009) The transcriptional coactivator PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle. Proc Natl Acad Sci U S A 106:21401–6. doi: 10.1073/pnas.0909131106

Rowe GC, Raghuram S, Jang C, et al (2014) PGC-1α induces SPP1 to activate macrophages and orchestrate functional angiogenesis in skeletal muscle. Circ Res 115:504–517. doi: 10.1161/CIRCRESAHA.115.303829

Arany Z, Foo S-Y, Ma Y, et al (2008) HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature 451:1008–12. doi: 10.1038/nature06613

Thom R, Rowe GC, Jang C, et al (2014) Hypoxic induction of vascular endothelial growth factor (VEGF) and angiogenesis in muscle by truncated peroxisome proliferator-activated receptor γ coactivator (PGC)-1α. J Biol Chem 289:8810–7. doi: 10.1074/jbc.M114.554394

Hoeben A, Landuyt B, Highley MS, et al (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56:549–580. doi: 10.1124/pr.

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: The next generation. Cell 144:646–674. doi: 10.1016/j.cell.2011.02.013

Feinberg T, Herbig J, Kohl I, et al (2017) Cancer metabolism: the volatile signature of glycolysis-in vitro model in lung cancer cells. J Breath Res 11:16008. doi: 10.1088/1752-7163/aa51d6

Vazquez F, Lim JH, Chim H, et al (2013) PGC1α Expression Defines a Subset of Human Melanoma Tumors with Increased Mitochondrial Capacity and Resistance to Oxidative Stress. Cancer Cell 23:287–301. doi: 10.1016/j.ccr.2012.11.020

Lim JH, Luo C, Vazquez F, Puigserver P (2014) Targeting mitochondrial oxidative metabolism in melanoma causes metabolic compensation through glucose and glutamine utilization. Cancer Res 74:3535–3545. doi: 10.1158/0008-5472.CAN-13-2893-T

Almuhaideb A, Papathanasiou N, Bomanji J (2011) 18F-FDG PET/CT imaging in oncology. Ann Saudi Med 31:3–13. doi: 10.4103/0256-4947.75771

Kimura M, Naito T, Kenmotsu H, et al (2014) Prognostic impact of cancer cachexia in patients with advanced non-small cell lung cancer. Support Care Cancer. doi: 10.1007/s00520-014-2534-3

das Neves W, Alves CRR, de Almeida NR, et al (2016) Loss of strength capacity is associated with mortality, but resistance exercise training promotes only modest effects during cachexia progression. Life Sci 163:11–22. doi: 10.1016/j.lfs.2016.08.025

Wewege M, van den Berg R, Ward RE, Keech A (2017) The effects of high-intensity interval training vs. moderate-intensity continuous training on body composition in overweight and obese adults: a systematic review and meta-analysis. Obes Rev 18:635–646. doi: 10.1111/obr.12532

Chen DS, Mellman I (2013) Oncology meets immunology: The cancer-immunity cycle. Immunity 39:1–10. doi: 10.1016/j.immuni.2013.07.012

Betof AS, Lascola CD, Weitzel D, et al (2015) Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise. J Natl Cancer Inst. doi: 10.1093/jnci/djv040

Turley SJ, Cremasco V, Astarita JL (2015) Immunological hallmarks of stromal cells in the tumour microenvironment. Nat Rev Immunol 15:669–682. doi: 10.1038/nri3902

K. F (2014) Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 12: 489-495.

Fearon KCH, Glass DJ, Guttridge DC (2012) Cancer cachexia: Mediators, signaling, and metabolic pathways. Cell Metab 16:153–166. doi: 10.1016/j.cmet.2012.06.011

Springer J, Von Haehling S, Morley JE, et al (2017) Ethical guidelines for publishing in the journal of cachexia, sarcopenia and muscle rapid communications. J Cachexia, Sarcopenia Muscle - Rapid Commun 1:1.


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