Endurance training attenuates TNF-α elevation in a murine model of lung adenocarcinoma cachexia: A pilot study

Abstract

Introduction: Cancer cachexia is a multifactorial syndrome characterized by weight loss, skeletal muscle wasting, and systemic inflammation. Tumor necrosis factor-alpha (TNF-α) plays a central role in cachexia pathophysiology; however, the anti-inflammatory effects of endurance exercise in lung adenocarcinoma-associated cachexia remain insufficiently defined.

Objective: This study aimed to investigate the effects of endurance training on systemic inflammation, as assessed by circulating TNF-α levels, and cachexia-related outcomes in a murine orthotopic model of lung adenocarcinoma.

Methods: Male BALB/cAJcl-nu/nu mice were assigned to four groups: non-exercise control, exercise control, non-exercise lung adenocarcinoma cachexia, and exercise lung adenocarcinoma cachexia (n= 6 per group). An orthotopic lung adenocarcinoma model was established by trans-airway implantation of A549 cells. Endurance training was performed at 20 m/min for 30 min, five days per week for six weeks. Body weight, gastrocnemius wet weight, circulating TNF-α levels, and lung macroscopic and histological findings were evaluated. Data were analyzed using one-way and two-way analyses of variance.

Results: After six weeks, tumor-bearing mice exhibited significant body weight loss and skeletal muscle atrophy compared with controls, confirming successful induction of cachexia. Endurance training partially attenuated body weight loss in tumor-bearing mice. Macroscopic and histological analyses confirmed lung tumor presence in both non-exercise and exercise cachexia groups. Circulating TNF-α levels were significantly elevated in tumor-bearing mice compared with controls; notably, endurance training significantly reduced TNF-α levels in cachexia mice. Two-way analysis revealed significant main effects of tumor burden and exercise on TNF-α levels.

Conclusion: Endurance training attenuates systemic TNF-α elevation in a murine model of lung adenocarcinoma cachexia without suppressing tumor establishment. These findings support endurance exercise as a supportive anti-inflammatory strategy in cancer cachexia.

Keywords

Lung adenocarcinoma / Cancer cachexia / Endurance exercise / TNF-α / Inflammation

References

[1] Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009; 89(2):381-410. doi: 10.1152/physrev.00016.2008

[2] Argilés JM, Busquets S, Stemmler B, López-Soriano FJ. Cancer cachexia: understanding the molecular basis. Nat Rev Cancer. 2014; 14(11):754-762. doi: 10.1038/nrc3829

[3] Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011; 12(5):489-495. doi: 10.1016/S1470-2045(10)70218-7

[4] Baracos VE, Martin L, Korc M, et al. Cancer-associated cachexia. Nat Rev Dis Primers. 2018; 4(1):17105. doi: 10.1038/nrdp.2017.105

[5] Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3):209-249. doi: 10.3322/caac.21660

[6] Skipworth RJ, Stewart GD, Dejong CH, Preston T, Fearon KC. Pathophysiology of cancer cachexia: much more than host-tumour interaction? Clin Nutr. 2007; 26(6):667-676. doi: 10.1016/j.clnu.2007.03.011

[7] Porporato PE. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis. 2016; 5(2):e200. doi: 10.1038/oncsis.2016.3

[8] Bonetto A, Aydogdu T, Jin X, et al. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am J Physiol Endocrinol Metab. 2012; 303(3):E410-E421. doi: 10.1152/ajpendo.00039.2012

[9] Sandri M. Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda). 2008; 23(3):160-170. doi: 10.1152/physiol.00041.2007

[10] Cohen S, Nathan JA, Goldberg AL. Muscle wasting in disease: molecular mechanisms and therapeutic strategies. Nat Rev Drug Discov. 2015; 14(1):58-74. doi: 10.1038/nrd4467

[11] Muscaritoli M, Arends J, Bachmann P, et al. ESPEN practical guideline: clinical nutrition in cancer. Clin Nutr. 2021; 40(5):2898-2913. doi: 10.1016/j.clnu.2021.02.005

[12] Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2012; 8(8):457-465. doi: 10.1152/physrev.90100.2007

[13] Pedersen BK. The diseasome of physical inactivity-and the role of myokines in muscle-fat cross talk. J Physiol. 2009; 587(23):5559-5568. doi: 10.1113/jphysiol.2009.179515

[14] Petersen AMW, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol. 2005; 98(4):1154-1162. doi: 10.1152/japplphysiol.00164.2004

[15] Hardee JP, Counts BR, Carson JA. Understanding the role of exercise in cancer cachexia therapy. Am J Lifestyle Med. 2017; 13(1):46-60. doi: 10.1177/1559827617725283

[16] Ballarò R, Costelli P, Penna F. Animal models for cancer cachexia. Curr Opin Support Palliat Care. 2016; 10(4):281-287. doi: 10.1097/spc.0000000000000233

[17] Onn A, Isobe T, Itasaka S, et al. Development of an orthotopic model to study the biology and therapy of primary human lung cancer in nude mice. Clin Cancer Res. 2003; 9(15):5532-5539.

[18] Du Sert NP, Hurst V, Ahluwalia A, et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol. 2020; 18(7):e3000410. doi: 10.1371/journal.pbio.3000410

[19] Fearon KCH, Glass DJ, Guttridge DC. Cancer cachexia: mediators, signaling pathways. Cell Metab. 2012; 16(2):153-166. doi: 10.1016/j.cmet.2012.06.011

[20] Brown JC, Winters-Stone K, Lee A, Schmitz KH. Cancer, physical activity, and exercise. Compr Physiol. 2012; 2(4):2775-2809. doi: 10.1002/j.2040-4603.2012.tb00476.x

[21] Schiaffino S, Dyar KA, Ciciliot S, et al. Mechanisms regulating skeletal muscle growth. FEBS J. 2013; 280(17):4294-4314. doi: 10.1111/febs.12253

[22] Egan B, Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 2013; 17(2):162-184. doi: 10.1016/j.cmet.2012.12.012

[23] Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008; 88(4):1379-1406. doi: 10.1152/physrev.90100.2007

[24] Hojman P, Dethlefsen C, Brandt C, et al. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab. 2011; 301(3):E504-E510. doi: 10.1152/ajpendo.00520.2010

[25] Boström P, Wu J, Jedrychowski MP, et al. A PGC1-α- dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012; 481(7382):463-468. doi: 10.1038/nature10777

[26] Steensberg A, Fischer CP, Keller C, et al. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab. 2003; 285(2):E433-E437. doi: 10.1152/ajpendo.00074.2003

[27] Petersen AMW, Pedersen BK. The role of IL-6 in mediating the anti-inflammatory effects of exercise. J Physiol Pharmacol. 2006; 57(10):43-51.

[28] Bonaldo P, Sandri M. Cellular and molecular mechanisms of muscle atrophy. Dis Model Mech. 2013; 6(1):25-39. doi: 10.1242/dmm.010389

[29] Jones LW, Eves ND, Haykowsky M, Freedland SJ, Mackey JR. Exercise intolerance in cancer and the role of exercise therapy to reverse dysfunction. Lancet Oncol. 2009; 10(6):598-605. doi: 10.1016/S1470-2045(09)70031-2

[30] Roussos ET, Condeelis JS, Patsialou A. Chemotaxis in cancer. Nat Rev Cancer. 2011; 11(8):573-587. doi: 10.1038/nrc3078

[31] Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol. 2013; 10(2):90-99. doi: 10.1038/nrclinonc.2012.209

[32] Solheim TS, Laird BJA, Balstad TR, et al. A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer. J Cachexia Sarcopenia Muscle. 2017; 8(5):778-788. doi: 10.1002/jcsm.12201

[33] Spruit MA, Singh SJ, Garvey C, et al. An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med. 2013; 188(8):e13-e64. doi: 10.1164/rccm.201309-1634ST

[34] Jones LW, Alfano CM. Exercise-oncology research: past, present, and future. Acta Oncol. 2013; 52(2):195-215. doi: 10.3109/0284186X.2012.742564