The Role of Systemic Inflammation in Cancer-Associated Muscle Wasting and Rationale for Exercise as a Therapeutic Intervention

Calvin Lloyd Cole, Ian R. Kleckner, Aminah Jatoi, Edward Schwarz, Richard F. Dunne


Progressive skeletal muscle wasting in cancer cachexia involves a process of dysregulated protein synthesis and breakdown.  This catabolism may be the result of mal-nutrition, and an upregulation of both pro-inflammatory cytokines and the ubiquitin proteasome pathway (UPP), which can subsequently increase myostatin and activin A release.  The skeletal muscle wasting associated with cancer cachexia is clinically significant, it can contribute to treatment toxicity or the premature discontinuation of treatments resulting in increases in morbidity and mortality.  Thus, there is a need for further investigation into the pathophysiology of muscle wasting in cancer cachexia to develop effective prophylactic and therapeutic interventions.  Several studies have identified a central role for chronic-systemic inflammation in initiating and perpetuating muscle wasting in patients with cancer.  Interestingly, while exercise has shown efficacy in improving muscle quality, only recently have investigators begun to assess the impact that exercise has on chronic-systemic inflammation.  To put this new information into context with established paradigms, here we review several biological pathways (e.g. dysfunctional inflammatory response, hypothalamus pituitary adrenal axis, and increased myostatin/activin A activity) that may be responsible for the muscle wasting in patients with cancer.  Additionally, we discuss the potential impact that exercise has on these pathways in the treatment of cancer cachexia.  Exercise is an attractive intervention for muscle wasting in this population, partially because it disrupts chronic-systemic inflammation mediated catabolism.  Most importantly, exercise is a potent stimulator of muscle synthesis, and therefore this therapy may reverse muscle damage caused by cancer cachexia. 

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Evans WJ, Morley JE, Argiles J, et al. Cachexia: a new definition. Clinical nutrition (Edinburgh, Scotland). 2008;27(6):793-9. doi:10.1016/j.clnu.2008.06.013

Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. The Lancet. Oncology. 2011;12(5):489-95. doi:10.1016/s1470-2045(10)70218-7

Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nature Reviews Clinical Oncology. 2013;10:90+.

Argiles JM, Busquets S, Stemmler B, Lopez-Soriano FJ. Cancer cachexia: understanding the molecular basis. Nature reviews. Cancer. 2014;14(11):754-62. doi:10.1038/nrc3829

Al-Majid S, Waters H. The biological mechanisms of cancer-related skeletal muscle wasting: the role of progressive resistance exercise. Biological research for nursing. 2008;10(1):7-20.

Fearon Kenneth CH, Glass David J, Guttridge Denis C. Cancer Cachexia: Mediators, Signaling, and Metabolic Pathways. Cell Metabolism. 2012;16(2):153-66. doi:

Andreyev HJ, Norman AR, Oates J, Cunningham D. Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? European journal of cancer (Oxford, England : 1990). 1998;34(4):503-9.

Attaix D, Ventadour S, Codran A, Bechet D, Taillandier D, Combaret L. The ubiquitin-proteasome system and skeletal muscle wasting. Essays in biochemistry. 2005;41:173-86. doi:10.1042/eb0410173

Prado CM, Baracos VE, McCargar LJ, et al. Sarcopenia as a determinant of chemotherapy toxicity and time to tumor progression in metastatic breast cancer patients receiving capecitabine treatment. Clinical cancer research : an official journal of the American Association for Cancer Research. 2009;15(8):2920-6. doi:10.1158/1078-0432.ccr-08-2242

Muscaritoli M, Bossola M, Aversa Z, Bellantone R, Rossi Fanelli F. Prevention and treatment of cancer cachexia: new insights into an old problem. European journal of cancer (Oxford, England : 1990). 2006;42(1):31-41. doi:10.1016/j.ejca.2005.07.026

Fielitz J. Cancer cachexia-when proteasomal inhibition is not enough. Journal of cachexia, sarcopenia and muscle. 2016;7(3):239-45. doi:10.1002/jcsm.12124

Utech AE, Tadros EM, Hayes TG, Garcia JM. Predicting survival in cancer patients: the role of cachexia and hormonal, nutritional and inflammatory markers. Journal of Cachexia, Sarcopenia and Muscle. 2012;3(4):245-51. doi:10.1007/s13539-012-0075-5

Inagaki J, Rodriguez V, Bodey GP. Proceedings: Causes of death in cancer patients. Cancer. 1974;33(2):568-73.

Skipworth RJ, Stewart GD, Dejong CH, Preston T, Fearon KC. Pathophysiology of cancer cachexia: much more than host-tumour interaction? Clinical nutrition (Edinburgh, Scotland). 2007;26(6):667-76. doi:10.1016/j.clnu.2007.03.011

Bosaeus I. Nutritional support in multimodal therapy for cancer cachexia. Supportive Care in Cancer. 2008;16(5):447. doi:10.1007/s00520-007-0388-7

Han HQ, Zhou X, Mitch WE, Goldberg AL. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential. The international journal of biochemistry & cell biology. 2013;45(10):2333-47. doi:10.1016/j.biocel.2013.05.019

Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S, Glass DJ. Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size. American journal of physiology. Cell physiology. 2009;296(6):C1258-70. doi:10.1152/ajpcell.00105.2009

Acharyya S, Butchbach ME, Sahenk Z, et al. Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia. Cancer cell. 2005;8(5):421-32. doi:10.1016/j.ccr.2005.10.004

Loumaye A, de Barsy M, Nachit M, et al. Role of Activin A and myostatin in human cancer cachexia. The Journal of clinical endocrinology and metabolism. 2015;100(5):2030-8. doi:10.1210/jc.2014-4318

Williams A, Sun X, Fischer JE, Hasselgren P-O. The expression of genes in the ubiquitin-proteasome proteolytic pathway is increased in skeletal muscle from patients with cancer. Surgery. 1999;126(4):744-50. doi:

Kotler DP. Cachexia. Annals of Internal Medicine. 2000;133(8):622-34. doi:10.7326/0003-4819-133-8-200010170-00015

Bosaeus I. Nutritional support in multimodal therapy for cancer cachexia. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2008;16(5):447-51. doi:10.1007/s00520-007-0388-7

Penna F, Bonetto A, Aversa Z, et al. Effect of the specific proteasome inhibitor bortezomib on cancer‐related muscle wasting. Journal of Cachexia, Sarcopenia and Muscle. 2016;7(3):345-54. doi:10.1002/jcsm.12050

Vaughan VC, Martin P, Lewandowski PA. Cancer cachexia: impact, mechanisms and emerging treatments. Journal of cachexia, sarcopenia and muscle. 2013;4(2):95-109. doi:10.1007/s13539-012-0087-1

Saligan LN, Olson K, Filler K, et al. The biology of cancer-related fatigue: a review of the literature. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2015;23(8):2461-78. doi:10.1007/s00520-015-2763-0

Illman J, Corringham R, Robinson D, Jr., et al. Are inflammatory cytokines the common link between cancer-associated cachexia and depression? The journal of supportive oncology. 2005;3(1):37-50.

Adamsen L, Quist M, Andersen C, et al. Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial. Bmj. 2009;339:b3410. doi:10.1136/bmj.b3410

Donges CE, Burd NA, Duffield R, et al. Concurrent resistance and aerobic exercise stimulates both myofibrillar and mitochondrial protein synthesis in sedentary middle-aged men. Journal of applied physiology (Bethesda, Md. : 1985). 2012;112(12):1992-2001. doi:10.1152/japplphysiol.00166.2012

Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(48):20405-10. doi:10.1073/pnas.0911570106

Camera DM, Edge J, Short MJ, Hawley JA, Coffey VG. Early time course of Akt phosphorylation after endurance and resistance exercise. Med Sci Sports Exerc. 2010;42(10):1843-52. doi:10.1249/MSS.0b013e3181d964e4

Hulmi JJ, Ahtiainen JP, Kaasalainen T, et al. Postexercise myostatin and activin IIb mRNA levels: effects of strength training. Med Sci Sports Exerc. 2007;39(2):289-97. doi:10.1249/01.mss.0000241650.15006.6e

Grande AJ, Silva V, Maddocks M. Exercise for cancer cachexia in adults: Executive summary of a Cochrane Collaboration systematic review. Journal of Cachexia, Sarcopenia and Muscle. 2015;6(3):208-11. doi:10.1002/jcsm.12055

Bonaldo P, Sandri M. Cellular and molecular mechanisms of muscle atrophy. Disease Models & Mechanisms. 2013;6(1):25-39. doi:10.1242/dmm.010389

Atherton PJ, Smith K. Muscle protein synthesis in response to nutrition and exercise. The Journal of physiology. 2012;590(Pt 5):1049-57. doi:10.1113/jphysiol.2011.225003

Bowen TS, Schuler G, Adams V. Skeletal muscle wasting in cachexia and sarcopenia: molecular pathophysiology and impact of exercise training. Journal of cachexia, sarcopenia and muscle. 2015;6(3):197-207. doi:10.1002/jcsm.12043

Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M. Mechanisms regulating skeletal muscle growth and atrophy. FEBS Journal. 2013;280(17):4294-314. doi:10.1111/febs.12253

Schiaffino S, Mammucari C. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skeletal muscle. 2011;1:4-. doi:10.1186/2044-5040-1-4

McCarthy JJ, Esser KA. Anabolic and catabolic pathways regulating skeletal muscle mass. Current opinion in clinical nutrition and metabolic care. 2010;13(3):230-5. doi:10.1097/MCO.0b013e32833781b5

Egerman MA, Glass DJ. Signaling pathways controlling skeletal muscle mass. Critical Reviews in Biochemistry and Molecular Biology. 2014;49(1):59-68. doi:10.3109/10409238.2013.857291

Argiles JM, Orpi M, Busquets S, Lopez-Soriano FJ. Myostatin: more than just a regulator of muscle mass. Drug discovery today. 2012;17(13-14):702-9. doi:10.1016/j.drudis.2012.02.001

Milan G, Romanello V, Pescatore F, et al. Regulation of autophagy and the ubiquitin–proteasome system by the FoxO transcriptional network during muscle atrophy. 2015;6:6670. doi:10.1038/ncomms7670

Sartori R, Milan G, Patron M, et al. Smad2 and 3 transcription factors control muscle mass in adulthood. American journal of physiology. Cell physiology. 2009;296(6):C1248-57. doi:10.1152/ajpcell.00104.2009

Costamagna D, Costelli P, Sampaolesi M, Penna F. Role of Inflammation in Muscle Homeostasis and Myogenesis. Mediators of Inflammation. 2015;2015:14. doi:10.1155/2015/805172

Costelli P, Carbó N, Tessitore L, et al. Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model. Journal of Clinical Investigation. 1993;92(6):2783-9.

Gelin J, Moldawer LL, Lönnroth C, Sherry B, Chizzonite R, Lundholm K. Role of Endogenous Tumor Necrosis Factor α and Interleukin 1 for Experimental Tumor Growth and the Development of Cancer Cachexia. Cancer Research. 1991;51(1):415-21.

Baltgalvis KA, Berger FG, Pena MMO, Davis JM, Muga SJ, Carson JA. Interleukin-6 and cachexia in ApcMin/+ mice. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2008;294(2):R393-R401.

Seruga B, Zhang H, Bernstein LJ, Tannock IF. Cytokines and their relationship to the symptoms and outcome of cancer. Nature Reviews Cancer. 2008;8(11):887-99.

Mantovani G, Macciò A, Mura L, et al. Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites. Journal of Molecular Medicine. 2000;78(10):554-61.

Chu W-M. Tumor necrosis factor. Cancer letters. 2013;328(2):222-5. doi:10.1016/j.canlet.2012.10.014

Han Y, Weinman S, Boldogh I, Walker RK, Brasier AR. Tumor necrosis factor-alpha-inducible IkappaBalpha proteolysis mediated by cytosolic m-calpain. A mechanism parallel to the ubiquitin-proteasome pathway for nuclear factor-kappab activation. The Journal of biological chemistry. 1999;274(2):787-94.

Tisdale MJ. Biology of cachexia. Journal of the National Cancer Institute. 1997;89(23):1763-73.

Jatoi A, Ritter HL, Dueck A, et al. A placebo-controlled, double-blind trial of infliximab for cancer-associated weight loss in elderly and/or poor performance non-small cell lung cancer patients (N01C9). Lung Cancer. 2010;68(2):234-9.

Jatoi A, Dakhil SR, Nguyen PL, et al. A placebo-controlled double blind trial of etanercept for the cancer anorexia/weight loss syndrome: results from N00C1 from the North Central Cancer Treatment Group. Cancer. 2007;110(6):1396-403. doi:10.1002/cncr.22944

Catalano MG, Fortunati N, Arena K, et al. Selective up-regulation of tumor necrosis factor receptor I in tumor-bearing rats with cancer-related cachexia. International journal of oncology. 2003;23(2):429-36.

Patra SK, Arora S. Integrative role of neuropeptides and cytokines in cancer anorexia-cachexia syndrome. Clinica chimica acta; international journal of clinical chemistry. 2012;413(13-14):1025-34. doi:10.1016/j.cca.2011.12.008

Tijerina AJ. The biochemical basis of metabolism in cancer cachexia. Dimensions of critical care nursing : DCCN. 2004;23(6):237-43.

Seruga B, Zhang H, Bernstein LJ, Tannock IF. Cytokines and their relationship to the symptoms and outcome of cancer. Nature reviews. Cancer. 2008;8(11):887-99.

Stranahan AM, Lee K, Mattson MP. Central Mechanisms of HPA axis Regulation by Voluntary Exercise. Neuromolecular medicine. 2008;10(2):118-27. doi:10.1007/s12017-008-8027-0

O'brien J, Ames D, Schweitzer I, Mastwyk M, Colman P. Enhanced adrenal sensitivity to adrenocorticotrophic hormone (ACTH) is evidence of HPA axis hyperactivity in Alzheimer's disease. Psychological medicine. 1996;26(01):7-14.

Crofford LJ. The hypothalamic-pituitary-adrenal axis in the pathogenesis of rheumatic diseases. Endocrinology and metabolism clinics of North America. 2002;31(1):1-13.

Gold SM, Mohr DC, Huitinga I, Flachenecker P, Sternberg EM, Heesen C. The role of stress-response systems for the pathogenesis and progression of MS. Trends in immunology. 2005;26(12):644-52. doi:10.1016/

TURNBULL AV, RIVIER CL. Regulation of the Hypothalamic-Pituitary-Adrenal Axis by Cytokines: Actions and Mechanisms of Action. Physiological reviews. 1999;79(1):1-71.

Turnbull AV, Rivier CL. Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiological reviews. 1999;79(1):1-71.

Albertus B, Lambertus GT. Review: Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. Journal of Endotoxin Research. 2003;9(1):3-24. doi:10.1177/09680519030090010101

Curti BD, Urba WJ, Longo DL, et al. Endocrine Effects of IL-1 [alpha] and [beta] Administered in a Phase I Trial to Patients with Advanced Cancer. Journal of Immunotherapy. 1996;19(2):142-8.

Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. The Journal of Clinical Endocrinology & Metabolism. 1993;77(6):1690-4.

Nolten W, Goldstein D, Lindstrom M, et al. Effects of cytokines on the pituitary–adrenal axis in cancer patients. Journal of interferon research. 1993;13(5):349-57.

Gisslinger H, Svoboda T, Clodi M, et al. Interferon-α stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro. Neuroendocrinology. 1993;57(3):489-95.

Mastorakos G, Weber JS, Magiakou M, Gunn H, Chrousos GP. Hypothalamic-pituitary-adrenal axis activation and stimulation of systemic vasopressin secretion by recombinant interleukin-6 in humans: potential implications for the syndrome of inappropriate vasopressin secretion. The Journal of Clinical Endocrinology & Metabolism. 1994;79(4):934-9.

Tsigos C, Papanicolaou DA, Defensor R, Mitsiadis CS, Kyrou I, Chrousos G. Dose effects of recombinant human lnterleukin-6 on pituitary hormone secretion and energy expenditure. Neuroendocrinology. 1997;66(1):54-62.

Woloski B, Smith E, Meyer W, Fuller G, Blalock J. Corticotropin-releasing activity of monokines. Science (New York, N.Y.). 1985;230(4729):1035-7. doi:10.1126/science.2997929

Smith EM, Blalock JE. Human lymphocyte production of corticotropin and endorphin-like substances: association with leukocyte interferon. Proceedings of the National Academy of Sciences of the United States of America. 1981;78(12):7530-4.

Berkenbosch F, van Oers J, del Rey A, Tilders F, Besedovsky H. Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science (New York, N.Y.). 1987;238(4826):524-6.

Zargar-Shoshtari K, Hill AG. Postoperative fatigue: a review. World journal of surgery. 2009;33(4):738-45. doi:10.1007/s00268-008-9906-0

Mueller TC, Bachmann J, Prokopchuk O, Friess H, Martignoni ME. Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia--can findings from animal models be translated to humans? BMC cancer. 2016;16:75. doi:10.1186/s12885-016-2121-8

Menconi M, Fareed M, O’Neal P, Poylin V, Wei W, Hasselgren P-O. Role of glucocorticoids in the molecular regulation of muscle wasting. Critical care medicine. 2007;35(9):S602-S8.

Argilés JM, Fontes-Oliveira CC, Toledo M, López-Soriano FJ, Busquets S. Cachexia: a problem of energetic inefficiency. Journal of Cachexia, Sarcopenia and Muscle. 2014;5(4):279-86. doi:10.1007/s13539-014-0154-x

Gaude E, Frezza C. Defects in mitochondrial metabolism and cancer. Cancer & Metabolism. 2014;2:10-. doi:10.1186/2049-3002-2-10

Argiles JM, Lopez-Soriano FJ, Busquets S. Muscle wasting in cancer: the role of mitochondria. Current opinion in clinical nutrition and metabolic care. 2015;18(3):221-5. doi:10.1097/mco.0000000000000164

Dumas JF, Goupille C, Julienne CM, et al. Efficiency of oxidative phosphorylation in liver mitochondria is decreased in a rat model of peritoneal carcinosis. Journal of hepatology. 2011;54(2):320-7. doi:10.1016/j.jhep.2010.08.012

Shum AM, Mahendradatta T, Taylor RJ, et al. Disruption of MEF2C signaling and loss of sarcomeric and mitochondrial integrity in cancer-induced skeletal muscle wasting. Aging. 2012;4(2):133-43. doi:10.18632/aging.100436

McLean JB, Moylan JS, Andrade FH. Mitochondria dysfunction in lung cancer-induced muscle wasting in C2C12 myotubes. Frontiers in physiology. 2014;5:503. doi:10.3389/fphys.2014.00503

Fontes-Oliveira CC, Busquets S, Toledo M, et al. Mitochondrial and sarcoplasmic reticulum abnormalities in cancer cachexia: Altered energetic efficiency? Biochimica et Biophysica Acta (BBA) - General Subjects. 2013;1830(3):2770-8. doi:

Antunes D, Padrão AI, Maciel E, et al. Molecular insights into mitochondrial dysfunction in cancer-related muscle wasting. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2014;1841(6):896-905. doi:

Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443(7113):787-95.

Buck M, Chojkier M. Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants. The EMBO Journal. 1996;15(8):1753-65.

White JP, Puppa MJ, Sato S, et al. IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the ApcMin/+ mouse. Skeletal muscle. 2012;2:14. doi:10.1186/2044-5040-2-14

Baltgalvis KA, Berger FG, Pena MM, Davis JM, Muga SJ, Carson JA. Interleukin-6 and cachexia in ApcMin/+ mice. American journal of physiology. Regulatory, integrative and comparative physiology. 2008;294(2):R393-401. doi:10.1152/ajpregu.00716.2007

Lee SJ, McPherron AC. Myostatin and the control of skeletal muscle mass. Current opinion in genetics & development. 1999;9(5):604-7.

Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(16):9306-11. doi:10.1073/pnas.151270098

Sidis Y, Mukherjee A, Keutmann H, Delbaere A, Sadatsuki M, Schneyer A. Biological Activity of Follistatin Isoforms and Follistatin-Like-3 Is Dependent on Differential Cell Surface Binding and Specificity for Activin, Myostatin, and Bone Morphogenetic Proteins. Endocrinology. 2006;147(7):3586-97. doi:doi:10.1210/en.2006-0089

Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFβ activation. Journal of Cell Science. 2003;116(2):217-24. doi:10.1242/jcs.00229

Wolfman NM, McPherron AC, Pappano WN, et al. Activation of latent myostatin by the BMP-1/tolloid family of metalloproteinases. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(26):15842-6. doi:10.1073/pnas.2534946100

Elkasrawy MN, Hamrick MW. Myostatin (GDF-8) as a key factor linking muscle mass and bone structure. Journal of musculoskeletal & neuronal interactions. 2010;10(1):56-63.

McFarlane C, Plummer E, Thomas M, et al. Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-κB-independent, FoxO1-dependent mechanism. Journal of Cellular Physiology. 2006;209(2):501-14. doi:10.1002/jcp.20757

Bossola M, Muscaritoli M, Costelli P, et al. Increased muscle ubiquitin mRNA levels in gastric cancer patients. American journal of physiology. Regulatory, integrative and comparative physiology. 2001;280(5):R1518-23.

DeJong CH, Busquets S, Moses AG, et al. Systemic inflammation correlates with increased expression of skeletal muscle ubiquitin but not uncoupling proteins in cancer cachexia. Oncology reports. 2005;14(1):257-63.

McFarlane C, Hennebry A, Thomas M, et al. Myostatin signals through Pax7 to regulate satellite cell self-renewal. Experimental Cell Research. 2008;314(2):317-29. doi:

Bilezikjian LM, Blount AL, Donaldson CJ, Vale WW. Pituitary actions of ligands of the TGF-beta family: activins and inhibins. Reproduction (Cambridge, England). 2006;132(2):207-15. doi:10.1530/rep.1.01073

Bilezikjian LM, Blount AL, Leal AMO, Donaldson CJ, Fischer WH, Vale WW. Autocrine/paracrine regulation of pituitary function by activin, inhibin and follistatin. Molecular and Cellular Endocrinology. 2004;225(1–2):29-36. doi:

Bilezikjian LM, Corrigan AZ, Vaughan JM, Vale WM. Activin-A regulates follistatin secretion from cultured rat anterior pituitary cells. Endocrinology. 1993;133(6):2554-60. doi:doi:10.1210/endo.133.6.8243277

Tsuchida K, Nakatani M, Hitachi K, et al. Activin signaling as an emerging target for therapeutic interventions. Cell Communication and Signaling. 2009;7(1):1.

Clotman F, Lemaigre FP. Control of Hepatic Differentiation by Activin/TGFβ Signaling. Cell Cycle. 2006;5(2):168-71. doi:10.4161/cc.5.2.2341

Poulaki V, Mitsiades N, Kruse FE, et al. Activin A in the Regulation of Corneal Neovascularization and Vascular Endothelial Growth Factor Expression. The American Journal of Pathology. 2004;164(4):1293-302. doi:

Zhou X, Wang JL, Lu J, et al. Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival. Cell. 2010;142(4):531-43. doi:

LeBrasseur NK, Schelhorn TM, Bernardo BL, Cosgrove PG, Loria PM, Brown TA. Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged mice. The journals of gerontology. Series A, Biological sciences and medical sciences. 2009;64(9):940-8. doi:10.1093/gerona/glp068

Aversa Z, Bonetto A, Penna F, et al. Changes in Myostatin Signaling in Non-Weight-Losing Cancer Patients. Annals of Surgical Oncology. 2012;19(4):1350-6. doi:10.1245/s10434-011-1720-5

Gonzalez-Cadavid NF, Taylor WE, Yarasheski K, et al. Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wasting. Proceedings of the National Academy of Sciences of the United States of America. 1998;95(25):14938-43.

Sun DF, Chen Y, Rabkin R. Work-induced changes in skeletal muscle IGF-1 and myostatin gene expression in uremia. Kidney international. 2006;70(3):453-9. doi:10.1038/

Ju C-R, Chen R-C. Serum myostatin levels and skeletal muscle wasting in chronic obstructive pulmonary disease. Respiratory Medicine. 2012;106(1):102-8. doi:

Risbridger GP, Mellor SL, McPherson SJ, Schmitt JF. The contribution of inhibins and activins to malignant prostate disease. Molecular and Cellular Endocrinology. 2001;180(1–2):149-53. doi:

Terpos E, Kastritis E, Christoulas D, et al. Circulating activin-A is elevated in patients with advanced multiple myeloma and correlates with extensive bone involvement and inferior survival; no alterations post-lenalidomide and dexamethasone therapy. Annals of Oncology. 2012;23(10):2681-6. doi:10.1093/annonc/mds068

Wildi S, Kleeff J, Maruyama H, Maurer CA, Buchler MW, Korc M. Overexpression of activin A in stage IV colorectal cancer. Gut. 2001;49(3):409-17.

Kleeff J, Ishiwata T, Friess H, Buchler MW, Korc M. Concomitant over-expression of activin/inhibin beta subunits and their receptors in human pancreatic cancer. International journal of cancer. 1998;77(6):860-8.

Evans WK, Makuch R, Clamon GH, et al. Limited impact of total parenteral nutrition on nutritional status during treatment for small cell lung cancer. Cancer Res. 1985;45(7):3347-53.

Loprinzi CL, Schaid DJ, Dose AM, Burnham NL, Jensen MD. Body-composition changes in patients who gain weight while receiving megestrol acetate. Journal of Clinical Oncology. 1993;11(1):152-4. doi:doi:10.1200/JCO.1993.11.1.152

Simons JP, Schols AM, Hoefnagels JM, Westerterp KR, ten Velde GP, Wouters EF. Effects of medroxyprogesterone acetate on food intake, body composition, and resting energy expenditure in patients with advanced, nonhormone-sensitive cancer: a randomized, placebo-controlled trial. Cancer. 1998;82(3):553-60.

Morley JE, Thomas DR, Wilson MM. Cachexia: pathophysiology and clinical relevance. Am J Clin Nutr. 2006;83(4):735-43.

Temel JS, Abernethy AP, Currow DC, et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. The Lancet. Oncology. 2016;17(4):519-31. doi:10.1016/s1470-2045(15)00558-6

Tawa NE, Jr., Odessey R, Goldberg AL. Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying rat skeletal muscles. The Journal of clinical investigation. 1997;100(1):197-203. doi:10.1172/jci119513

Zhang L, Tang H, Kou Y, et al. MG132-mediated inhibition of the ubiquitin-proteasome pathway ameliorates cancer cachexia. Journal of cancer research and clinical oncology. 2013;139(7):1105-15. doi:10.1007/s00432-013-1412-6

Tisdale MJ. Biology of cachexia. Journal of the National Cancer Institute. 1997;89(23):1763-73.

Lissoni P, Paolorossi F, Tancini G, et al. Is there a role for melatonin in the treatment of neoplastic cachexia? European journal of cancer (Oxford, England : 1990). 1996;32a(8):1340-3.

Goldberg RM, Loprinzi CL, Mailliard JA, et al. Pentoxifylline for treatment of cancer anorexia and cachexia? A randomized, double-blind, placebo-controlled trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1995;13(11):2856-9. doi:10.1200/jco.1995.13.11.2856

Benny Klimek ME, Aydogdu T, Link MJ, Pons M, Koniaris LG, Zimmers TA. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochem Biophys Res Commun. 2010;391(3):1548-54. doi:10.1016/j.bbrc.2009.12.123

Bonetto A, Penna F, Minero VG, et al. Deacetylase inhibitors modulate the myostatin/follistatin axis without improving cachexia in tumor-bearing mice. Current cancer drug targets. 2009;9(5):608-16.

Busquets S, Toledo M, Orpi M, et al. Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance. Journal of cachexia, sarcopenia and muscle. 2012;3(1):37-43. doi:10.1007/s13539-011-0049-z

Keller C, Keller P, Giralt M, Hidalgo J, Pedersen BK. Exercise normalises overexpression of TNF-alpha in knockout mice. Biochem Biophys Res Commun. 2004;321(1):179-82. doi:10.1016/j.bbrc.2004.06.129

Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2003;17(8):884-6. doi:10.1096/fj.02-0670fje

Wittert GA, Livesey JH, Espiner EA, Donald RA. Adaptation of the hypothalamopituitary adrenal axis to chronic exercise stress in humans. Medicine and science in sports and exercise. 1996;28(8):1015-9. doi:10.1097/00005768-199608000-00011

Fediuc S, Campbell JE, Riddell MC. Effect of voluntary wheel running on circadian corticosterone release and on HPA axis responsiveness to restraint stress in Sprague-Dawley rats. Journal of Applied Physiology. 2006;100(6):1867-75. doi:10.1152/japplphysiol.01416.2005

White JP, Puppa MJ, Sato S, et al. IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the Apc Min/+ mouse. Skeletal muscle. 2012;2(1):1.

Psilander N. The effect of different exercise regimens on mitochondrial biogenesis and performance: Inst för fysiologi och farmakologi/Dept of Physiology and Pharmacology; 2014.

Tonkonogi M, Sahlin K. Physical exercise and mitochondrial function in human skeletal muscle. Exerc Sport Sci Rev. 2002;30(3):129-37.

Bueno PG, Bassi D, Contrera DG, et al. Post-exercise changes in myostatin and actRIIB expression in obese insulin-resistant rats. Mol Cell Endocrinol. 2011;339(1-2):159-64. doi:10.1016/j.mce.2011.04.006

Hittel DS, Axelson M, Sarna N, Shearer J, Huffman KM, Kraus WE. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med Sci Sports Exerc. 2010;42(11):2023-9. doi:10.1249/MSS.0b013e3181e0b9a8

Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nature reviews. Immunology. 2011;11(9):607-15. doi:10.1038/nri3041

Lara Fernandes J, Serrano CV, Jr., Toledo F, et al. Acute and chronic effects of exercise on inflammatory markers and B-type natriuretic peptide in patients with coronary artery disease. Clinical research in cardiology : official journal of the German Cardiac Society. 2011;100(1):77-84. doi:10.1007/s00392-010-0215-x

Ford ES. Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults. Epidemiology (Cambridge, Mass.). 2002;13(5):561-8. doi:10.1097/01.ede.0000023965.92535.c0

Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: regulation, integration, and adaptation. Physiological reviews. 2000;80(3):1055-81.

Nieman DC. Exercise effects on systemic immunity. Immunol Cell Biol. 2000;78(5):496-501.

Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. The Journal of physiology. 1999;515 ( Pt 1):287-91.

Steensberg A, Keller C, Starkie RL, Osada T, Febbraio MA, Pedersen BK. IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle. American journal of physiology. Endocrinology and metabolism. 2002;283(6):E1272-8. doi:10.1152/ajpendo.00255.2002

Febbraio MA, Pedersen BK. Muscle-derived interleukin-6: mechanisms for activation and possible biological roles. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2002;16(11):1335-47. doi:10.1096/fj.01-0876rev

Pedersen BK. The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. Essays in biochemistry. 2006;42:105-17. doi:10.1042/bse0420105

Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. Journal of applied physiology (Bethesda, Md. : 1985). 2005;98(4):1154-62. doi:10.1152/japplphysiol.00164.2004

Helmark IC, Mikkelsen UR, Borglum J, et al. Exercise increases interleukin-10 levels both intraarticularly and peri-synovially in patients with knee osteoarthritis: a randomized controlled trial. Arthritis research & therapy. 2010;12(4):R126. doi:10.1186/ar3064

Droste SK, Gesing A, Ulbricht S, Muller MB, Linthorst AC, Reul JM. Effects of long-term voluntary exercise on the mouse hypothalamic-pituitary-adrenocortical axis. Endocrinology. 2003;144(7):3012-23. doi:10.1210/en.2003-0097

Campbell JE, Kiraly MA, Atkinson DJ, D'Souza A M, Vranic M, Riddell MC. Regular exercise prevents the development of hyperglucocorticoidemia via adaptations in the brain and adrenal glands in male Zucker diabetic fatty rats. American journal of physiology. Regulatory, integrative and comparative physiology. 2010;299(1):R168-76. doi:10.1152/ajpregu.00155.2010

Dishman RK, Bunnell B, Youngstedt SD, Yoo H, Mougey E, Meyerhoff J. Activity wheel running blunts increased plasma adrenocorticotrophin (ACTH) after footshock and cage-switch stress. Physiology & behavior. 1998;63(5):911-7.

Campeau S, Nyhuis TJ, Sasse SK, et al. Hypothalamic pituitary adrenal axis responses to low-intensity stressors are reduced after voluntary wheel running in rats. Journal of neuroendocrinology. 2010;22(8):872-88. doi:10.1111/j.1365-2826.2010.02007.x

Mahner S, Baasch C, Schwarz J, et al. C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma. British Journal of Cancer. 2008;99(8):1269-75. doi:10.1038/sj.bjc.6604650

Arsalan Damirchi PB, Meysam Gholamali and Kamal Ranjbar. Mitochondrial Biogenesis in Skeletal Muscle: Exercise and Aging, Skeletal Muscle Julianna Cseri, IntechOpen, . 2012:24. doi:DOI: 10.5772/48411

Holloszy JO. Biochemical adaptations in muscle. Effects of exercise on mitochondrial oxygen uptake and respiratory enzyme activity in skeletal muscle. The Journal of biological chemistry. 1967;242(9):2278-82.

Rowe GC, El-Khoury R, Patten IS, Rustin P, Arany Z. PGC-1α is Dispensable for Exercise-Induced Mitochondrial Biogenesis in Skeletal Muscle. PloS one. 2012;7(7):e41817. doi:10.1371/journal.pone.0041817

Silva LA, Pinho CA, Scarabelot KS, et al. Physical exercise increases mitochondrial function and reduces oxidative damage in skeletal muscle. European journal of applied physiology. 2009;105(6):861-7. doi:10.1007/s00421-008-0971-8

Phielix E, Meex R, Moonen-Kornips E, Hesselink MKC, Schrauwen P. Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals. Diabetologia. 2010;53(8):1714-21. doi:10.1007/s00125-010-1764-2

Lumini JA, Magalhães J, Oliveira PJ, Ascensão A. Beneficial Effects of Exercise on Muscle Mitochondrial Function in Diabetes Mellitus. Sports Medicine. 2008;38(9):735-50. doi:10.2165/00007256-200838090-00003

Menshikova EV, Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH. Effects of Exercise on Mitochondrial Content and Function in Aging Human Skeletal Muscle. The Journals of Gerontology: Series A. 2006;61(6):534-40. doi:10.1093/gerona/61.6.534

Menshikova EV, Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH. Effects of Exercise on Mitochondrial Content and Function in Aging Human Skeletal Muscle. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2006;61(6):534-40.

Hansen J, Rinnov A, Brandt C, Plomgaard P. Activin A suppression during acute exercise. Signaling Originating from Membrane Receptors: Endocrine Society; 2013. p. MON-398-MON-.

Dieli-Conwright CM, Spektor TM, Rice JC, Sattler FR, Schroeder ET. Hormone Therapy and Maximal Eccentric Exercise Alters Myostatin-Related Gene Expression in Postmenopausal Women. The Journal of Strength & Conditioning Research. 2012;26(5):1374-82. doi:10.1519/JSC.0b013e318251083f

Matsakas A, Friedel A, Hertrampf T, Diel P. Short-term endurance training results in a muscle-specific decrease of myostatin mRNA content in the rat. Acta physiologica Scandinavica. 2005;183(3):299-307. doi:10.1111/j.1365-201X.2005.01406.x

Kopple JD, Cohen AH, Wang H, et al. Effect of exercise on mRNA levels for growth factors in skeletal muscle of hemodialysis patients. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2006;16(4):312-24. doi:10.1053/j.jrn.2006.04.028

Bassi D, Bueno PdG, Nonaka KO, Selistre-Araujo HS, Leal AMdO. Exercise alters myostatin protein expression in sedentary and exercised streptozotocin-diabetic rats. Archives of Endocrinology and Metabolism. 2015;59:148-53.

Lenk K, Schur R, Linke A, et al. Impact of exercise training on myostatin expression in the myocardium and skeletal muscle in a chronic heart failure model. European Journal of Heart Failure. 2009;11(4):342-8. doi:10.1093/eurjhf/hfp020

Konopka AR, Douglass MD, Kaminsky LA, et al. Molecular adaptations to aerobic exercise training in skeletal muscle of older women. The journals of gerontology. Series A, Biological sciences and medical sciences. 2010;65(11):1201-7. doi:10.1093/gerona/glq109

Haidet AM, Rizo L, Handy C, et al. Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(11):4318-22. doi:10.1073/pnas.0709144105

Hansen J, Brandt C, Nielsen AR, et al. Exercise Induces a Marked Increase in Plasma Follistatin: Evidence That Follistatin Is a Contraction-Induced Hepatokine. Endocrinology. 2011;152(1):164-71. doi:10.1210/en.2010-0868

Dieli-Conwright CM, Spektor TM, Rice JC, Sattler FR, Schroeder ET. Influence of hormone replacement therapy on eccentric exercise induced myogenic gene expression in postmenopausal women. Journal of applied physiology (Bethesda, Md. : 1985). 2009;107(5):1381-8. doi:10.1152/japplphysiol.00590.2009

Jensky NE, Sims JK, Rice JC, Dreyer HC, Schroeder ET. The influence of eccentric exercise on mRNA expression of skeletal muscle regulators. European journal of applied physiology. 2007;101(4):473-80. doi:10.1007/s00421-007-0521-9

Jensky NE, Sims JK, Dieli-Conwright CM, Sattler FR, Rice JC, Schroeder ET. Exercise does not influence myostatin and follistatin messenger RNA expression in young women. Journal of strength and conditioning research. 2010;24(2):522-30. doi:10.1519/JSC.0b013e3181c8664f

Watts R, McAinch AJ, Dixon JB, O'Brien PE, Cameron-Smith D. Increased Smad signaling and reduced MRF expression in skeletal muscle from obese subjects. Obesity (Silver Spring). 2013;21(3):525-8. doi:10.1002/oby.20070

Zhu X, Topouzis S, Liang L-f, Stotish RL. Myostatin signaling through Smad2, Smad3 and Smad4 is regulated by the inhibitory Smad7 by a negative feedback mechanism. Cytokine. 2004;26(6):262-72. doi:

Yin H, Li D, Wang Y, et al. Myogenic regulatory factor (MRF) expression is affected by exercise in postnatal chicken skeletal muscles. Gene. 2015;561(2):292-9. doi:

Costa A, Dalloul H, Hegyesi H, et al. Impact of repeated bouts of eccentric exercise on myogenic gene expression. European journal of applied physiology. 2007;101(4):427-36. doi:10.1007/s00421-007-0510-z

Raue U, Slivka D, Jemiolo B, Hollon C, Trappe S. Myogenic gene expression at rest and after a bout of resistance exercise in young (18–30 yr) and old (80–89 yr) women. Journal of Applied Physiology. 2006;101(1):53-9. doi:10.1152/japplphysiol.01616.2005

Psilander N, Damsgaard R, Pilegaard H. Resistance exercise alters MRF and IGF-I mRNA content in human skeletal muscle. Journal of Applied Physiology. 2003;95(3):1038-44.

Kosek DJ, Kim J-s, Petrella JK, Cross JM, Bamman MM. Efficacy of 3 days/wk resistance training on myofiber hypertrophy and myogenic mechanisms in young vs. older adults. Journal of Applied Physiology. 2006;101(2):531-44. doi:10.1152/japplphysiol.01474.2005

Kleckner IR, Dunne, R. F., Asare, M., Cole, C., Fleming, F., Fung, C., Lin, P., Mustian, K. M. . Exercise for Toxicity Management in Cancer: A Narrative Review. Oncology & Hematology Review. 2018;14(1).

Dunne RF, Mustian KM, Garcia JM, et al. Research priorities in cancer cachexia: The University of Rochester Cancer Center NCI Community Oncology Research Program Research Base Symposium on Cancer Cachexia and Sarcopenia. Current opinion in supportive and palliative care. 2017;11(4):278-86. doi:10.1097/SPC.0000000000000301

Mustian KM, Sprod LK, Palesh OG, et al. Exercise for the management of side effects and quality of life among cancer survivors. Current sports medicine reports. 2009;8(6):325-30. doi:10.1249/JSR.0b013e3181c22324

Temel JS, Abernethy AP, Currow DC, et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. The Lancet. Oncology. 2016. doi:10.1016/S1470-2045(15)00558-6

Ebner N, von Haehling S. Unlocking the wasting enigma: Highlights from the 8th Cachexia Conference. Journal of cachexia, sarcopenia and muscle. 2016;7(1):90-4. doi:10.1002/jcsm.12106

Litterini AJ, Fieler VK, Cavanaugh JT, Lee JQ. Differential effects of cardiovascular and resistance exercise on functional mobility in individuals with advanced cancer: a randomized trial. Archives of physical medicine and rehabilitation. 2013;94(12):2329-35. doi:10.1016/j.apmr.2013.06.008

Oldervoll LM, Loge JH, Lydersen S, et al. Physical exercise for cancer patients with advanced disease: a randomized controlled trial. The oncologist. 2011;16(11):1649-57. doi:10.1634/theoncologist.2011-0133

Stene GB, Helbostad JL, Balstad TR, Riphagen, II, Kaasa S, Oldervoll LM. Effect of physical exercise on muscle mass and strength in cancer patients during treatment--a systematic review. Critical reviews in oncology/hematology. 2013;88(3):573-93. doi:10.1016/j.critrevonc.2013.07.001

Grande AJ, Silva V, Maddocks M. Exercise for cancer cachexia in adults: Executive summary of a Cochrane Collaboration systematic review. Journal of cachexia, sarcopenia and muscle. 2015;6(3):208-11. doi:10.1002/jcsm.12055

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. Journal of cachexia, sarcopenia and muscle. 2017;8(5):778-88. doi:10.1002/jcsm.12201



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