Exercise as a therapy for cancer-induced muscle wasting

Abstract

Cancer cachexia is a progressive disorder characterized by body weight, fat, and muscle loss. Cachexia induces metabolic disruptions that can be analogous and distinct from those observed in cancer, obscuring both diagnosis and treatment options. Inflammation, hypogonadism, and physical inactivity are widely investigated as systemic mediators of cancer-induced muscle wasting. At the cellular level, dysregulation of protein turnover and energy metabolism can negatively impact muscle mass and function. Exercise is well known for its anti-inflammatory effects and potent stimulation of anabolic signaling. Emerging evidence suggests the potential for exercise to rescue muscle's sensitivity to anabolic stimuli, reduce wasting through protein synthesis modulation, myokine release, and subsequent downregulation of proteolytic factors. To date, there is no recommendation for exercise in the management of cachexia. Given its complex nature, a multimodal approach incorporating exercise offers promising potential for cancer cachexia treatment. This review's primary objective is to summarize the growing body of research examining exercise regulation of cancer cachexia. Furthermore, we will provide evidence for exercise interactions with established systemic and cellular regulators of cancer-induced muscle wasting.

Keywords

Physical activity / Anabolic resistance / Inflammation / IL-6 / Metabolic dysfunction / Protein turnover

References

[[1]] M. Muscaritoli, S.D. Anker, J. Argiles, Z. Aversa, J.M. Bauer, G. Biolo, et al.. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG)“cachexia-anorexia in chronic wasting diseases” and “nutrition in geriatrics”. Clin Nutr, 29 (2) ( 2010), pp. 154-159, DOI: 10.1016/j.clnu.2009.12.004

[[2]] V.E. Baracos, L. Martin, M. Korc, D.C Guttridge, K. C H Fearon, et al.. Cancer-associated cachexia. Nat Rev Dis Primers, 4 ( 2018), p. 17105, DOI: 10.1038/nrdp.2017.105

[[3]] J.P. Hardee, R.N. Montalvo, J.A. Carson.Linking cancer cachexia-induced anabolic resistance to skeletal muscle oxidative metabolism. Oxid Med Cell Longev, 2017 ( 2017), p. 8018197, DOI: 10.1155/2017/8018197

[[4]] F. Dworzak, P. Ferrari, C. Gavazzi, C Maiorana, F. Bozzetti, et al.. Effects of cachexia due to cancer on whole body and skeletal muscle protein turnover. Cancer, 82 (1) ( 1998), pp. 42-48, DOI: 10.1002/(Sici)1097-0142(19980101)82:13.0.Co;2-M

[[5]] K.L. Smith, M.J. Tisdale. Increased protein degradation and decreased protein synthesis in skeletal muscle during cancer cachexia. Br J Canc, 67 (4) ( 1993), pp. 680-685, DOI: 10.1038/bjc.1993.126

[[6]] P.W. Emery, R.H. Edwards, M.J. Rennie, R.L. Souhami, D. Halliday, et al.. Protein synthesis in muscle measured in vivo in cachectic patients with cancer. Br Med J, 289 (6445) ( 1984), pp. 584-586, DOI: 10.1136/bmj.289.6445.584

[[7]] S. Antoun, B. Raynard. Muscle protein anabolism in advanced cancer patients: response to protein and amino acids support, and to physical activity. Ann Oncol, 29 (suppl_2) ( 2018), pp. ii10-ii17

[[8]] N.P. Gullett, V.C. Mazurak, G. Hebbar, T.R. Ziegler, et al.. Nutritional interventions for cancer-induced cachexia. Curr Probl Canc, 35 (2) ( 2011), pp. 58-90, DOI: 10.1016/j.currproblcancer.2011.01.001

[[9]] C. S Fry, B. B Rasmussen. Skeletal muscle protein balance and metabolism in the elderly. Curr Aging Sci, 4 (3) ( 2011), pp. 260-268, DOI: 10.2174/1874609811104030260

[[10]] J.M. Dickinson, E. Volpi, B.B. Rasmussen. Exercise and nutrition to target protein synthesis impairments in aging skeletal muscle. Exerc Sport Sci Rev, 41 (4) ( 2013), pp. 216-223, DOI: 10.1097/JES.0b013e3182a4e699

[[11]] R.N. Montalvo, J.P. Hardee, B.N. VanderVeen, J.A. Carson, et al.. Resistance exercise's ability to reverse cancer-induced anabolic resistance. Exerc Sport Sci Rev, 46 (4) ( 2018), pp. 247-253, DOI: 10.1249/JES.0000000000000159

[[12]] C.J. Mitchell, T.A. Churchward-Venne, L. Bellamy, G. Parise, S.K. Baker, S.M. Phillips, et al.. Muscular and systemic correlates of resistance training-induced muscle hypertrophy. PloS One, 8 (10) ( 2013), Article e78636, DOI: 10.1371/journal.pone.0078636

[[13]] R. Ogasawara, S. Fujita, T.A. Hornberger, et al.. The role of mTOR signalling in the regulation of skeletal muscle mass in a rodent model of resistance exercise. Sci Rep, 6 ( 2016), p. 31142, DOI: 10.1038/srep31142

[[14]] J.P. Hardee, R.R. Porter, X. Sui, et al.. The effect of resistance exercise on all-cause mortality in cancer survivors. Mayo Clin Proc, 89 (8) ( 2014), pp. 1108-1115, DOI: 10.1016/j.mayocp.2014.03.018

[[15]] E.J. Roeland, K. Bohlke, V.E. Baracos, et al.. Management of cancer cachexia: ASCO guideline. J Clin Oncol, 38 (21) ( 2020), pp. 2438-2453, DOI: 10.1200/JCO.20.00611

[[16]] A.J. Grande, V. Silva, M. Maddocks. Exercise for cancer cachexia in adults: executive summary of a Cochrane Collaboration systematic review. J Cachexia Sarcopenia Muscle, 6 (3) ( 2015), pp. 208-211, DOI: 10.1002/jcsm.12055

[[17]] J.M. Argilés, S. Busquets, F.J. López-Soriano, P. Costelli, F. Penna, et al.. Are there any benefits of exercise training in cancer cachexia?. Journal of cachexia, sarcopenia and muscle, 3 (2) ( 2012), pp. 73-76, DOI: 10.1007/s13539-012-0067-5

[[18]] D.W.D. West, N.A. Burd, A.W. Staples, S.M. Phillips, et al.. Human exercise-mediated skeletal muscle hypertrophy is an intrinsic process. Int J Biochem Cell Biol, 42 (9) ( 2010), pp. 1371-1375, DOI: 10.1016/j.biocel.2010.05.012

[[19]] F.W. Booth, B.S. Tseng, M. Flück, J.A. Carson. Molecular and cellular adaptation of muscle in response to physical training. Acta Physiol Scand, 162 (3) ( 1998), pp. 343-350, DOI: 10.1046/j.1365-201X.1998.0326e.x

[[20]] K.L. Piercy, R.P. Troiano, R.M. Ballard, et al.. The physical activity guidelines for Americans. Jama, 320 (19) ( 2018), pp. 2020-2028, DOI: 10.1001/jama.2018.14854

[[21]] E. Pigna, E. Berardi, P. Aulino, et al.. Aerobic exercise and pharmacological treatments counteract cachexia by modulating autophagy in colon cancer. Sci Rep, 6 ( 2016), p. 26991. DOI: 10.1038/srep26991

[[22]] M.L. Irwin, A.W. Smith, A. McTiernan, et al.. Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol, 26 (24) ( 2008), pp. 3958-3964, DOI: 10.1200/JCO.2007.15.9822

[[23]] J.A. Meyerhardt, E.L. Giovannucci, M.D. Holmes, et al.. Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol, 24 (22) ( 2006), pp. 3527-3534, DOI: 10.1200/JCO.2006.06.0855

[[24]] F. Sanchis-Gomar, S. Lopez-Lopez, C. Romero-Morales, N. Maffulli, G. Lipipi, H. Pareja-Galeano, et al.. Neuromuscular electrical stimulation: a new therapeutic option for chronic diseases based on contraction-induced myokine secretion. Front Physiol, 10 ( 2019), p. 1463, DOI: 10.3389/fphys.2019.01463

[[25]] W. Fan, R.M. Evans. Exercise mimetics: impact on health and performance. Cell Metabol, 25 (2) ( 2017), pp. 242-247, DOI: 10.1016/j.cmet.2016.10.022

[[26]] S.C. Kandarian, E.J. Stevenson. Molecular events in skeletal muscle during disuse atrophy. Exerc Sport Sci Rev, 30 (3) ( 2002), pp. 111-116, DOI: 10.1097/00003677-200207000-00004

[[27]] C.J. Malavaki, G.K. Sakkas, G.I. Mitrou, et al.. Skeletal muscle atrophy: disease-induced mechanisms may mask disuse atrophy. J Muscle Res Cell Motil, 36 (6) ( 2015), pp. 405-421, DOI: 10.1007/s10974-015-9439-8

[[28]] A. Morikawa, T. Natio, M. Sugiyama, et al.. Impact of cancer cachexia on hospitalization-associated physical inactivity in elderly patients with advanced non-small-cell lung cancer. Asia Pac J Oncol Nurs, 5 (4) ( 2018), pp. 377-382, DOI: 10.4103/apjon.apjon_20_18

[[29]] J.P. Hardee, B.R. Counts, J.A. Carson. Understanding the role of exercise in cancer cachexia therapy. Am J Lifestyle Med, 13 (1) ( 2019), pp. 46-60, DOI: 10.1177/1559827617725283

[[30]] I.R. Kleckner, A. Jatoi, E.M. Schwarz, R.F. Dunne, et al.. The role of systemic inflammation in cancer-associated muscle wasting and rationale for exercise as a therapeutic intervention. JCSM clinical reports, 3 (2) ( 2018), pp. 1-19

[[31]] J.M. Argiles, F.J. Lopez-Soriano, S. Busquets. Mediators of cachexia in cancer patients. Nutrition, 66 ( 2019), pp. 11-15, DOI: 10.1016/j.nut.2019.03.012

[[32]] K. Hetzler, J.P. Hardee, M.J. Puppa, et al.. IL-6 signaling during cancer cachexia progression: the female response. Faseb J, 29 (1_supplement) ( 2015), p. 1038, DOI: 10.1016/j.bbadis.2014.12.015. 11

[[33]] H.J. Patel, B.M. Patel. TNF-alpha and cancer cachexia: molecular insights and clinical implications. Life Sci, 170 ( 2017), pp. 56-63, DOI: 10.1016/j.lfs.2016.11.033

[[34]] J.P. White, M.J. Puppa, S. Gao, S. Sato, S.L. Welle, J.A. Carson, et al.. Muscle mTORC 1 suppression by IL-6 during cancer cachexia: a role for AMPK. Am J Physiol Endocrinol Metab, 304 (10) ( 2013), pp. E1042-E1052, DOI: 10.1152/ajpendo.00410.2012

[[35]] J.P. White, M.J. Puppa, S. Gao, S. Sato, et al.. IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the Apc>Min mouse. Skeletal Muscle, 2 (1) ( 2012), p. 14, DOI: 10.1186/2044-5040-2-14

[[36]] A. Yakovenko, M. Cameron, J.G. Trevino. Molecular therapeutic strategies targeting pancreatic cancer induced cachexia. World J Gastrointest Surg, 10 (9) ( 2018), pp. 95-106, DOI: 10.4240/wjgs.v10.i9.95

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

[[38]] T.A. Zimmers, M.L. Fishel, A. Bonetto. STAT3 in the systemic inflammation of cancer cachexia. Semin Cell Dev Biol, 54 ( 2016), pp. 28-41, DOI: 10.1016/j.semcdb.2016.02.009

[[39]] C. Dogra, H. Changoua, N. Wedhas, X. Qin, J.E. Wergedal, A. Kumar, et al.. TNF-related weak inducer of apoptosis (TWEAK) is a potent skeletal muscle-wasting cytokine. Faseb J, 21 (8) ( 2007), pp. 1857-1869, DOI: 10.1096/fj.06-7537com

[[40]] A.A. Narsale, J.A. Carson.Role of IL-6 in cachexia-therapeutic implications. Curr Opin Support Palliat Care, 8 (4) ( 2014), p. 321, DOI: 10.1097/SPC.0000000000000091

[[41]] C. Bilir, H. Engin, M. Can, Y.B. Temi, D. Demirtas, et al.. The prognostic role of inflammation and hormones in patients with metastatic cancer with cachexia. Med Oncol, 32 (3) ( 2015), p. 56, DOI: 10.1007/s12032-015-0497-y

[[42]] J.M. McClung, A.R Judge, S.K. Powers, Z. Yan, et al.. p 38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting. Am J Physiol Cell Physiol, 298 (3) ( 2010), pp. C542-C549, DOI: 10.1152/ajpcell.00192.2009

[[43]] V. Moresi, S. Adamo, L. Berghella.The JAK/STAT pathway in skeletal muscle pathophysiology. Front Physiol, 10 ( 2019), p. 500, DOI: 10.3389/fphys.2019.00500

[[44]] D.C. G uttridge, M.W. Mayo, L.V. Madrid, C. Wang, A.S. Baldwin Jr, et al.. NF-kappaB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science, 289 (5488) ( 2000), pp. 2363-2366, DOI: 10.1126/science.289.5488.2363

[[45]] R. Moore-Carrasco, et al.. Both AP-1 and NF-κB seem to be involved in tumour growth in an experimental rat hepatoma. Anticancer Res, 29 (4) ( 2009), pp. 1315-1317

[[46]] B. Seruga, H. Zhang, L.J Bernstein, I.F. Tannock, et al.. Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Canc, 8 (11) ( 2008), pp. 887-899, DOI: 10.1038/nrc2507

[[47]] R. Dev, E. Del Fabbro, S. Dalal. Endocrinopathies and cancer cachexia. Curr Opin Support Palliat Care, 13 (4) ( 2019), pp. 286-291, DOI: 10.1097/SPC.0000000000000464

[[48]] J.A. Carson, S.C. Manolagas. Effects of sex steroids on bones and muscles: similarities, parallels, and putative interactions in health and disease. Bone, 80 ( 2015), pp. 67-78, DOI: 10.1016/j.bone.2015.04.015

[[49]] J.P. White, M.J. Puppa, A. Narsale, J.A. Carson, et al.. Characterization of the male ApcMin/+ mouse as a hypogonadism model related to cancer cachexia. Biology open, 2 (12) ( 2013), pp. 1346-1353, DOI: 10.1242/bio.20136544

[[50]] A.M. Horstman, E.L. Dillon, R.J. Urban, M. Sheffield-Moore, et al.. The role of androgens and estrogens on healthy aging and longevity. J Gerontol A Biol Sci Med Sci, 67 (11) ( 2012), pp. 1140-1152, DOI: 10.1093/gerona/gls068

[[51]] J.L. Steiner, D.H. Fukuda, M.L. Rossetti, J.R. Hoffman, B.S. Gordon, et al.. Castration alters protein balance after high-frequency muscle contraction. J Appl Physiol, 122 (2) ( 2017), pp. 264-272, DOI: 10.1152/japplphysiol.00740.2016

[[52]] J.M. McClung, J.M. Davis, M.A. Wilson, E.C Goldsmith, J.A. Carson, et al.. Estrogen status and skeletal muscle recovery from disuse atrophy. J Appl Physiol, 100 (6) ( 2006), pp. 2012-2023, DOI: 10.1152/japplphysiol.01583.2005

[[53]] H. Lin, X. Gu, S. Zhang, et al.. Analysis on incidence and mean age at diagnosis for Global Cancer. Zhonghua zhong liu za zhi [Chinese journal of oncology], 40 (7) ( 2018), pp. 543-549, DOI: 10.3760/cma.j.issn.0253-3766.2018.07.012

[[54]] K.M. Haizlip, B.C. Harrison, L.A. Leinwand. Sex-based differences in skeletal muscle kinetics and fiber-type composition. Physiology, 30 (1) ( 2015), pp. 30-39, DOI: 10.1152/physiol.00024.2014

[[55]] A.C. Maher, M.H. Fu, R.J. Isfort, A.R. Varbanov, X.A. Qu, M. A, et al.. Sex differences in global mRNA content of human skeletal muscle. PloS One, 4 (7) ( 2009), p. e6335, DOI: 10.1371/journal.pone.0006335

[[56]] S. Welle, R. Tawil, C.A. Thornton.Sex-related differences in gene expression in human skeletal muscle. PloS One, 3 (1) ( 2008), p. e1385, DOI: 10.1371/journal.pone.0001385

[[57]] Z.A. Razzak, A.A. Khan, S.I. Farooqui.Effect of aerobic and anaerobic exercise on estrogen level, fat mass, and muscle mass among postmenopausal osteoporotic females. Int J Health Sci, 13 (4) ( 2019), p. 10

[[58]] W. Daly, C.A Seegers, D.A Rubin, J.D Dobridge, A.C. Hackney, et al.. Relationship between stress hormones and testosterone with prolonged endurance exercise. Eur J Appl Physiol, 93 (4) ( 2005), pp. 375-380, DOI: 10.1007/s00421-004-1223-1

[[59]] B.O. Burney, T.G. Hayes, J. Smiechowska, et al.. Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia. J Clin Endocrinol Metab, 97 (5) ( 2012), pp. E700-E709, DOI: 10.1210/jc.2011-2387

[[60]] R.T. Chlebowski, D. Heber. Hypogonadism in male patients with metastatic cancer prior to chemotherapy. Canc Res, 42 (6) ( 1982), pp. 2495-2498

[[61]] J. Antonio, J.D. Wilson, F.W. George. Effects of castration and androgen treatment on androgen-receptor levels in rat skeletal muscles. J Appl Physiol, 87 (6) ( 1999), pp. 2016-2019, DOI: 10.1152/jappl.1999.87.6.2016

[[62]] S. Bhasin, T.W. Storer, N. Berman, et al.. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab, 82 (2) ( 1997), pp. 407-413, DOI: 10.1210/jcem.82.2.3733

[[63]] T.J. Wright, E.L. Dillon, W.J. Durham, et al.. A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women. J Cachexia Sarcopenia Muscle, 9 (3) ( 2018), pp. 482-496, DOI: 10.1002/jcsm.12295

[[64]] J.P. White, S. Gao, M.J. Puppa, S. Sato, S.L. Welle, J.A. Carson, et al.. Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle. Mol Cell Endocrinol, 365 (2) ( 2013), pp. 174-186, DOI: 10.1016/j.mce.2012.10.019

[[65]] K. Burckart, S. Beca, R.J. Urban, M. Sheffield-Moore, et al.. Pathogenesis of muscle wasting in cancer cachexia: targeted anabolic and anti-catabolic therapies. Curr Opin Clin Nutr Metab Care, 13 (4) ( 2010), p. 410, DOI: 10.1097/MCO.0b013e328339fdd2

[[66]] C. Serra, N.C. Sandor, H. Jang, et al.. The effects of testosterone deprivation and supplementation on proteasomal and autophagy activity in the skeletal muscle of the male mouse: differential effects on high-androgen responder and low-androgen responder muscle groups. Endocrinology, 154 (12) ( 2013), pp. 4594-4606, DOI: 10.1210/en.2013-1004

[[67]] R.N. Montalvo, B.R. Counts, J.A. Carson. Understanding sex differences in the regulation of cancer-induced muscle wasting. Curr Opin Support Palliat Care, 12 (4) ( 2018), pp. 394-403, DOI: 10.1097/SPC.0000000000000380

[[68]] X. Zhong, T.A. Zimmers. Sex differences in cancer cachexia. Curr Osteoporos Rep ( 2020), pp. 1-9, DOI: 10.1007/s11914-020-00628-w

[[69]] K.L. Hetzler, J.P. Hardee, H.A. LaVoie, E.A. Murphy, J.A. Carson, et al.. Ovarian function's role during cancer cachexia progression in the female mouse. Am J Physiol Endocrinol Metab, 312 (5) ( 2017), pp. E447-E459, DOI: 10.1152/ajpendo.00294.2016

[[70]] E.E. Spangenburg, P.C. Geiger, L.A. Leinwand, D.A. Lowe, et al.. Regulation of physiological and metabolic function of muscle by female sex steroids. Med Sci Sports Exerc, 44 (9) ( 2012), pp. 1653-1662, DOI: 10.1249/MSS.0b013e31825871fa

[[71]] K.L. Hetzler, J.P Hardee, M.J. Puppa, et al.. Sex differences in the relationship of IL-6 signaling to cancer cachexia progression. Biochim Biophys Acta, 1852 (5) ( 2015), pp. 816-825, DOI: 10.1016/j.bbadis.2014.12.015

[[72]] R. Kjobsted, J.R. Hingst, J. Fentz, et al.. AMPK in skeletal muscle function and metabolism. Faseb J, 32 (4) ( 2018), pp. 1741-1777, DOI: 10.1096/fj.201700442R

[[73]] E. Pollanen, P.H.A. Ronkainen, M. Horttanainen, et al.. Effects of combined hormone replacement therapy or its effective agents on the IGF-1 pathway in skeletal muscle. Growth Hormone IGF Res, 20 (5) ( 2010), pp. 372-379, DOI: 10.1016/j.ghir.2010.07.003

[[74]] B. Counts, D. Fix, J. Carson.The effect of estradiol administration on muscle mass loss and cachexia progression in female ApcMin/+ mice. Front Endocrinol, 10 ( 2019), p. 720, DOI: 10.3389/fendo.2019.00720

[[75]] J.B. Hopkinson. Psychosocial impact of cancer cachexia. J Cachexia Sarcopenia Muscle, 5 (2) ( 2014), pp. 89-94, DOI: 10.1007/s13539-014-0142-1

[[76]] J. Hopkinson. Psychosocial support in cancer cachexia syndrome: the evidence for supported self-management of eating problems during radiotherapy or chemotherapy treatment. Asia Pac J Oncol Nurs, 5 (4) ( 2018), pp. 358-368, DOI: 10.4103/apjon.apjon_12_18

[[77]] M.J. Tisdale. Cancer anorexia and cachexia. Nutrition, 17 (5) ( 2001), pp. 438-442, DOI: 10.1016/s0899-9007(01)00506-8

[[78]] K.N. Jeejeebhoy. Malnutrition, fatigue, frailty, vulnerability, sarcopenia and cachexia: overlap of clinical features. Curr Opin Clin Nutr Metab Care, 15 (3) ( 2012), pp. 213-219, DOI: 10.1097/MCO.0b013e328352694f

[[79]] P. Ravasco, I. Monteiro-Grillo, P.M Vidal, M.E. Camilo, et al.. Cancer: disease and nutrition are key determinants of patients' quality of life. Support Care Canc, 12 (4) ( 2004), pp. 246-252, DOI: 10.1007/s00520-003-0568-z

[[80]] A.M. Ryan, D.G. Power, L. Daly, S.J. Cushen, Ē.N Bhuachalla, C.M. Prado, et al.. Cancer-associated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later. Proc Nutr Soc, 75 (2) ( 2016), pp. 199-211, DOI: 10.1017/S002966511500419X

[[81]] J.M. Argiles.Cancer-associated malnutrition. Eur J Oncol Nurs, 9 (Suppl 2) ( 2005), pp. S39-S50, DOI: 10.1016/j. ejon.2005.09.006

[[82]] K.A. Baltgalvis, F.G. Berger, M.M.O. Peña, J.M. Davis, J.P. White, J.A. Carson, et al.. Activity level, apoptosis, and development of cachexia in Apc Min/+ mice. J Appl Physiol, 109 (4) ( 2010), pp. 1155-1161, DOI: 10.1152/japplphysiol.00442.2010

[[83]] M. Toledo, S. Busquets, S. Sirisi, et al.. Cancer cachexia: physical activity and muscle force in tumour-bearing rats. Oncol Rep, 25 (1) ( 2011), pp. 189-193

[[84]] B.R. Counts, J.P. Hardee, D.K. Fix, B.N. VanderVeen, R.N. Montalvo, J.A. Carson, et al.. Cachexia disrupts diurnal regulation of activity, feeding, and muscle mechanistic target of rapamycin complex 1 in mice. Med Sci Sports Exerc, 52 (3) ( 2020), pp. 577-587, DOI: 10.1249/MSS.0000000000002166

[[85]] M.J. Drummond, J.M Dickinson, C.S. Fry, et al.. Bed rest impairs skeletal muscle amino acid transporter expression, mTORC 1 signaling, and protein synthesis in response to essential amino acids in older adults. Am J Physiol Endocrinol Metab, 302 (9) ( 2012), pp. E1113-E1122, DOI: 10.1152/ajpendo.00603.2011

[[86]] A.R. Kelleher, S.R. Kimball, M.D. Dennis, R.J. Schilder, L.S. Jefferson, et al.. The mTORC 1 signaling repressors REDD1/2 are rapidly induced and activation of p70S6K1 by leucine is defective in skeletal muscle of an immobilized rat hindlimb. Am J Physiol Endocrinol Metab, 304 (2) ( 2012), pp. E229-E236, DOI: 10.1152/ajpendo.00409.2012

[[87]] S.C. Bodine, T.N. Stitt, M. Gonzalez, et al.. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol, 3 (11) ( 2001), pp. 1014-1019, DOI: 10.1038/ncb1101-1014

[[88]] S.K. Powers, A.J. Smuder, A.R. Judge. Oxidative stress and disuse muscle atrophy: cause or consequence?. Curr Opin Clin Nutr Metab Care, 15 (3) ( 2012), pp. 240-245, DOI: 10.1097/MCO.0b013e328352b4c2

[[89]] J. Argilés, S. Busquets, F. López-Soriano. Muscle protein kinetics in cancer cachexia. The Molecular Nutrition of Amino Acids and Proteins ( 2016), pp. 133-144, DOI: 10.1097/SPC.0b013e328359e6dd

[[90]] J.A. Carson, J.P. Hardee, B.N. VanderVeen. The emerging role of skeletal muscle oxidative metabolism as a biological target and cellular regulator of cancer-induced muscle wasting. Semin Cell Dev Biol, 54 ( 2016), pp. 53-67, DOI: 10.1016/j.semcdb.2015.11.005

[[91]] E.E. Talbert, D.C. Guttridge. Impaired regeneration: a role for the muscle microenvironment in cancer cachexia. Semin Cell Dev Biol, 54 ( 2016), pp. 82-91, DOI: 10.1016/j.semcdb.2015.09.009

[[92]] J.A. Carson, K.A. Baltgalvis. Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc Sport Sci Rev, 38 (4) ( 2010), pp. 168-176, DOI: 10.1097/JES.0b013e3181f44f11

[[93]] J. Han, C. Lu, Q. Meng, A. Halim, T. Yean, G. Wu, et al.. Plasma concentration of interleukin-6 was upregulated in cancer cachexia patients and was positively correlated with plasma free fatty acid in female patients. Nutr Metab, 16 (1) ( 2019), p. 80, DOI: 10.1186/s12986-019-0409-9

[[94]] M.J. Puppa, S. Gao, A.A. Narsale, J.A Carson, et al.. Skeletal muscle glycoprotein 130's role in Lewis lung carcinoma-induced cachexia. Faseb J, 28 (2) ( 2014), pp. 998-1009, DOI: 10.1096/fj.13-240580

[[95]] E. Yamada, C.C Bastie, H. Koga, Y. Wang, A.M. Cuervo, J.E. Pessin, et al.. Mouse skeletal muscle fiber-type-specific macroautophagy and muscle wasting are regulated by a Fyn/STAT3/Vps 34 signaling pathway. Cell Rep, 1 (5) ( 2012), pp. 557-569, DOI: 10.1016/j.celrep.2012.03.014

[[96]] J.P. Hardee, D.K. Fix, X. Wang, E.C. Goldsmith, H. Koh, J.A. Carson, et al.. Systemic IL-6 regulation of eccentric contraction-induced muscle protein synthesis. Am J Physiol Cell Physiol, 315 (1) ( 2018), pp. C91-C103, DOI: 10.1152/ajpcell.00063.2018

[[97]] B.N. VanderVeen, D.K. Fix, J.A. Carson.Disrupted skeletal muscle mitochondrial dynamics, mitophagy, and biogenesis during cancer cachexia: a role for inflammation. Oxid Med Cell Longev ( 2017), p. 3292087, DOI: 10.1155/2017/3292087. 2017

[[98]] N.E.P. Deutz, A. Safar, S. Schutzler, et al.. Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food. Clin Nutr, 30 (6) ( 2011), pp. 759-768, DOI: 10.1016/j.clnu.2011.05.008

[[99]] F. Pin, M.E. Couch, A. Bonetto. Preservation of muscle mass as a strategy to reduce the toxic effects of cancer chemotherapy on body composition. Curr Opin Support Palliat Care, 12 (4) ( 2018), pp. 420-426, DOI: 10.1097/Spc.0000000000000382

[[100]] V.E. Baracos. Regulation of skeletal-muscle-protein turnover in cancer-associated cachexia. Nutrition, 16 (10) ( 2000), pp. 1015-1018, DOI: 10.1016/s0899-9007(00)00407-x

[[101]] M. Sandri. Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin-proteasome. Int J Biochem Cell Biol, 45 (10) ( 2013), pp. 2121-2129, DOI: 10.1016/j.biocel.2013.04.023

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

[[103]] D. Cuthbertson, et al.. Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. Faseb J, 19 (3) ( 2005), pp. 422-424, DOI: 10.1096/fj.04-2640fje

[[104]] A. Winter, J. MacAdams, S. Chevalier. Normal protein anabolic response to hyperaminoacidemia in insulin-resistant patients with lung cancer cachexia. Clin Nutr, 31 (5) ( 2012), pp. 765-773, DOI: 10.1016/j.clnu.2012.05.003

[[105]] P. Costelli, M. Muscaritoli, M. Bossola, et al.. IGF-1 is downregulated in experimental cancer cachexia. Am J Physiol Regul Integr Comp Physiol, 291 (3) ( 2006), pp. R674-R683, DOI: 10.1152/ajpregu.00104.2006

[[106]] L. Lantier, R. Mourner, J. Leclerc, M. Pende, M. Foretz, B. Viollet, et al.. Coordinated maintenance of muscle cell size control by AMP-activated protein kinase. Faseb J, 24 (9) ( 2010), pp. 3555-3561, DOI: 10.1096/fj.10-155994

[[107]] J.P. White, J.W. Baynes, S.L. Welle, et al.. The regulation of skeletal muscle protein turnover during the progression of cancer cachexia in the ApcMin/+ mouse. PloS One, 6 (9) ( 2011), DOI: 10.1371/journal.pone.0024650. e24650

[[108]] T.P. Braun, D.L. Marks.The regulation of muscle mass by endogenous glucocorticoids. Front Physiol, 6 ( 2015), p. 12, DOI: 10.3389/fphys.2015.00012

[[109]] J. Hentila, T.A Nissinen, A. Korkmaz, et al.. Activin receptor ligand blocking and cancer have distinct effects on protein and redox homeostasis in skeletal muscle and liver. Front Physiol, 9 ( 2019), p. 1917, DOI: 10.3389/fphys.2018.01917

[[110]] R.W. Jackman, E.W. Cornwell, C. Wu, S.C. Kandarian, et al.. Nuclear factor-kappaB signalling and transcriptional regulation in skeletal muscle atrophy. Exp Physiol, 98 (1) ( 2013), pp. 19-24, DOI: 10.1113/expphysiol.2011.063321

[[111]] R.W. Jackman, S.C. Kandarian. The molecular basis of skeletal muscle atrophy. Am J Physiol Cell Physiol, 287 (4) ( 2004), pp. C834-C843, DOI: 10.1152/ajpcell.00579.2003

[[112]] G.S. de Castro, E. Simoes, J.D.C.C. Lima, et al.. Human cachexia induces changes in mitochondria, autophagy and apoptosis in the skeletal muscle. Cancers, 11 (9) ( 2019), p. 1264, DOI: 10.3390/cancers11091264

[[113]] J. Du, X. Wang, C. Miereles, et al.. Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J Clin Invest, 113 (1) ( 2004), pp. 115-123, DOI: 10.1172/Jci200418330

[[114]] S. Busquets, et al.. Apoptosis is present in skeletal muscle of cachectic gastro-intestinal cancer patients. Clin Nutr, 26 (5) ( 2007), pp. 614-618, DOI: 10.1016/j.clnu.2007.06.005

[[115]] J.E. Belizario, M.J. Lorite, M.J. Tisdale. Cleavage of caspases-1, -3, -6, -8 and -9 substrates by proteases in skeletal muscles from mice undergoing cancer cachexia. Br J Canc, 84 (8) ( 2001), pp. 1135-1140, DOI: 10.1054/bjoc.2001.1700

[[116]] M. Figueras, S. Busquets, N. Carbó, et al.. Interleukin-15 is able to suppress the increased DNA fragmentation associated with muscle wasting in tumour-bearing rats. FEBS Lett, 569 (1-3) ( 2004), pp. 201-206, DOI: 10.1016/j.febslet.2004.05.066

[[117]] V. Moarbes, D. Mayaki, L. Huck, et al.. Differential regulation of myofibrillar proteins in skeletal muscles of septic mice. Phys Rep, 7 (20) ( 2019), Article e14248, DOI: 10.14814/phy2.14248

[[118]] F. Penna, R. Ballarò, P. Martinez-Cristobal, et al.. Autophagy exacerbates muscle wasting in cancer cachexia and impairs mitochondrial function. J Mol Biol, 431 (15) ( 2019), pp. 2674-2686, DOI: 10.1016/j.jmb.2019.05.032

[[119]] V.E. Baracos, et al.. Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma. Am J Physiol, 268 (5 Pt 1) ( 1995), pp. E996-E1006, DOI: 10.1152/ajpendo.1995.268.5.E996

[[120]] M. van der Ende, S. Grefte, R. Plas, et al.. Mitochondrial dynamics in cancer-induced cachexia. Biochim Biophys Acta Rev Canc, 1870 (2) ( 2018), pp. 137-150, DOI: 10.1016/j.bbcan.2018.07.008

[[121]] J.L. Halle, G.S. Pena, H.G. Paez, et al.. Tissue-specific dysregulation of mitochondrial respiratory capacity and coupling control in colon-26 tumor-induced cachexia. Am J Physiol Regul Integr Comp Physiol, 317 (1) ( 2019), pp. R68-R82, DOI: 10.1152/ajpregu.00028.2019

[[122]] K.K. Baskin, B.R. Winders, E.N. Olson. Muscle as a “mediator” of systemic metabolism. Cell Metabol, 21 (2) ( 2015), pp. 237-248, DOI: 10.1016/j.cmet.2014.12.021

[[123]] D.D. Weber, S. Aminzadeh-Gohari, J. Tulipan, L. Catalano, R.G. Feichtinger, B. Kofler, et al.. Ketogenic diet in the treatment of cancer-where do we stand?. Molecular metabolism, 33 ( 2020), pp. 102-121, DOI: 10.1016/j.molmet.2019.06.026

[[124]] H.H. Thomsen, et al.. Effects of 3-hydroxybutyrate and free fatty acids on muscle protein kinetics and signaling during LPS-induced inflammation in humans: anticatabolic impact of ketone bodies. Am J Clin Nutr, 108 (4) ( 2018), pp. 857-867, DOI: 10.1093/ajcn/nqy170

[[125]] A.P. Koutnik, D.P. D'Agostino, B. Egan. Anticatabolic effects of ketone bodies in skeletal muscle. Trends Endocrinol Metabol, 30 (4) ( 2019), pp. 227-229, DOI: 10.1016/j.tem.2019.01.006

[[126]] K.C Fearon, W. Borland, T. Preston, M.J. Tisdale, A. Shenkin, K.C. Calman, et al.. Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism. Am J Clin Nutr, 47 (1) ( 1988), pp. 42-48

[[127]] S.K. Shukla, T. Gebregiworgis, V. Purohit, et al.. Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia. Canc Metabol, 2 (1) ( 2014), p. 18, DOI: 10.1186/2049-3002-2-18

[[128]] K. Nakamura, H. Tonouchi, A. Sasayama, K. Ashida, et al.. A ketogenic formula prevents tumor progression and cancer cachexia by attenuating systemic inflammation in colon 26 tumor-bearing mice. Nutrients, 10 (2) ( 2018), p. 206, DOI: 10.3390/nu10020206

[[129]] Q.Y. Ang, M. Alexander, J.C. Newman, et al.. Ketogenic diets alter the gut microbiome resulting in decreased intestinal Th17 cells. Cell, 181 (6) ( 2020), pp. 1263-1275, DOI: 10.1016/j.cell.2020.04.027. e16

[[130]] J.L. Brown, M.E Rosa-Caldwell, D.E. Lee, et al.. Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice. J Cachexia Sarcopenia Muscle, 8 (6) ( 2017), pp. 926-938, DOI: 10.1002/jcsm.12232

[[131]] J.P. White, K.A. Baltgalvis, M.J. Puppa, S. Sato, J.W. Baynes, J.A. Carson, et al.. Muscle oxidative capacity during IL-6-dependent cancer cachexia. Am J Physiol Regul Integr Comp Physiol, 300 (2) ( 2011), pp. R201-R211, DOI: 10.1152/ajpregu.00300.2010

[[132]] J. Cannavino, L. Brocca, M. Sandri, B. Grassi, R. Bottinelli, M.A. Pellegrino, et al.. The role of alterations in mitochondrial dynamics and PGC-1alpha over-expression in fast muscle atrophy following hindlimb unloading. J Physiol, 593 (8) ( 2015), pp. 1981-1995, DOI: 10.1113/jphysiol.2014.286740

[[133]] A. Wagatsuma, N. Kotake, T. Kawachi, M. Shiozuka, S. Yamada, R. Matsuda, et al.. Mitochondrial adaptations in skeletal muscle to hindlimb unloading. Mol Cell Biochem, 350 (1-2) ( 2011), pp. 1-11, DOI: 10.1007/s11010-010-0677-1

[[134]] D.J. Mazzatti, M.A. Smith, R.C. Oita, F Lim, A.J. White, M.B. Reid, et al.. Muscle unloading-induced metabolic remodeling is associated with acute alterations in PPARδ and UCP-3 expression. Physiol Genom, 34 (2) ( 2008), pp. 149-161, DOI: 10.1152/physiolgenomics.00281.2007

[[135]] F. Nagatomo, H. Fujino, H. Kondo, et al.. PGC-1alpha and FOXO 1 mRNA levels and fiber characteristics of the soleus and plantaris muscles in rats after hindlimb unloading. Histol Histopathol, 26 (12) ( 2011), pp. 1545-1553, DOI: 10.14670/HH-26.1545

[[136]] M.E. Rosa-Caldwell, S. Lim, W.S Haynie, et al.. Altering aspects of mitochondrial quality to improve musculoskeletal outcomes in disuse atrophy. J Appl Physiol ( 1985), p. 2020, DOI: 10.1152/japplphysiol.00407.2020

[[137]] V.A. Lira, C.R. Benton, Z. Yan, A. Bonen, et al.. PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab, 299 (2) ( 2010), pp. E145-E161, DOI: 10.1152/ajpendo.00755.2009

[[138]] D.C. Wright, D. Han, P.M. Garcia-Roves, P.C.. Geiger, T.E. Jones, J.O. Holloszy, et al.. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1α expression. J Biol Chem, 282 (1) ( 2007), pp. 194-199, DOI: 10.1074/jbc.M606116200

[[139]] M.J. Puppa, E.A. Murphy, R. Fayad, G.A. Hand, J.A. Carson, et al.. Cachectic skeletal muscle response to a novel bout of low-frequency stimulation. J Appl Physiol, 116 (8) ( 2014), pp. 1078-1087, DOI: 10.1152/japplphysiol.01270.2013

[[140]] M. Gleeson, N.C. Bishop, D.J. Stensel, M.R. Lindley, S.S. Mastana, M.A. Nimmo, et al.. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol, 11 (9) ( 2011), pp. 607-615, DOI: 10.1038/nri3041

[[141]] B. Egan, J.R. Zierath. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metabol, 17 (2) ( 2013), pp. 162-184, DOI: 10.1016/j.cmet.2012.12.012

[[142]] P.J. Pinckaers, T.A. Churchward-Venne, D. Bailey, L.J.C.v. Loon, et al.. Ketone bodies and exercise performance: the next magic bullet or merely hype?. Sports Med, 47 (3) ( 2017), pp. 383-391, DOI: 10.1007/s40279-016-0577-y

[[143]] P. Rojas-Morales, J. Pedraza-Chaverri, E. Tapia.Ketone bodies, stress response, and redox homeostasis. Redox Biol, 29 ( 2020), p. 101395, DOI: 10.1016/j.redox.2019.101395

[[144]] M. Evans, K.E. Cogan, B. Egan. Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol, 595 (9) ( 2017), pp. 2857-2871, DOI: 10.1113/JP273185

[[145]] S. Liu, Y. Niu, L. Fu.Metabolic adaptations to exercise training. Journal of Science in Sport and Exercise, 2 (1) ( 2020), p. 1, DOI: 10.1007/s42978-019-0018-3

[[146]] K.S. Rockl, C.A. Witczak, L.J. Goodyear. Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise. IUBMB Life, 60 (3) ( 2008), pp. 145-153, DOI: 10.1002/iub.21

[[147]] S. Gao, J.A. Carson. Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes. Am J Physiol Cell Physiol, 310 (1) ( 2016), pp. C66-C79, DOI: 10.1152/ajpcell.00052.2015

[[148]] D. Dardevet, C. Sornet, M. Balage, J. Grizard, et al.. Stimulation of in vitro rat muscle protein synthesis by leucine decreases with age. J Nutr, 130 (11) ( 2000), pp. 2630-2635, DOI: 10.1093/jn/130.11.2630

[[149]] Y. Gao, Y. Arfat, H. Wang, N. Goswami, et al.. Muscle atrophy induced by mechanical unloading: mechanisms and potential countermeasures. Front Physiol, 9 ( 2018), p. 235, DOI: 10.3389/fphys.2018.00235

[[150]] M. Li, C. Li, W.S. Parkhouse. Age-related differences in the des IGF-I-mediated activation of Akt-1 and p70 S6K in mouse skeletal muscle. Mech Ageing Dev, 124 (7) ( 2003), pp. 771-778, DOI: 10.1016/s0047-6374(03)00124-6

[[151]] V.C. Figueiredo, J.F. Markworth. Mechanisms of protein synthesis activation following exercise: new pieces to the increasingly complex puzzle. J Physiol, 593 (21) ( 2015), pp. 4693-4695, DOI: 10.1113/JP271431

[[152]] G.A. Nader, K.A. Esser. Intracellular signaling specificity in skeletal muscle in response to different modes of exercise. J Appl Physiol, 90 (5) ( 2001), pp. 1936-1942, DOI: 10.1152/jappl.2001.90.5.1936

[[153]] J.D. Parkington, N.K. LeBrasseur, A.P. Siebert, R.A. Fielding, et al.. Contraction-mediated mTOR, p70S6k, and ERK1/2 phosphorylation in aged skeletal muscle. J Appl Physiol, 97 (1) ( 2004), pp. 243-248, DOI: 10.1152/japplphysiol.01383.2003

[[154]] K. Baar, K. Esser. Phosphorylation of p70S6kcorrelates with increased skeletal muscle mass following resistance exercise. Am J Physiol Cell Physiol, 276 (1) ( 1999), pp. C120-C127, DOI: 10.1152/ajpcell.1999.276.1.C120

[[155]] A. Kumar, I. Chaudhry, M.B. Reid, A.M. Boriek, et al.. Distinct signaling pathways are activated in response to mechanical stress applied axially and transversely to skeletal muscle fibers. J Biol Chem, 277 (48) ( 2002), pp. 46493-46503, DOI: 10.1074/jbc.M203654200

[[156]] U. Widegren, J.W. Ryder, J.R. Zierath. Mitogen-activated protein kinase signal transduction in skeletal muscle: effects of exercise and muscle contraction. Acta Physiol Scand, 172 (3) ( 2001), pp. 227-238, DOI: 10.1046/j.1365-201x.2001.00855.x

[[157]] A. Carriere, Y. Romeo, H.A. Acosta-Jaquez, et al.. ERK1/2 phosphorylate Raptor to promote Ras-dependent activation of mTOR complex 1 ( mTORC1). J Biol Chem, 286 (1) ( 2011), pp. 567-577, DOI: 10.1074/jbc.M110.159046

[[158]] S.S. Lin, Y.W. Liu.Mechanical stretch induces mTOR recruitment and activation at the phosphatidic acid-enriched macropinosome in muscle cell. Frontiers in Cell and Developmental Biology, 7 ( 2019), p. 78, DOI: 10.3389/fcell.2019.00078

[[159]] J.S. You, J.W. Frey, T.A. Hornberger. Mechanical stimulation induces mTOR signaling via an ERK-independent mechanism: implications for a direct activation of mTOR by phosphatidic acid. PloS One, 7 (10) ( 2012), Article e47258, DOI: 10.1371/journal.pone.0047258

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

[[161]] E.M. Salomao, A.T. Toneto, G.O. Silva, M.C.C. Gomes-Marcondes, et al.. Physical exercise and a leucine-rich diet modulate the muscle protein metabolism in Walker tumor-bearing rats. Nutr Canc, 62 (8) ( 2010), pp. 1095-1104, DOI: 10.1080/01635581.2010.492082

[[162]] M.J. Puppa, J.P White, K.T. Velázquez, et al.. The effect of exercise on IL-6-induced cachexia in the Apc Min/+ mouse. Journal of cachexia, sarcopenia and muscle, 3 (2) ( 2012), pp. 117-137, DOI: 10.1007/s13539-011-0047-1

[[163]] A.D. Re Cecconi, M. Forti, M. Chiappa, et al.. Musclin, A myokine induced by aerobic exercise, retards muscle atrophy during cancer cachexia in mice. Cancers, 11 (10) ( 2019), p. 1541, DOI: 10.3390/cancers11101541

[[164]] D.I. Patel, K. Abuchowski, B. Sheikh, P. Rivas, N. Musi, A.P. Kumar, et al.. Exercise preserves muscle mass and force in a prostate cancer mouse model. European Journal of Translational Myology, 29 (4) ( 2019)

[[165]] M. Tanaka, K. Sugimoto, T. Fujimoto, et al.. Differential effects of pre-exercise on cancer cachexia-induced muscle atrophy in fast- and slow-twitch muscles. Faseb J, 34 (11) ( 2020), pp. 14389-14406, DOI: 10.1096/fj.202001330R

[[166]] B.A. Guigni, D.K. Fix, J.J. Bivona 3rd, B.M Palmer, J.A. Carson, M.J. Toth, et al.. Electrical stimulation prevents doxorubicin-induced atrophy and mitochondrial loss in cultured myotubes. Am J Physiol Cell Physiol, 317 (6) ( 2019), pp. C1213-C1228, DOI: 10.1152/ajpcell.00148.2019

[[167]] S. Sato, S. Gao, M.J. Puppa, M.C. Kostek, L.B. Wilson, J.A. Carson, et al.. High-frequency stimulation on skeletal muscle maintenance in female cachectic mice. Med Sci Sports Exerc, 51 (9) ( 2019), pp. 1828-1837, DOI: 10.1249/MSS.0000000000001991

[[168]] J.P. Hardee, J.E. Mangum, S. Gao, et al.. Eccentric contraction-induced myofiber growth in tumor-bearing mice. J Appl Physiol, 120 (1) ( 2016), pp. 29-37, DOI: 10.1152/japplphysiol.00416.2015

[[169]] R. Barreto, G. Mandili, F.A. Witzmann, F. Novelli, T.A Zimmers, A. Bonetto, et al.. Cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. Front Physiol, 7 ( 2016), p. 472, DOI: 10.3389/fphys.2016.00472

[[170]] Y. Quan-Jun, H. Yan, H. Yong-Long, et al.. Selumetinib attenuates skeletal muscle wasting in murine cachexia model through ERK inhibition and AKT activation. Mol Canc Therapeut, 16 (2) ( 2017), pp. 334-343, DOI: 10.1158/1535-7163.Mct-16-0324

[[171]] F. Penna, R. Ballaro, P. Costelli. The redox balance: a target for interventions against muscle wasting in cancer cachexia?. Antioxidants Redox Signal, 33 (8) ( 2020), pp. 542-558, DOI: 10.1089/ars.2020.8041

[[172]] S.S. Sabharwal, P.T. Schumacker. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?. Nat Rev Canc, 14 (11) ( 2014), pp. 709-721, DOI: 10.1038/nrc3803

[[173]] D. Wasley, N. Gale, S. Roberts, et al.. Patients with established cancer cachexia lack the motivation and self-efficacy to undertake regular structured exercise. Psycho Oncol, 27 (2) ( 2018), pp. 458-464, DOI: 10.1002/pon.4512

[[174]] S.K. Powers, Z. Radak, L.L. Ji. Exercise-induced oxidative stress: past, present and future. J Physiol, 594 (18) ( 2016), pp. 5081-5092, DOI: 10.1113/JP270646

[[175]] L.L. Ji. Antioxidants and oxidative stress in exercise. Proc Soc Exp Biol Med, 222 (3) ( 1999), pp. 283-292, DOI: 10.1046/j.1525-1373.1999.d01-145.x

[[176]] H. Miyazaki, S. Oh-ishi, T. Ookawara, et al.. Strenuous endurance training in humans reduces oxidative stress following exhausting exercise. Eur J Appl Physiol, 84 (1-2) ( 2001), pp. 1-6, DOI: 10.1007/s004210000342

[[177]] F. He, J. Li, Z. Liu, C. Chuang, W. Yang, L. Zuo, et al.. Redox mechanism of reactive oxygen species in exercise. Front Physiol, 7 ( 2016), p. 486, DOI: 10.3389/fphys.2016.00486

[[178]] R. Ballaro, F. Penna, F. Pin, M.C. Gómez-Cabrera, J. Viña, P. Costelli, et al.. Moderate exercise improves experimental cancer cachexia by modulating the redox homeostasis. Cancers, 11 (3) ( 2019), p. 285, DOI: 10.3390/cancers11030285

[[179]] C.R.R. Alves, W.d Neves, N.R.d. Almeida, et al.. Exercise training reverses cancer-induced oxidative stress and decrease in muscle COPS2/TRIP15/ALIEN. Mol Metab, 39 ( 2020), p. 101012, DOI: 10.1016/j.molmet.2020.101012

[[180]] C.P. Repka, R. Hayward. Effects of an exercise intervention on cancer-related fatigue and its relationship to markers of oxidative stress. Integr Canc Ther, 17 (2) ( 2018), pp. 503-510, DOI: 10.1177/1534735418766402

[[181]] A.J. Smuder. Exercise stimulates beneficial adaptations to diminish doxorubicin-induced cellular toxicity. Am J Physiol Regul Integr Comp Physiol, 317 (5) ( 2019), pp. R662-R672, DOI: 10.1152/ajpregu.00161.2019

[[182]] N.A. Burd, S.H. Gorissen, L.J. van Loon. Anabolic resistance of muscle protein synthesis with aging. Exerc Sport Sci Rev, 41 (3) ( 2013), pp. 169-173, DOI: 10.1097/JES.0b013e318292f3d5

[[183]] L. Breen, S.M. Phillips.Skeletal muscle protein metabolism in the elderly: interventions to counteract the 'anabolic resistance' of ageing. Nutr Metab, 8 (1) ( 2011), p. 68, DOI: 10.1186/1743-7075-8-68

[[184]] S.G. Liva, YC. Tseng, AM. Dauki, et al.. Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor. EMBO Mol Med, 12 (2) ( 2020), DOI: 10.15252/emmm.201809910. e9910

[[185]] A.P. Borzotta, M.B. Clague, I.D. Johnston. The effects of gastrointestinal malignancy on whole body protein metabolism. J Surg Res, 43 (6) ( 1987), pp. 505-512, DOI: 10.1016/0022-4804(87)90123-5

[[186]] S.J.D. O'Keefe, J. Ogden, G. Ramjee, et al.. Contribution of elevated protein turnover and anorexia to cachexia in patients with hepatocellular carcinoma. Canc Res, 50 (4) ( 1990), pp. 1226-1230

[[187]] David P.J. Marcel C.G. van de Poll, Alastair G.W. Moses, et al.. Effects of oral meal feeding on whole body protein breakdown and protein synthesis in cachectic pancreatic cancer patients. J Cachexia Sarcopenia Muscle, 6 (3) ( 2015), pp. 212-221, DOI: 10.1002/jcsm.12029

[[188]] J.P. Williams, B.E. Phillips, K. Smith, et al.. Effect of tumor burden and subsequent surgical resection on skeletal muscle mass and protein turnover in colorectal cancer patients. Am J Clin Nutr, 96 (5) ( 2012), pp. 1064-1070, DOI: 10.3945/ajcn.112.045708

[[189]] A. Dolly, J.F. Dumas, S. Servais. Cancer cachexia and skeletal muscle atrophy in clinical studies: what do we really know?. J Cachexia, Sarcopenia Muscle ( 2020). DOI: 10.1002/jcsm.12633

This work was supported by National Institutes of Health Grants R01 CA-121249 (National Cancer Institute) and R21 CA-231131 to JAC.