Molecular and cellular adaptations to exercise training in skeletal muscle from cancer patients treated with chemotherapy

  • Andreas Buch Møller
  • Simon Lønbro
  • Jean Farup
  • Thomas Schmidt Voss
  • Nikolaj Rittig
  • Jakob Wang
  • Inger Højris
  • Ulla Ramer Mikkelsen
  • Niels JessenEmail author
Original Article – Cancer Research



A growing body of evidence suggests that exercise training has beneficial effects in cancer patients. The aim of the present study was to investigate the molecular basis underlying these beneficial effects in skeletal muscle from cancer patients.


We investigated expression of selected proteins involved in cellular processes known to orchestrate adaptation to exercise training by western blot. Skeletal muscle biopsies were sampled from ten cancer patients before and after 4–7 weeks of ongoing chemotherapy, and subsequently after 10 weeks of continued chemotherapy in combination with exercise training. Biopsies from ten healthy matched subjects served as reference.


The expression of the insulin-regulated glucose transporter, GLUT4, increased during chemotherapy and continued to increase during exercise training. A similar trend was observed for ACC, a key enzyme in the biosynthesis and oxidation of fatty acids, but we did not observe any changes in other regulators of substrate metabolism (AMPK and PDH) or mitochondrial proteins (Cyt-C, COX-IV, SDHA, and VDAC). Markers of proteasomal proteolysis (MURF1 and ATROGIN-1) decreased during chemotherapy, but did not change further during chemotherapy combined with exercise training. A similar pattern was observed for autophagy-related proteins such as ATG5, p62, and pULK1 Ser757, but not ULK1 and LC3BII/LC3BI. Phosphorylation of FOXO3a at Ser318/321 did not change during chemotherapy, but decreased during exercise training. This could suggest that FOXO3a-mediated transcriptional regulation of MURF1 and ATROGIN-1 serves as a mechanism by which exercise training maintains proteolytic systems in skeletal muscle in cancer patients. Phosphorylation of proteins that regulate protein synthesis (mTOR at Ser2448 and 4EBP1 at Thr37/46) increased during chemotherapy and leveled off during exercise training. Finally, chemotherapy tended to increase the number of satellite cells in type 1 fibers, without any further change during chemotherapy and exercise training. Conversely, the number of satellite cells in type 2 fibers did not change during chemotherapy, but increased during chemotherapy combined with exercise training.


Molecular signaling cascades involved in exercise training are disturbed during cancer and chemotherapy, and exercise training may prevent further disruption of these pathways.

Trial registration

The study was approved by the local Scientific Ethics Committee of the Central Denmark Region (Project ID: M-2014-15-14; date of approval: 01/27/2014) and the Danish Data Protection Agency (case number 2007-58-0010; date of approval: 01/28/2015). The trial was registered at http// (registration number: NCT02192216; date of registration 07/17-2014).


Cancer cachexia Endurance Resistance Molecular mechanisms Rehabilitation 



Acetyl-CoA carboxylase


AMP-activated protein kinase


Autophagy-related protein 5




Cytochrome-C oxidase IV


Eukaryotic translation initiation factor 4E binding protein 1


F-Box protein 32


Forkhead transcription factor 3a


Inhibitor of NFκB


Mammalian target of rapamycin


Microtubule-associated protein B


Muscle RING-finger protein 1


Nuclear factor κ B


Pyrovate dehydrogenase


Satellite cell


Sequestome 1


Subunit 6 rbosomal protein


Succinate dehydrogenase alpha


UNC-51-like kinase 1


Voltage-dependent anion channel



Signe Bentsen and Morten Ørskov are thanked for their technical assistance during the studies.

Author contributions

ABM, SL, URM, IH, NJ conception and design of research; ABM, SL, TV, NR, URM, JW, JF performed experiments and collected data; ABM, JF, JW, SL, URM, and NJ analyzed and/or interpreted data; ABM prepared figures and first draft of manuscript; all authors revised the draft and approved the final version of the manuscript.


The study was supported by the Danish Medical Research Council, the A.P. Møller Foundation for the Advancement of Medical Science, Knud Højgaard Foundation, P. A. Messerschmidt og Hustrus Fond, and Augustinus Foundation. Funding was provided by Fonden til Lægevidenskabens Fremme (17-L-0304).

Compliance with ethical standards

Conflict of interest

No conflicts of interest are declared by the authors.

Ethics approval and consent to participate

The study was approved by the local Scientific Ethics Committee of the Central Denmark Region (journal number: 1-10-72-15-14) and the Danish Data Protection Agency (case number: 2007-58-0010). The trial was registered at http// (Clinical trial registration number: NCT02192216).

Consent for publication

Consent for publication has been obtained by the participants.

Availability of data and material

All data generated and analyzed during the current study are available from the corresponding author upon reasonable request.

Supplementary material

432_2019_2911_MOESM1_ESM.pdf (1.6 mb)
Supplementary material 1 (PDF 1599 kb)


  1. Adamsen L et al (2009) Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial. BMJ (Clinical research ed) 339:b3410. CrossRefGoogle Scholar
  2. Baehr LM, Tunzi M, Bodine SC (2014) Muscle hypertrophy is associated with increases in proteasome activity that is independent of MuRF1 and MAFbx expression. Front Physiol 5:69. CrossRefGoogle Scholar
  3. Bak AM et al (2016) Differential regulation of lipid and protein metabolism in obese vs lean subjects before and after a 72-h fast. Am J Physiol Endocrinol Metab 311:E224–E235. CrossRefGoogle Scholar
  4. Bu Y et al (2016) A phosphomimetic mutant of RelA/p65 at Ser536 induces apoptosis and senescence: an implication for tumor-suppressive role of Ser536 phosphorylation. Int J Cancer 138:1186–1198. CrossRefGoogle Scholar
  5. Coffey VG, Hawley JA (2007) The molecular bases of training adaptation. Sports Med (Auckland, NZ) 37:737–763CrossRefGoogle Scholar
  6. Collaborators GBDCoD (2017) Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet (London, England) 390:1151–1210CrossRefGoogle Scholar
  7. Crouch ML, Knowels G, Stuppard R, Ericson NG, Bielas JH, Marcinek DJ, Syrjala KL (2017) Cyclophosphamide leads to persistent deficits in physical performance and in vivo mitochondria function in a mouse model of chemotherapy late effects. PLoS One 12:e0181086. CrossRefGoogle Scholar
  8. Egan B, Zierath JR (2013) Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab 17:162–184. CrossRefGoogle Scholar
  9. Farup J, Rahbek SK, Knudsen IS, de Paoli F, Mackey AL, Vissing K (2014) Whey protein supplementation accelerates satellite cell proliferation during recovery from eccentric exercise. Amino Acids 46:2503–2516. CrossRefGoogle Scholar
  10. Farup J, Madaro L, Puri PL, Mikkelsen UR (2015) Interactions between muscle stem cells, mesenchymal-derived cells and immune cells in muscle homeostasis, regeneration and disease. Cell Death Dis 6:e1830. CrossRefGoogle Scholar
  11. Frosig C, Jorgensen SB, Hardie DG, Richter EA, Wojtaszewski JF (2004) 5′-AMP-activated protein kinase activity and protein expression are regulated by endurance training in human skeletal muscle. Am J Physiol Endocrinol Metab 286:E411–E417. CrossRefGoogle Scholar
  12. Gilliam LA, St Clair DK (2011) Chemotherapy-induced weakness and fatigue in skeletal muscle: the role of oxidative stress. Antioxid Redox Signal 15:2543–2563. CrossRefGoogle Scholar
  13. Gilliam LA, Ferreira LF, Bruton JD, Moylan JS, Westerblad H, St Clair DK, Reid MB (2009) Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle. J Appl Physiol (Bethesda, Md: 1985) 107:1935–1942. CrossRefGoogle Scholar
  14. Green HJ, Helyar R, Ball-Burnett M, Kowalchuk N, Symon S, Farrance B (1992) Metabolic adaptations to training precede changes in muscle mitochondrial capacity. J Appl Physiol (Bethesda, Md: 1985) 72:484–491. CrossRefGoogle Scholar
  15. Gurtler A et al (2013) Stain-free technology as a normalization tool in Western blot analysis. Anal Biochem 433:105–111. CrossRefGoogle Scholar
  16. Hawley JA, Lessard SJ (2008) Exercise training-induced improvements in insulin action. Acta Physiol (Oxford, England) 192:127–135. CrossRefGoogle Scholar
  17. Hvid T et al (2016) Effect of a 2-year home-based endurance training intervention on physiological function and PSA doubling time in prostate cancer patients. Cancer Causes Control CCC 27:165–174. CrossRefGoogle Scholar
  18. Jessen N, Sundelin EI, Moller AB (2014) AMP kinase in exercise adaptation of skeletal muscle. Drug Discov Today. Google Scholar
  19. Lonbro S et al (2013) Progressive resistance training rebuilds lean body mass in head and neck cancer patients after radiotherapy—results from the randomized DAHANCA 25B trial. Radiother Oncol J Eur Soc Ther Radiol Oncol 108:314–319. CrossRefGoogle Scholar
  20. Lonbro S, Farup J, Bentsen S, Voss TS, Rittig N, Wang J, Ørskov M, Højris I, Mikkelsen UR (2017) Lean body mass, muscle fibre size and muscle function in cancer patients during chemotherapy and 10 weeks of exercise. JCSM Clin Rep 2(1):1–15Google Scholar
  21. McLoon LK, Falkenberg JH, Dykstra D, Iaizzo PA (1998) Doxorubicin chemomyectomy as a treatment for cervical dystonia: histological assessment after direct injection into the sternocleidomastoid muscle. Muscle Nerve 21:1457–1464.;2-y CrossRefGoogle Scholar
  22. Mijwel S et al (2018) Exercise training during chemotherapy preserves skeletal muscle fiber area, capillarization, and mitochondrial content in patients with breast cancer. FASEB J Off Publ Fed Am Soc Exp Biol. Google Scholar
  23. Milan G et al (2015) Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy. Nat Commun 6:6670. CrossRefGoogle Scholar
  24. Moller AB, Vendelbo MH, Rahbek SK, Clasen BF, Schjerling P, Vissing K, Jessen N (2013) Resistance exercise, but not endurance exercise, induces IKKbeta phosphorylation in human skeletal muscle of training-accustomed individuals. Pflugers Arch Eur J Physiol 465:1785–1795. CrossRefGoogle Scholar
  25. Moller AB, Voss TS, Vendelbo MH, Pedersen SB, Moller N, Jessen N (2018) Insulin inhibits autophagy signaling independent of counter-regulatory hormone levels, but does not affect the effects of exercise. J Appl Physiol (Bethesda, Md: 1985). Google Scholar
  26. Pilegaard H, Saltin B, Neufer PD (2003) Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 546:851–858CrossRefGoogle Scholar
  27. Rahbek SK, Farup J, Moller AB, Vendelbo MH, Holm L, Jessen N, Vissing K (2014) Effects of divergent resistance exercise contraction mode and dietary supplementation type on anabolic signalling, muscle protein synthesis and muscle hypertrophy. Amino Acids 46:2377–2392. CrossRefGoogle Scholar
  28. Scheede-Bergdahl C, Jagoe RT (2013) After the chemotherapy: potential mechanisms for chemotherapy-induced delayed skeletal muscle dysfunction in survivors of acute lymphoblastic leukaemia in childhood. Front Pharmacol 4:49. CrossRefGoogle Scholar
  29. Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M (2013) Mechanisms regulating skeletal muscle growth and atrophy. FEBS J 280:4294–4314. CrossRefGoogle Scholar
  30. Senkus E et al (2015) Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol 26(Suppl 5):v8–v30. CrossRefGoogle Scholar
  31. Sjoberg KA et al (2017) exercise increases human skeletal muscle insulin sensitivity via coordinated increases in microvascular perfusion and molecular signaling. Diabetes 66:1501–1510. CrossRefGoogle Scholar
  32. Spina RJ, Chi MM, Hopkins MG, Nemeth PM, Lowry OH, Holloszy JO (1996) Mitochondrial enzymes increase in muscle in response to 7–10 days of cycle exercise. J Appl Physiol (Bethesda, Md: 1985) 80:2250–2254. CrossRefGoogle Scholar
  33. Stefanetti RJ, Lamon S, Wallace M, Vendelbo MH, Russell AP, Vissing K (2015) Regulation of ubiquitin proteasome pathway molecular markers in response to endurance and resistance exercise and training. Pflugers Arch Eur J Physiol 467:1523–1537. CrossRefGoogle Scholar
  34. Tong JF, Yan X, Zhu MJ, Du M (2009) AMP-activated protein kinase enhances the expression of muscle-specific ubiquitin ligases despite its activation of IGF-1/Akt signaling in C2C12 myotubes. J Cell Biochem 108:458–468. CrossRefGoogle Scholar
  35. Vendelbo MH et al (2014a) Fasting increases human skeletal muscle net phenylalanine release and this is associated with decreased mTOR signaling. PLoS One 9:e102031. CrossRefGoogle Scholar
  36. Vendelbo MH et al (2014b) Sustained AS160 and TBC1D1 phosphorylations in human skeletal muscle 30 min after a single bout of exercise. J Appl Physiol (Bethesda, Md: 1985) 117:289–296. CrossRefGoogle Scholar
  37. Wackerhage H, Rennie MJ (2006) How nutrition and exercise maintain the human musculoskeletal mass. J Anat 208:451–458CrossRefGoogle Scholar
  38. Zampieri S et al (2016) Physical exercise in aging human skeletal muscle increases mitochondrial calcium uniporter expression levels and affects mitochondria dynamics. Physiol Rep. Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Andreas Buch Møller
    • 1
    • 2
  • Simon Lønbro
    • 3
    • 4
  • Jean Farup
    • 1
  • Thomas Schmidt Voss
    • 2
    • 5
  • Nikolaj Rittig
    • 2
    • 5
  • Jakob Wang
    • 3
  • Inger Højris
    • 6
  • Ulla Ramer Mikkelsen
    • 3
    • 7
  • Niels Jessen
    • 1
    • 2
    • 8
    Email author
  1. 1.Research Laboratory for Biochemical Pathology, Department of Clinical MedicineHEALTH, Aarhus University HospitalAarhus NDenmark
  2. 2.Steno Diabetes Center AarhusAarhus University HospitalAarhusDenmark
  3. 3.Section of Sports Science, Department of Public HealthHEALTH, Aarhus UniversityAarhusDenmark
  4. 4.Department of Experimental Clinical OncologyAarhus University HospitalAarhusDenmark
  5. 5.Medical Research Laboratory, Department of Clinical MedicineHEALTH, Aarhus UniversityAarhusDenmark
  6. 6.Department of OncologyAarhus University HospitalAarhusDenmark
  7. 7.Department of Orthopedic Surgery, Bispebjerg Hospital and Center for Healthy Aging, Institute of Sports Medicine, Faculty of Health ScienceUniversity of CopenhagenCopenhagenDenmark
  8. 8.Department of Clinical PharmacologyAarhus University HospitalAarhusDenmark

Personalised recommendations