Top

Journal of Cancer Research and Clinical Oncology

Published in:

01-06-2019 | Cytostatic Therapy | Original Article – Cancer Research

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

Authors: Andreas Buch Møller, Simon Lønbro, Jean Farup, Thomas Schmidt Voss, Nikolaj Rittig, Jakob Wang, Inger Højris, Ulla Ramer Mikkelsen, Niels Jessen

Published in: Journal of Cancer Research and Clinical Oncology | Issue 6/2019

Abstract

Background

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.

Methods

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.

Results

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 Ser^318/321 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 Thr^37/46) 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.

Conclusions

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//www.clinicaltrials.gov (registration number: NCT02192216; date of registration 07/17-2014).

Available only for authorised users

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. https://doi.org/10.1136/bmj.b3410 CrossRef

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. https://doi.org/10.3389/fphys.2014.00069 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1152/ajpendo.00464.2015 CrossRefPubMed

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. https://doi.org/10.1002/ijc.29852 CrossRefPubMed

Coffey VG, Hawley JA (2007) The molecular bases of training adaptation. Sports Med (Auckland, NZ) 37:737–763CrossRef

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) 390:1151–1210CrossRef

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. https://doi.org/10.1371/journal.pone.0181086 CrossRefPubMedPubMedCentral

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

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. https://doi.org/10.1007/s00726-014-1810-3 CrossRefPubMed

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. https://doi.org/10.1038/cddis.2015.198 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1152/ajpendo.00317.2003 CrossRefPubMed

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. https://doi.org/10.1089/ars.2011.3965 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1152/japplphysiol.00776.2009 CrossRef

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. https://doi.org/10.1152/jappl.1992.72.2.484 CrossRef

Gurtler A et al (2013) Stain-free technology as a normalization tool in Western blot analysis. Anal Biochem 433:105–111. https://doi.org/10.1016/j.ab.2012.10.010 CrossRefPubMed

Hawley JA, Lessard SJ (2008) Exercise training-induced improvements in insulin action. Acta Physiol (Oxford, England) 192:127–135. https://doi.org/10.1111/j.1748-1716.2007.01783.x CrossRef

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. https://doi.org/10.1007/s10552-015-0694-1 CrossRefPubMed

Jessen N, Sundelin EI, Moller AB (2014) AMP kinase in exercise adaptation of skeletal muscle. Drug Discov Today. https://doi.org/10.1016/j.drudis.2014.03.009 CrossRefPubMed

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. https://doi.org/10.1016/j.radonc.2013.07.002 CrossRef

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):1–15

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. https://doi.org/10.1002/(sici)1097-4598(199811)21:11%3c1457:aid-mus14%3e3.0.co;2-y CrossRefPubMed

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. https://doi.org/10.1096/fj.201700968r CrossRef

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. https://doi.org/10.1038/ncomms7670 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1007/s00424-013-1318-9 CrossRef

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). https://doi.org/10.1152/japplphysiol.00490.2018 CrossRef

Pilegaard H, Saltin B, Neufer PD (2003) Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 546:851–858CrossRefPubMedPubMedCentral

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. https://doi.org/10.1007/s00726-014-1792-1 CrossRef

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. https://doi.org/10.3389/fphar.2013.00049 CrossRefPubMedPubMedCentral

Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M (2013) Mechanisms regulating skeletal muscle growth and atrophy. FEBS J 280:4294–4314. https://doi.org/10.1111/febs.12253 CrossRefPubMed

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. https://doi.org/10.1093/annonc/mdv298 CrossRef

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. https://doi.org/10.2337/db16-1327 CrossRefPubMed

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. https://doi.org/10.1152/jappl.1996.80.6.2250 CrossRef

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. https://doi.org/10.1007/s00424-014-1587-y CrossRef

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. https://doi.org/10.1002/jcb.22272 CrossRefPubMed

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. https://doi.org/10.1371/journal.pone.0102031 CrossRefPubMedPubMedCentral

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. https://doi.org/10.1152/japplphysiol.00044.2014 CrossRef

Wackerhage H, Rennie MJ (2006) How nutrition and exercise maintain the human musculoskeletal mass. J Anat 208:451–458CrossRefPubMedPubMedCentral

Zampieri S et al (2016) Physical exercise in aging human skeletal muscle increases mitochondrial calcium uniporter expression levels and affects mitochondria dynamics. Physiol Rep. https://doi.org/10.14814/phy14812.13005 CrossRefPubMedPubMedCentral

Title: Molecular and cellular adaptations to exercise training in skeletal muscle from cancer patients treated with chemotherapy
Authors: Andreas Buch Møller
Simon Lønbro
Jean Farup
Thomas Schmidt Voss
Nikolaj Rittig
Jakob Wang
Inger Højris
Ulla Ramer Mikkelsen
Niels Jessen
Publication date: 01-06-2019
Publisher: Springer Berlin Heidelberg
Keyword: Cytostatic Therapy
Published in: Journal of Cancer Research and Clinical Oncology / Issue 6/2019
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-019-02911-5

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

Trial registration

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

Please log in to get access to this content

Other articles of this Issue 6/2019

Different statistical techniques dealing with confounding in observational research: measuring the effect of breast-conserving therapy and mastectomy on survival

The role of PD-1/PD-L1 axis and macrophage in the progression and treatment of cancer

IL-6 signaling contributes to radioresistance of prostate cancer through key DNA repair-associated molecules ATM, ATR, and BRCA 1/2

First-line afatinib vs gefitinib for patients with EGFR mutation-positive NSCLC (LUX-Lung 7): impact of afatinib dose adjustment and analysis of mode of initial progression for patients who continued treatment beyond progression

Alternative and canonical NF-kB pathways DNA-binding hierarchies networks define Hodgkin lymphoma and Non-Hodgkin diffuse large B Cell lymphoma respectively

Chemopreventive effect of Callistemon citrinus (Curtis) Skeels against colon cancer induced by 1,2-dimethylhydrazine in rats

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page