BACKGROUND: Platinum-based chemotherapy provides curative treatment to more than 95% of patients with testicular germ cell tumor but it has negative cardiometabolic and neurological effects. Regular exercise can alleviate late chemotherapy-related toxicities. We examined the impact of a 6-month supervised aerobic-strength training on cognitive and cardiometabolic health and residual level of platinum in cancer survivors. METHODS: Twenty-eight middle-aged (42.1 ± 7.6 years) testicular germ cell tumor survivors subjected to platinum-based chemotherapy (1-8 cycles, 0-24 years ago) were recruited into exercise (n = 20) and control (n = 8) groups. Effects of 6-month exercise training on the whole-body and muscle metabolism, cognitive functions, cardiopulmonary fitness, residual plasma platinum, and plasma adiponectin were examined. RESULTS: Exercise intervention improved cardiopulmonary fitness and cognitive functions, reduced residual plasma platinum, visceral adiposity and muscle lipids, improved glucose (glycosylated hemoglobin) and lipid (high-density lipoprotein cholesterol) metabolism, and enhanced dynamics of muscle post-exercise phosphocreatine recovery. Exercise-related decline in plasma platinum was paralleled by decline of muscle glycerophosphocholines and by the enhanced metabolic flexibility during low-intensity exercise, and predicted training-induced increase in cognitive functions. CONCLUSIONS: The 6-month exercise intervention resulted in improved cognitive and cardiometabolic health in testicular germ cell tumor survivors, which was paralleled by reduced plasma platinum, providing evidence that structured supervised exercise brings multiple health benefits to testicular germ cell tumor survivors.

2nd Department of Oncology Faculty of Medicine Comenius University and National Cancer Institute Bratislava Slovakia

Department of Analytical Chemistry Faculty of Science Palacky University Olomouc Olomouc Czech Republic

Department of Metabolic Disease Research Institute of Experimental Endocrinology Biomedical Research Center Slovak Academy of Sciences Bratislava Slovakia

Division of Endocrinology and Metabolism Department of Medicine 3 Medical University of Vienna Vienna Austria

Faculty of Physical Education and Sport Comenius University Bratislava Slovakia

Institute of Medical Chemistry Biochemistry and Clinical Biochemistry Faculty of Medicine Comenius University Bratislava Slovakia

Institute of Pathophysiology Faculty of Medicine Comenius University Bratislava Slovakia

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Ghazarian AA, Kelly SP, Altekruse SF, Rosenberg PS, McGlynn KA. Future of testicular germ cell tumor incidence in the United States: forecast through 2026. Cancer. 2017;123(12):2320‐2328.

Fung C, Dinh PC, Fossa SD, Travis LB. Testicular cancer survivorship. J Natl Compr Canc Netw. 2019;17(12):1557‐1568.

Chovanec M, Abu Zaid M, Hanna N, El‐Kouri N, Einhorn LH. Albany C. Long‐term toxicity of cisplatin in germ‐cell tumor survivors. Ann Oncol. 2017;28(11):2670‐2679.

Amiri A, Chovanec M, Oliva V, et al. Chemotherapy‐induced toxicity in patients with testicular germ cell tumors: the impact of physical fitness and regular exercise. Andrology. 2021;9(6):1879‐1892.

Hjelle LV, Gundersen PO, Oldenburg J, et al. Long‐term platinum retention after platinum‐based chemotherapy in testicular cancer survivors: a 20‐year follow‐up study. Anticancer Res. 2015;35(3):1619‐1625.

Boer H, Proost JH, Nuver J, et al. Long‐term exposure to circulating platinum is associated with late effects of treatment in testicular cancer survivors. Ann Oncol. 2015;26(11):2305‐2310.

Sprauten M, Darrah TH, Peterson DR, et al. Impact of long‐term serum platinum concentrations on neuro‐ and ototoxicity in cisplatin‐treated survivors of testicular cancer. J Clin Oncol. 2012;30(3):300‐307.

Chovanec M, Vasilkova L, Setteyova L, et al. Long‐term cognitive functioning in testicular germ‐cell tumor survivors. Oncologist. 2018;23(5):617‐623.

Amidi A, Wu LM, Agerbæk M, et al. Cognitive impairment and potential biological and psychological correlates of neuropsychological performance in recently orchiectomized testicular cancer patients. Psychooncology. 2015;24(9):1174‐1780.

Amiri A, Krumpolec P, Mego M, Ukropcová B, Chovanec M, Ukropec J. Habitual physical activity modulates cardiometabolic health in long‐term testicular cancer survivors. Support Care Cancer. 2023;31(9):539.

Turner RR, Steed L, Quirk H, et al. Interventions for promoting habitual exercise in people living with and beyond cancer. Cochrane Database Syst Rev. 2018;9(9).

Ukropcova B, Sereda O, de Jonge L, et al. Family history of diabetes links impaired substrate switching and reduced mitochondrial content in skeletal muscle. Diabetes. 2007;56(3):720‐727.

Bull CJ, Hazelwood E, Legge DN, et al. Impact of weight loss on cancer‐related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes. EBioMedicine. 2024;100:104977.

Monette MC, Baird A, Jackson DL. A meta‐analysis of cognitive functioning in nondemented adults with type 2 diabetes mellitus. Can J Diabetes. 2014;38(6):401‐408.

Pedersen BK. Physical activity and muscle‐brain crosstalk. Nat Rev Endocrinol. 2019;15(7):383‐392.

Bloemer J, Pinky PD, Govindarajulu M, et al. Role of adiponectin in central nervous system disorders. Neural Plast. 2018;2018:4593530.

Schön M, Kovaničová Z, Košutzká Z, et al. Effects of running on adiponectin, insulin and cytokines in cerebrospinal fluid in healthy young individuals. Sci Rep. 2019;9(1):1959.

Rizzo MR, Fasano R, Paolisso G. Adiponectin and cognitive decline. Int J Mol Sci. 2020;21(6):2010.

Arvanitakis Z, Capuano AW, Tong H, et al. Associations of serum insulin and related measures with neuropathology and cognition in older persons with and without diabetes. Ann Neurol. 2024.

Posa DK, Miller J, Hoetker D, et al. Skeletal muscle analysis of cancer patients reveals a potential role for carnosine in muscle wasting. J Cachexia Sarcopenia Muscle. 2023;14(4):1802‐1814.

de Courten B, Jakubova M, de Courten MP, et al. Effects of carnosine supplementation on glucose metabolism: pilot clinical trial. Obesity (Silver Spring). 2016;24(5):1027‐1034.

Schön M, Just I, Krumpolec P, et al. Supplementation‐induced change in muscle carnosine is paralleled by changes in muscle metabolism, protein glycation and reactive carbonyl species sequestering. Physiol Res. 2023;72(1):87‐97.

Regazzoni L, de Courten B, Garzon D, et al. A carnosine intervention study in overweight human volunteers: bioavailability and reactive carbonyl species sequestering effect. Sci Rep. 2016;6:27224.

Schön M, Mousa A, Berk M, et al. The potential of carnosine in brain‐related disorders: a comprehensive review of current evidence. Nutrients. 2019;11(6):1196.

Saezde M, Asteasu L, Martínez‐Velilla N, et al. Inter‐individual variability in response to exercise intervention or usual care in hospitalized older adults. J Cachexia Sarcopenia Muscle. 2019;10(6):1266‐1275.

Palmer BF, Clegg DJ. Metabolic flexibility and its impact on health outcomes. Mayo Clin Proc. 2022;97(4):761‐776.

Mancilla RF, Lindeboom L, Grevendonk L, et al. Skeletal muscle mitochondrial inertia is associated with carnitine acetyltransferase activity and physical function in humans. JCI Insight. 2023;8(1).

Klepochová R, Valkovič L, Hochwartner T, et al. Differences in muscle metabolism between triathletes and normally active volunteers investigated using multinuclear magnetic resonance spectroscopy at 7T. Front Physiol. 2018;9:300.

Kent‐Braun JA, McCully KK, Chance B. Metabolic effects of training in humans: a 31P‐MRS study. J Appl Physiol. 1985;69(3):1165‐1170.

Cikes D, Leutner M, Cronin SJF, et al. Gpcpd1‐GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism. Nat Aging. 2024;4(1):80‐94.

Baecke JA, Burema J, Frijters JE. A short questionnaire for the measurement of habitual physical activity in epidemiological studies. Am J Clin Nutr. 1982;36(5):936‐942.

Fayers P, Bottomley A. Group EQoL, unit QoL. Quality of life research within the EORTC‐the EORTC QLQ‐C30. European Organisation for Research and Treatment of Cancer. Eur J Cancer. 2002;38(4):S125‐S133.

Beck AT, Steer RA, Brown G. Beck Depression Inventory—II. Psychological assessment. 1996.

Wagner LI, Sweet J, Butt Z, Lai J‐S, Cella D. Measuring patient self‐reported cognitive function: development of the functional assessment of cancer therapy‐cognitive function instrument. J Support Oncol. 2009;7(6):W32‐W9.

Van der Elst W, van Boxtel MP, van Breukelen GJ, Jolles J. Rey's verbal learning test: normative data for 1855 healthy participants aged 24–81 years and the influence of age, sex, education, and mode of presentation. J Int Neuropsychol Soc. 2005;11(3):290‐302.

Maruff P, Thomas E, Cysique L, et al. Validity of the CogState brief battery: relationship to standardized tests and sensitivity to cognitive impairment in mild traumatic brain injury, schizophrenia, and AIDS dementia complex. Arch Clin Neuropsychol. 2009;24(2):165‐178.

Goluch S, Kuehne A, Meyerspeer M, et al. A form‐fitted three channel 31P, two channel 1H transceiver coil array for calf muscle studies at 7 T. Magnetic Reson Med. 2015;73(6):2376‐2389.

Krššák M, Lindeboom L, Schrauwen‐Hinderling V, et al. Proton magnetic resonance spectroscopy in skeletal muscle: experts' consensus recommendations. NMR Biomed. 2021;34(5):e4266.

Krumpolec P, Klepochová R, Frollo I, et al. Multinuclear MRS at 7T uncovers exercise driven differences in skeletal muscle energy metabolism between young and seniors. Front Physiol. 2020;11:514645.

Klepochová R, Leutner M, Bastian M, et al. Muscle‐specific relation of acetylcarnitine and intramyocellular lipids to chronic hyperglycemia: a pilot 3‐T 1H MRS study. Obesity. 2020;28(8):1405‐1411.

Meyerspeer M, Boesch C, Cameron D, et al. 31P magnetic resonance spectroscopy in skeletal muscle: experts' consensus recommendations. NMR Biomed. 2021;34(5):e4246.

Valkovič L, Chmelík M, Krššák M. In‐vivo 31P‐MRS of skeletal muscle and liver: a way for non‐invasive assessment of their metabolism. Anal Biochem. 2017;529:193‐215.

Kurdiova T, Balaz M, Vician M, et al. Effects of obesity, diabetes and exercise on Fndc5 gene expression and irisin release in human skeletal muscle and adipose tissue: in vivo and in vitro studies. J Physiol. 2014;592(5):1091‐1107.

Koevoets EW, Schagen SB, de Ruiter MB, et al. Effect of physical exercise on cognitive function after chemotherapy in patients with breast cancer: a randomized controlled trial (PAM study). Breast Cancer Res. 2022;24(1):36.

Fang YY, Lee YH, Chan JC, et al. Effects of exercise interventions on social and cognitive functioning of men with prostate cancer: a meta‐analysis. Support Care Cancer. 2020;28(5):2043‐2057.

Stillman CM, Esteban‐Cornejo I, Brown B, Bender CM, Erickson KI. Effects of exercise on brain and cognition across age groups and health states. Trends Neurosci. 2020;43(7):533‐543.

Etnier JL, Nowell PM, Landers DM, Sibley BA. A meta‐regression to examine the relationship between aerobic fitness and cognitive performance. Brain Res Rev. 2006;52(1):119‐130.

Tsai CL, Pai MC, Ukropec J, Ukropcová B. The role of physical fitness in the neurocognitive performance of task switching in older persons with mild cognitive impairment. J Alzheimers Dis. 2016;53(1):143‐159.

Mundell NL, Owen PJ, Dalla Via J, et al. Effects of a multicomponent resistance‐based exercise program with protein, vitamin D and calcium supplementation on cognition in men with prostate cancer treated with ADT: secondary analysis of a 12‐month randomised controlled trial. BMJ Open. 2022;12(6):e060189.

Adams SC, DeLorey DS, Davenport MH, Fairey AS, North S, Courneya KS. Effects of high‐intensity interval training on fatigue and quality of life in testicular cancer survivors. Br J Cancer. 2018;118(10):1313‐1321.

Smith RL, Soeters MR, Wüst RCI, Houtkooper RH. Metabolic flexibility as an adaptation to energy resources and requirements in health and disease. Endocr Rev. 2018;39(4):489‐517.

Goodpaster BH, Sparks LM. Metabolic flexibility in health and disease. Cell Metab. 2017;25(5):1027‐1036.

Bergouignan A, Antoun E, Momken I, et al. Effect of contrasted levels of habitual physical activity on metabolic flexibility. J Appl Physiol. 1985;114(3):371‐379.

Morant‐Ferrando B, Jimenez‐Blasco D, Alonso‐Batan P, et al. Fatty acid oxidation organizes mitochondrial supercomplexes to sustain astrocytic ROS and cognition. Nat Metab. 2023;5(8):1290‐1302.

Moreira‐Pais A, Ferreira R, Gil da Costa R. Platinum‐induced muscle wasting in cancer chemotherapy: mechanisms and potential targets for therapeutic intervention. Life Sci. 2018;208:1‐9.

Adamopoulos S, Coats AJ, Brunotte F, et al. Physical training improves skeletal muscle metabolism in patients with chronic heart failure. J Am Coll Cardiol. 1993;21(5):1101‐1106.

Klepochová R, Niess F, Meyerspeer M, et al. Correlation between skeletal muscle acetylcarnitine and phosphocreatine metabolism during submaximal exercise and recovery: interleaved 1H/31P MRS 7 T study. Sci Rep. 2024;14(1):3254.

Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol. 2004;24(1):29‐33.

Wang ZV, Scherer PE. Adiponectin, the past two decades. J Mol Cell Biol. 2016;8(2):93‐100.

Hjelle LV, Gundersen PO, Hellesnes R, et al. Long‐term serum platinum changes and their association with cisplatin‐related late effects in testicular cancer survivors. Acta Oncol. 2018;57(10):1392‐1400.

Lukaski HC. Low dietary zinc decreases erythrocyte carbonic anhydrase activities and impairs cardiorespiratory function in men during exercise. Am J Clin Nutr. 2005;81(5):1045‐1051.

Seino S, Sumi K, Narita M, et al. Effects of low‐dose dairy protein plus micronutrient supplementation during resistance exercise on muscle mass and physical performance in older adults: a randomized, controlled trial. J Nutr Health Aging. 2018;22(1):59‐67.

Yaffe K, Clemons TE, McBee WL, Lindblad AS, Group A‐REDSR. Impact of antioxidants, zinc, and copper on cognition in the elderly: a randomized, controlled trial. Neurology. 2004;63(9):1705‐1707.

Warburton DE, Bredin SS. Health benefits of physical activity: a systematic review of current systematic reviews. Curr Opinion Cardiol. 2017;32(5):541‐556.

Tan GA, Peiris CL, Dennett AM. Cancer survivors maintain health benefits 6 to 12 months after exercise‐based rehabilitation: a systematic review and meta‐analysis. J Cancer Survivorship. 2024;18(3):651‐672.

Fuller JT, Hartland MC, Maloney LT, Davison K. Therapeutic effects of aerobic and resistance exercises for cancer survivors: a systematic review of meta‐analyses of clinical trials. Br J Sports Med. 2018;52(20):1311.

PANEL E. American college of sports medicine roundtable on exercise guidelines for cancer survivors. J ACSM. 2010;42:1409‐1426.

Electrical pulse stimulation reflecting the episodic nature of real-life exercise modulates metabolic and secretory profile of primary human myotubes