Exercise in Testicular Germ Cell Cancer Survivors (ExCell)

Exercise in Prevention & Treatment of Chemotherapy-related Late Toxicity in Testicular Germ Cell Cancer Survivors: the Role of Skeletal Muscle

Regular exercise is effective in prevention & treatment of chronic diseases. Exercise can reduce late toxicity of chemotherapy, commonly found in cancer survivors, which is yet to be translated into clinical practice. Mechanisms of exercise benefits in oncologic patients are far from being elucidated, and include increase in muscle mass, reduction of fat mass, systemic inflammation and cardiometabolic risk. Synchronization of exercise adaptive response is, to an extent, mediated by bioactive molecules released from muscle, with anti-inflammatory & tumor-suppressing properties. Muscle satellite cells are a source of regeneration, muscle structural integrity & functional capacity. Phenotypes of muscle cells, such as secretory profile, lipid & glucose metabolism, mirror clinical phenotypes of the donor. Importantly, muscle cells' metabolism in vitro can be modulated by 8-12 week training in vivo. Epigenetic mechanisms regulating muscle & systemic metabolism in cancer survivors are not yet understood.

Aims: To assess the impact of 6-month supervised, individualized aerobic-strength exercise training intervention in cancer survivors with chemotherapy-induced late toxicity . (i) on the whole-body energy and glucose metabolism, anthropometric parameters, physical fitness & activity profile, motor functions and quality of life in testicular germ cell cancer (TGCC) survivors, more than 3 years after cisplatin-based chemotherapy; with the 2-year follow up; . (ii) on skeletal muscle mass, morphology as well as functional and metabolic state detected in vivo (31P-MR spectroscopy). (iii) on metabolic characteristics of primary skeletal muscle cells; To determine the impact of exercise intervention on circulating bioactive molecules (exerkines), putative mediators of exercise health benefits as well as on levels of circulating inflammatory cytokines, which likely contribute to the pathogenesis of chemotherapy-induced late toxicity; To evaluate the role of (a) selected exercise-regulated bioactive molecules, (b) exercise-mimicking treatment (by electric pulse stimulation) and (c) cisplatin treatment on metabolism and mitochondrial function of differentiated human muscle cells in culture; To investigate the associations between intervention-induced shifts in circulating bioactive molecules and selected metabolic, anthropometric and motor parameters. The generated results will enable us (i) to gain a better insight into pathomechanisms of muscle-associated chemotherapy-induced late toxicity and the role of skeletal muscle & systemic mediators in the exercise-induced health benefits in TGCC survivors; and (ii) to validate the effectiveness of the individually-tailored exercise intervention in reducing chemotherapy-related toxicity in patients with TGCC, with the aim to transfer this knowledge into clinical practice.

TGCT, exercise intervention, Magnetic resonance spectroscopy, skeletal muscle, chemotherapy-induced metabolic toxicity

TGCT survivors, men, 25-55 yrs old, 3 and more years after successful treatment of TGCT, with the capacity to undergo aerobic-strength intervention assessed by cardiologist

TGCT survivors, men, 25-55 yrs old, 3 and more years after successful treatment of TGCT, with the capacity to undergo aerobic-strength intervention assessed by cardiologist

change in resting energy expenditure calculated by Weir equation from VO2 and metabolic substrate preference RQ VCO2/VO2 (as measured by indirect calorimetry)

BMI (kg.m-2) , fat mass (% electric bioimpedance), lean body mass (% electric bioimpedance), visceral adiposity (%, elecgtric bioimpedance)

Inclusion Criteria: TGCT survivors, with chemotherapy-induced metabolic toxicity, men, 25-55 years old, with the capacity to undergo training, signed written informed consent Exclusion Criteria: serious / uncontrolled chronic diseases, non-compliance, other health issues as assessed by oncologists / investigators