Enhancing circulatory myokines and extracellular vesicle uptake with targeted exercise in patients with prostate cancer (the MYEX trial): a single-group crossover study

Abstract

Introduction: Physical activity is associated with improved disease progression and cancer-specific survival in patients with prostate cancer (PCa). However, the mechanisms underlying these associations remain unclear, while the relative impact of exercise modes is unknown. This study aims to examine the differential impact of exercise mode on tumour-suppressive skeletal muscle-associated systemic molecules as well as their delivery mechanism. This study will compare the effects of the two main exercise modes, aerobic and resistance, on (1) circulatory myokine levels, (2) skeletal muscle-induced extracellular vesicle abundance and cargo contents, and (3) uptake of extracellular vesicles (EVs) in PCa cells in patients with localised or advanced PCa.

Methods: A single-group cross-over design will be used for patients at opposite ends of the disease spectrum. A total of 32 patients (localised PCa, n = 16; metastatic castrate-resistant PCa, n = 16) will be recruited while capitalising on two ongoing studies. Ethics amendment has been approved for two ongoing trials to share data, implement the acute exercise sessions, and collect additional blood samples from patients. The patients will undertake two exercise sessions (aerobic only and resistance only) in random order one week apart. Blood will be collected before, after, and 30 min post-exercise. Circulating/EV-contained myokine levels (irisin, IL-6, IL-15, FGF-21, and SPARC) and plasma skeletal muscle-induced EVs will be measured using ELISA and flow cytometry. PCa cell line growth with or without collected plasma will be examined using PCa cell lines (LNCaP, DU-145, and PC-3), while evaluating cellular uptake of EVs. Ethics amendments have been approved for two capitalising studies to share data, implement acute exercise sessions and collect additional samples from the patients.

Discussion: If findings show a differential impact of exercise mode on the establishment of an anti-cancer systemic environment, this will provide fundamental knowledge for developing targeted exercise prescriptions for patients with PCa across different disease stages. Findings will be reported in peer-reviewed publications and scientific conferences, in addition to working with national support groups to translate findings for the broader community.

Trial registration: The registration for the two capitalising studies are NCT02730338 and ACTRN12618000225213.

Keywords: Exercise; Extracellular vesicles; Myokines; Prostate cancer.

Fig. 1

Effect of exercise on extracellular vesicles. Reprinted with permission from Zhang et al. ¹² Exercise may increase the secretion of extracellular vesicles into the circulatory system and alter the concentration of proteins and microRNAs (miRNAs) in skeletal muscle-derived extracellular vesicles. MicroRNAs in skeletal muscle-derived extracellular vesicles may induce epigenetic regulation in prostate cancer cells and reduce cell progression, transformation, and invasion. In addition, skeletal muscle-derived extracellular vesicles containing proteins, including myokines, have a direct tumour-suppressive effect

Fig. 2

Study design

Fig. 3

Exercise protocol Aerobic high-intensity interval exercise and resistance exercise will be performed in random order 1 week apart. Aerobic high-intensity interval exercise consists of 6 × 4-minute bouts of cycling at 70 ~ 85% of age-predicted maximum heart rate (RPE 6 ~ 8) with 2 min of low-intensity active recovery (RPE 3 ~ 4) between bouts, preceded by a 5-minute aerobic warm-up and concluding with a 5-minute cool-down. Resistance exercise consists of 6 different exercises involving the major muscle groups (bench press, lat pull down, seated row, knee extension, deadlift, and leg press). For each exercise, 1 set at ~ 15 repetition maximum (RM) will be undertaken as a warm-up, followed by 3 sets at 8–10 RM. Resistance exercise will not be performed to neuromuscular failure, but sets will cease with 1–2 repetitions in reserve