Prostate Cancer (PC) is the most frequent diagnosed malignancy in men in Europe and North America. The risk of PC increases with age, and the median age of onset is approximately 70 years. Treatment depends on stage, histology and the serum PSA level, beside the patients' general health and age. Radiotherapy combined with androgen deprivation therapy (ADT) is used in patients with locally advanced tumors and/or those with high Gleason scores, characterized as intermediate or high-risk profiles [1
]. ADT has potentially negative effects on several clinical outcomes, such as muscle atrophy [2
Physical exercise during and after cancer treatment has been shown to be effective to reduce several negative clinical consequences followed by cancer and cancer treatment [3
]. Compared to breast cancer patients relatively few studies in PC patients have been published [4
]. More evidence on the efficacy of strength training on clinical outcomes in PC patients is therefore desirable. At the same time more attention should be paid to the effect of ADT on the muscle cell level because the reduced testosterone levels influence the underlying regulators of muscle mass and muscle function. Furthermore, the effects of strength training on the same regulators are of particular interest during ADT, and as far as we know they have not previously been explored in PC patients.
Ageing is associated with a reduction in muscle mass, typically by 1-2% per decade from the age of 30 to the age of 50. Thereafter the rate of muscle loss increases progressively to 10% per decade [6
]. It is well known that decreased levels of serum testosterone are followed by reduced muscle mass [7
]. In PC patients treated with ADT for 6-12 months, lean body mass (LBM) has been reported to decrease by 3% [9
]. This reduction may affect muscle strength markedly because muscle mass is the dominant tissue in LBM.
Loss of bone mineral density (BMD) has been observed in PC patients on ADT [10
]. It has also been shown that ADT increases body weight and fat mass in these patients [9
]. Decreased levels of testosterone and body changes during ADT, may also influence mental health, fatigue and health-related quality of life (HRQOL) in PC patients [12
Total skeletal muscle mass reflects the size of all individual muscle groups in the body. Furthermore, the size of each muscle group is primarily determined by the size of the individual muscle fibers1
, and to a lesser extent by the number of fibers. Regulation of muscle fiber size is first and foremost driven by an increase in the number and size of myofibrils (contractile proteins) within the muscle fiber (Figure ). This process is normally supported by an increased number of satellite cells and (often) increased number of myonuclei (Figure ). Importantly, satellite cells seem to play a significant role in regulation of muscle fiber size. Satellite cells are mononuclear progenitor cells that are found between the sarcolemma and the basement membrane in the muscle fibers (Figure and Additional file 1
). Satellite cells are normally in a quiescent state, but are activated by adequate stimuli (e.g. strength training). Upon activation the satellite cells donate their nuclei to the existing muscle fibers and thus facilitate skeletal muscle hypertrophy by increasing the protein synthesis [14
]. During regeneration after muscle injury, satellite cells may also fuse and thereby form new mature muscle fibers [14
]. In addition, satellite cells seem to support muscle hypertrophy by production of local growth factors (e.g. IGF-1) [15
Figure 1 A schematic drawing of a muscle fiber (muscle cell) in longitudinal- and cross sectional plane. The muscle fiber is surrounded by two membranes, the plasma membrane (inner) and the basal lamina (outer). The satellite cells are located between these two (more ...)
In the muscle tissue, testosterone stimulates both the muscle protein synthesis in muscle fibers and activation of satellite cells through the interaction with the androgen receptor [16
]. Consequently, graded dosage of testosterone has been shown to both increase the muscle fiber size, reflected by increased muscle fiber cross sectional area, and number of satellite cells in a dose dependent pattern [17
]. Suppression of testosterone reduces the positive stimuli on muscle protein synthesis, and patients treated with ADT experience reduced LBM [19
]. Low levels of testosterone might also influence the regulation of muscle mass through its inhibition of the ubiquitin-proteasome system [21
]. Consequently, ADT might facilitate muscle atrophy both by inhibiting important pathways involved in muscle hypertrophy, as well as stimulating pathways involved in protein degradation.
Muscle strength is mainly determined by the size of muscles, but other qualities of muscles, such as endurance and stress tolerance, are more related to the content and function of stress proteins and proteins involved in the mitochondrial function [22
]. Interestingly, castration has been shown not only to reduce muscle fiber size, but also to affect the mitochondrial structure negatively in rat muscles [24
]. Furthermore, castration seems to reduce the stress induced up-regulation of stress proteins in heart muscle [25
]. Whether castration also affects the stress protein response and mitochondrial function in human skeletal muscles is currently not known.
Effects of strength training
Strength training has the potential to increase muscle mass and BMD in both young and elderly males and females [26
]. Although the response to strength training differs among individuals, most studies report an increase in muscle fibre cross sectional area by 10-60% over 9-30 weeks of training [30
]. Furthermore, an increase in BMD from 1 to 4% has been observed over 16-52 weeks of strength training [27
Effectiveness of exercise on clinical outcomes has been reported in numerous studies in cancer patients. Research has so far shown promising effects on among others muscle strength, aerobic fitness, fatigue, anxiety and quality of life [3
]. However, the effect of exercise during ADT in PC patients has been less studied [4
]. These studies have shown positive results in muscular and aerobic endurance, fatigue and QoL [5
]. Less promising is the effect of physical exercise on body-composition endpoints. It could therefore be hypothesized that ADT compromises some important cellular signals regulating the exercise induced increase in lean body mass with strength training.
The increase in muscle fiber size in response to strength training seems to be dependent, at least to some extent, on satellite cell activation in order to incorporate new myonuclei in the growing muscle fiber [14
]. In healthy subjects, strength training increases the number of myonuclei and the number of satellite cells in both young and elderly individuals [36
] (Figure ). The mechanisms behind the activation of satellite cells during strength training in humans are not fully understood, but changes in local growth factors and testosterone interactions seem to be important [38
]. Whereas reduced levels of testosterone during ADT negatively affect the regulation of muscle mass, strength training might counteract these detrimental effects on muscle fibres (Figure ). On the other hand, it might be that the very low testosterone levels, comparable with castration, blunt the effects of strength training in these patients. Interestingly, healthy young men treated with a GnRH analog over 12 weeks showed the same increase in mRNA of important local growth factors in response to strength training as placebo treated controls [39
]. Nevertheless, the accumulation of muscle mass during the strength training intervention was reduced in the testosterone-suppressed group compared to the placebo treated controls [40
Figure 2 Schematic muscular adaptations to strength training in healthy men and PC patients on ADT. Schematic muscular adaptations to strength training in healthy men (A), possible consequences of ADT on muscle fibers in PC patients (B), and possible muscular (more ...)
The effects of strength training on mitochondrial function and protection against cellular stress in muscle fibers are less studied than the effect on muscle size. Nevertheless, in previously untrained healthy men strength training has been observed to positively affect both mitochondrial proteins and stress proteins [41
]. Consequently, strength training has the potential to counteract several negative effects of ADT on muscle size and function.
To our knowledge no previous studies have investigated the effect of strength training on the regulation of muscle size and of muscular function on a cellular level in PC patients during ADT. Furthermore, previous clinical data need to be confirmed. Here, we present the design and methods of an ongoing trial called the Physical Exercise and Prostate Cancer (PEPC) trial, which aims to explore the effects of strength training on clinical outcomes as well as explore mechanisms of the effect on muscle cellular outcomes in patients with PC during ongoing (neo)-adjuvant ADT.
The overall aims of the PEPC trial are to evaluate the effectiveness of a high-load 16 week strength training program on a) clinical outcomes including serological parameters such as lipid profile (low and high density lipoprotein cholesterol) and low grade inflammation (C-reactive protein (CRP)) b) muscle cellular outcomes as muscle fiber size, regulators of muscle fiber size and regulators of muscle fiber function and c) feasibility of a high-load strength training program in PC patients who at intervention start have discontinued their high-dose radiotherapy and are on ongoing (neo)-adjuvant ADT throughout the intervention period.