Page 826 - Read Online

Ballarò et al. J Cancer Metastasis Treat 2019;5:61 I http://dx.doi.org/10.20517/2394-4722.2019.003 Page 3 of 9

Acute exercise leads to transient muscle molecular changes (e.g., temporary increase in specific mRNA
expression), whereas chronic exercise induces physiological adaptations that could modify muscle
[25]
phenotype . Regarding the differences in terms of exercise type, resistance training imposes a low-
repetition and high-intensity demand on the skeletal muscle, whereas endurance exercise does the
[26]
opposite , resulting in specific skeletal muscle adaptations. Thus, resistance training leads to the induction
of myofibrillar protein synthesis and increased anaerobic capacity, whereas endurance exercise sessions
mainly lead to improved mitochondrial density and function, oxygen delivery and uptake, anti-oxidant
[25]
defenses and resistance to fatigue . The beneficial effects of exercise have been tested in different chronic
conditions, including coronary heart disease, type 2 diabetes mellitus, obesity and aging [24,27] . Notably,
both exercise types exert beneficial effects in cachectic animals. Resistance training by ladder climbing
has been reported to relieve body weight loss, muscle wasting and inflammation in tumor-bearing rats [28,29]
[30]
and to increase the expression of factors associated with myogenesis in cachectic mice . In Apc +/Min
mice overexpressing IL-6, endurance exercise prevents body weight loss, improves insulin sensitivity,
increases mitochondrial biogenesis and muscle oxidative capacity and restores normal signaling through
Akt and 5’ AMP-activated protein kinase (AMPK) [31,32] . Endurance exercise by voluntary wheel running
is effective also in C26-bearing mice, reducing body weight loss, muscle wasting and the expression of
[33]
markers of autophagy and proteasome-dependent degradation . However, the combination of the two
types of exercise could result in better outcomes in cancer hosts. This was suggested by the results of an
exercise protocol in which the slope was increased in a mild intensity run protocol using a motorized
wheel. Indeed, this protocol mixed endurance exercise, due to the moderate and continuous training, to
the resistance exercise, resulting by the increased hill as compared to the flat treadmill run. Notably, C26
hosts performing this exercise protocol have shown improved muscle wasting and strength, together with
[34]
reduced autophagy and oxidative stress markers . On the contrary, endurance exercise with treadmill
[35]
in a flat mode does not succeed in improving cachexia in C26 hosts . The effect of exercise trough a
motorized wheel has also been tested in a model of cancer (C26 tumor) and chemotherapy-induced muscle
[21]
wasting, partially preventing the loss of muscle mass and strength . These improvements are associated
[21]
with a partial restoration of mitochondrial homeostasis . Notably, exercise increases mitochondrial
mass, normalizes the levels of PINK1, BNIP3 and Mfn2, improves the succinate dehydrogenase (SDH)
[21]
activity and increases energy stores . In a recent study, the resistance exercise component has been
further increased by combining the motorized wheel to the ladder climbing. This combined protocol
relieves muscle wasting in C26-bearing mice, reducing autophagy markers and increasing muscle oxidative
metabolism .
[36]
The effects of physical training in cancer patients may vary depending on tumor type, stage and exercise
modalities. A systematic review analyzing the effectiveness of aerobic exercise during chemotherapy
treatment in cancer patients, has shown beneficial effects in terms of both quality of life and muscle
[37]
function . In chemotherapy-treated breast cancer patients, exercise increases muscle fiber cross-sectional
area, citrate synthase activity, mitochondrial complex protein levels and muscle capillarization .
[38]
[39]
Supervised progressive resistance training increases muscle strength in pancreatic cancer hosts ;
[40]
similarly, it decreases fatigue and improves quality of life in head and neck cancer patients . Although
these encouraging data, exercise has some limitations in terms of feasibility and patient compliance. In this
regard, a study in a cohort of 196 cancer patients with established cachexia has shown a scarce adherence
[41]
to exercise programs, with low ability to perform either aerobic or resistance training . Along this line,
cancer patients with severe or refractory cachexia have a lack of interest in, or cannot cope with, exercise
[42]
or do not complete the initially planned program . In addition, exercise is not free of risks and may harm
cancer patients presenting with co-morbities (anemia or cardiac dysfunctions) or with excessive loss
[43]
of muscle mass and low energy availability. Depending on exercise type and duration, physical activity
may worsen body and muscle wasting also in cachectic animals. Notably, in C26-bearing mice 2-week-
[35]
long treadmill run exacerbates body and muscle wasting as compared to sedentary tumor bearers . In