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

The effects of boosting mitochondrial biogenesis have been tested also in cancer and chemotherapy-
induced muscle wasting. In this condition, PGC-1α overexpression does not improve muscle mass, whereas
[21]
this effect is achieved by moderate exercise . This could suggest that enhancing mitochondrial biogenesis
is not sufficient to mimic the effects of exercise and that it does not necessarily reflect an increase of
[21]
mitochondrial function, both being affected in chemotherapy-treated tumor hosts .

The modulations triggered by exercise may be mimicked by pharmacological and dietary compounds [44,56] .
Some of them have been extensively studied, such as 5-aminoimidazole-4-carboxyamide ribonucleoside
(AICAR), glitazones, metformin and sirtuin 1 (SIRT1) activators, also reporting their effectiveness in
preventing cancer-induced muscle wasting [10,44] . Also erythropoietin (EPO), an endogenous cytokine
essential for the growth and differentiation of red blood progenitor cells, has shown some exercise-like
effects that go beyond the increase in oxygen delivery. Indeed, the EPO receptor (EpoR) is expressed
in different tissues other than hematopoietic cells, such as heart, skeletal muscle, adipose tissue, brain
[57]
and pancreas . In this regard, EPO stimulates SIRT1 signaling in human cardiomyocytes treated with
doxorubicin, increasing the levels of PGC-1α, nuclear respiratory factor 1 (NRF1), citrate synthase and
[58]
cytochrome c oxidase IV . EPO exposure of C2C12 myocyte cultures and primary skeletal myoblasts
in vitro results in increased mitochondrial mass, PGC-1α levels, citrate synthase activity and oxygen
[59]
consumption rate . Similarly, transgenic mice expressing high levels of EPO show increased proportion
of oxidative fibers and improved mitochondrial activity in the skeletal muscle, together with increased
[59]
PGC-1α and AMPK activation . Recombinant EPO administration to humans also results in increased
[60]
mitochondrial oxidative phosphorylation and electron transport capacity . Consistently, LLC-
bearing mice treated with EPO show increased SDH activity, ATP content and PGC-1α expression in
[35]
the skeletal muscle . These effects are enhanced by combining exercise training and EPO, protecting
the mitochondrial compartment and resulting in increased muscle strength as compared to untreated
[35]
sedentary cancer hosts .
Another modulator of muscle metabolism is trimetazidine (TMZ). The effects of TMZ are primarily
related to the ability to block β-oxidation, by inhibiting the 3-ketoacyl-CoA thiolase (3-KAT) activity in the
[61]
mitochondrial matrix . This inhibition results in a metabolic shift towards glucose oxidation, optimizing
oxygen utilization and decreasing lactate levels . TMZ is used to treat chronic stable angina and ischemic
[62]
[63]
cardiomyopathy , reducing symptoms and improving exercise performance [63,64] . The effects on patients
with cardiovascular diseases could be also related to the protection of the mitochondrial compartment. In
this regard, TMZ is able to correct the toxicity induced by palmitate in cultured cardiomyocytes, increasing
mitochondria mass, volume and function . Positive effects have been achieved by TMZ also on C2C12
[65]
myotubes exposed to TNF-α or to growth factor deprivation. Notably, TMZ induces the activation of
anabolic pathways and reduces the expression of atrogin-1 and MuRF1, protecting C2C12 myotubes from
[66]
[66]
atrophy . Of relevance, TMZ is also able to induce autophagy in vitro . Moving to in vivo models, TMZ
improves muscle strength of aged mice, coupled with a muscle metabolic shift towards oxidative metabolism,
[67]
suggested by increased levels of the slow myosin heavy chain (MyHC) isoform . Similarly to aged muscle,
TMZ induces exercise-like effects also in the skeletal muscle of tumor-bearing animals. In this regard,
TMZ administration partially protects C26-bearing mice from muscle atrophy (myofiber cross sectional
area) and dysfunction, increasing slow MyHC content, SDH-positive myofibers and markers associated
[68]
with mitochondrial mass and biogenesis . An increase in vascular endothelial cadherin (Ve-cadherin) and
vascular endothelial growth factor (VEGF) expression, two known markers of angiogenesis, has also been
[68]
detected in tumor-bearing mice after TMZ administration . Of relevance, TMZ seems to induce its effects
quickly in the skeletal muscle. Indeed, 15 min ex-vivo TMZ treatment of EDL muscle (mostly composed by
[68]
glycolytic fibers) is enough to reduce both contraction and relaxation rates , favoring the occurrence of a
phenotype typical of slow-twitch muscle .
[69]