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Page 6 of 9 Ballarò et al. J Cancer Metastasis Treat 2019;5:61 I http://dx.doi.org/10.20517/2394-4722.2019.003

Figure 2. Exercise-like responses in the skeletal muscle may be induced by drugs acting on PGC-1α expression and activity. Exercise
modulates different pathways involved in the regulation of protein homeostasis and energy metabolism. During exercise, PGC-1α
activation increased mitochondrial biogenesis, favoring oxidative capacity, and inhibits FoxO3, reducing proteasome-dependent
degradation. Similarly to exercise, EPO and TMZ are able to activate energy sensors, such as AMPK and SIRT1, that induce PGC-1α
and its downstream targets

Exercise is also able to activate myogenesis, impinging on satellite cells (SCs) proliferation and
[70]
differentiation . Accordingly, TMZ treatment modulates the behavior of differentiating murine myoblast,
[71]
increasing fusion capacity, markers of myogenesis and MyHC levels . These effects are associated with
increased expression of metabolic regulators such as PGC-1α and activated AMPK, suggesting an increase
[71]
in oxidative metabolism . Similar results have been obtained in isolated murine SCs, in which TMZ
[71]
increases some markers of differentiation as compared to control . Myogenesis is impaired in cachectic
animals and cancer patients, likely contributing to muscle wasting [72,73] . In this regard, the effect of TMZ
on myogenesis markers has been tested on C26-bearing mice, showing increased levels of MyoD and
[71]
Myogenin . Such results suggest that TMZ could potentially protect against myogenesis impairments.

CONCLUSION
The research on the etiopathogenesis of cancer cachexia has unraveled different metabolic alterations
that lead to the wasting phenotype of cancer patients. Exercise training is one of the best approaches
able to correct the metabolic impairments of tumor hosts, such as inflammation, hypercatabolism and
energy deficit. However, being the skeletal muscle severely affected in cancer cachexia, often the physical
(and psychological) state of cancer patients is not permissive for practicing exercise. Also due to these
reasons the search for pharmacological strategies able to modulate exercise-induced pathways is rapidly
growing. In this regard, exercise beneficial effects in cancer cachexia could depend, partially at least, on
the expression of PGC-1α. Consistently, drugs able to enhance the expression of this co-transcription factor,
together with strategies that increase mitochondrial function, could be effective in improving muscle wasting
[Figure 2]. However, beyond the alterations of the mitochondrial homeostasis, muscle depletion relies also
on inflammation, activation of catabolic pathways and, frequently, depression of protein synthesis. Along
this line, a combinatorial therapy targeting each of these alterations could be the best choice to counteract
cancer-induced muscle wasting.