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Page 2 of 9 Ballarò et al. J Cancer Metastasis Treat 2019;5:61 I http://dx.doi.org/10.20517/2394-4722.2019.003

INTRODUCTION
Cachexia is a metabolic disorder that occurs in different chronic diseases, including cancer, heart failure,
[1]
kidney disease, chronic obstructive pulmonary disease, sepsis and rheumatoid arthritis . The prevalence
[2]
of cachexia is particularly high in cancer patients, ranging from 50% to 80%, depending on tumor type .
Cancer cachexia is characterized by body weight loss, systemic inflammation and metabolic alterations.
The occurrence of this syndrome affects patient’s quality of life and increases both morbidity and
[3,4]
mortality due to cardiovascular complications, immune disorders and nutritional deficiency . Body
weight loss is mainly due to the consistent depletion of muscle and fat mass, that is frequently worsened
by chemotherapy toxicity . Humoral mediators and altered energy balance activate proteolysis in the
[5]
[6]
skeletal muscle of cancer hosts, ultimately leading to protein and organelle disposal . However, the specific
blockade of intracellular muscle proteolytic systems does not prove effective in counteracting cancer-
[7-9]
induced wasting , focusing the investigation to upstream pathways that regulate muscle metabolism
and energetics. In particular, several lines of evidence show that alterations of the energy metabolism and
[10]
mitochondrial impairments may contribute to the onset and progression of muscle wasting in cancer .
[1]
In this regard, cancer hosts are characterized by low nutrient intake and increased energy expenditure .
Whereas the former is induced by anorexia, dysphagia and/or altered absorption, due to chemotherapy
or to tumors with esophageal/gastrointestinal localization , the latter is enhanced by tumor metabolism,
[11]
[1]
inflammation and mitochondrial alterations . Notably, one of the first evidences of energy wasting in
cancer cachexia derive from studies on uncoupling proteins (UCPs), whose expression is increased in the
skeletal muscle and adipose tissue of tumor-bearing animals and cancer patients [12-15] . Along this line, a
time-course analysis in lewis lung carcinoma (LLC)-bearing mice has shown that mitochondrial ROS
emission, mitochondrial degradation and respiratory function are impaired prior to the loss of muscle
[16]
mass in the host mice and, interestingly, some of these alterations appear early after tumor implantation .
A proteomic profiling of both skeletal and cardiac muscles of C26-bearing mice, another syngeneic model
of cancer cachexia, has revealed an impaired expression of proteins involved in energy homeostasis and
[17]
mitochondrial function . Consistently, cachectic cancer patients show altered levels of proteins accepted
as markers of mitophagy, such as Parkin, PTEN-induced putative kinase 1 (PINK1) and BCL2/adenovirus
E1B 19 kDa protein-interacting protein 3 (BNIP3), and mitochondrial dynamics, such as mitofusin 2
(Mfn2) and mitochondrial fission 1 protein (Fis1) [18,19] . In addition, it is well established that anti-cancer
treatments alter mitochondrial homeostasis. In this regard, healthy mice treated with FOLFOX or FOLFIRI
(the combination of 5-fluorouracil and leucovorin with either oxaliplatin or irinotecan, respectively)
[20]
present with reduced mitochondrial mass and oxidative capacity in the skeletal muscle . Similar results
[21]
have been reported in C26-bearing mice treated with chemotherapy (oxaliplatin and 5-fluorouracil) ,
showing that anti-cancer treatment significantly increased the lifespan of C26-bearing mice but exacerbate
[21]
muscle wasting as compared to untreated C26 hosts . Such wasting effect has been associated with
reduced peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and cytochrome
c expression and with increased markers of mitophagy, together with impaired oxidative capacity and
[21]
ATP levels . Using a proteomic approach, alterations of the tricarboxylic acid (TCA) cycle and impaired
expression of markers of mitochondrial fusion, fission and biogenesis have been reported in both untreated
[22]
and chemotherapy-treated C26-bearing mice . A metabolic profiling performed in the same C26 hosts
exposed to chemotherapy shows that glycolysis and β-oxidation are also impaired .
[23]
Overall, since muscle metabolic phenotype in cancer hosts is severely impaired by both tumor growth and
chemotherapy, strategies targeting mitochondria and/or improving the oxidative capacity could usefully
integrate a multimodal therapy for cancer cachexia.

EXERCISE AS A MODULATOR OF MUSCLE METABOLISM
Physical activity is associated with several metabolic adaptations that particularly affect the skeletal
muscle . Depending on the type and frequency of exercise, different targets are preferentially regulated.
[24]