Cancer cachexia is a frequently neglected debilitating syndrome that, beyond representing a primary cause of death and cancer therapy failure, negatively impacts on patients’ quality of life. Given the complexity of its multisystemic pathogenesis, affecting several organs beyond the skeletal muscle, defining an effective therapeutic approach has failed so far. Revamped attention of the scientific community working on cancer cachexia has focused on mitochondrial alterations occurring in the skeletal muscle as potential triggers of the complex metabolic derangements, eventually leading to hypercatabolism and tissue wasting. Mitochondrial dysfunction may be simplistically viewed as a cause of energy failure, thus inducing protein catabolism as a compensatory mechanism; however, other peculiar cachexia features may depend on mitochondria. On the one side, chemotherapy also impacts on muscle mitochondrial function while, on the other side, muscle-impaired regeneration may result from insufficient energy production from damaged mitochondria. Boosting mitochondrial function could thus improve the energetic status and chemotherapy tolerance, and relieve the myogenic process in cancer cachexia. In the present work, a focused review of the available literature on mitochondrial dysfunction in cancer cachexia is presented along with preliminary data dissecting the potential role of stimulating mitochondrial biogenesis via PGC-1α overexpression in distinct aspects of cancer-induced muscle wasting.

Cachexia is a debilitating syndrome that complicates the management of cancer patients. Muscle wasting, one of the main features of cachexia, is associated with hyper-activation of protein degradative pathways and altered mitochondrial function that could both result from impaired redox homeostasis. This study aimed to investigate the contribution of oxidative stress to cancer-induced cachexia in the presence or in the absence of moderate exercise training. Mice bearing the colon C26 carcinoma, either sedentary or exercised, were used. The former showed muscle wasting and redox imbalance, with the activation of an antioxidant response and with upregulation of markers of proteasome-dependent protein degradation and autophagy. Moderate exercise was able to relieve muscle wasting and prevented the loss of muscle strength; such a pattern was associated with reduced levels of Reactive Oxygen Species (ROS), carbonylated proteins and markers of autophagy and with improved antioxidant capacity. The muscle of sedentary tumor hosts also showed increased levels of molecular markers of mitophagy and reduced mitochondrial mass. Conversely, exercise in the C26 hosts led to increased mitochondrial mass. In conclusion, moderate exercise could be an effective non-pharmacological approach to prevent muscle wasting in cancer patients, decreasing muscle protein catabolism and oxidative stress and preserving mitochondria.

Objective: Cachexia is a complex metabolic syndrome frequently occurring in cancer patients and exacerbated by chemotherapy. In skeletal muscle of cancer hosts, reduced oxidative capacity and low intracellular ATP resulting from abnormal mitochondrial function were described. Methods: The present study aimed at evaluating the ability of the mitochondria-targeted compound SS-31 to counteract muscle wasting and altered metabolism in C26-bearing (C26) mice either receiving chemotherapy (OXFU: oxaliplatin plus 5-fluorouracil) or not. Results: Mitochondrial dysfunction in C26-bearing (C26) mice associated with alterations of cardiolipin fatty acid chains. Selectively targeting cardiolipin with SS-31 partially counteracted body wasting and prevented the reduction of glycolytic myofiber area. SS-31 prompted muscle mitochondrial succinate dehydrogenase (SDH) activity and rescued intracellular ATP levels, although it was unable to counteract mitochondrial protein loss. Progressively increased dosing of SS-31 to C26 OXFU mice showed transient (21 days) beneficial effects on body and muscle weight loss before the onset of a refractory end-stage condition (28 days). At day 21, SS-31 prevented mitochondrial loss and abnormal autophagy/mitophagy. Skeletal muscle, liver and plasma metabolomes were analyzed, showing marked energy and protein metabolism alterations in tumor hosts. SS-31 partially modulated skeletal muscle and liver metabolome, likely reflecting an improved systemic energy homeostasis. Conclusions: The results suggest that targeting mitochondrial function may be as important as targeting protein anabolism/catabolism for the prevention of cancer cachexia. With this in mind, prospective multi-modal therapies including SS-31 are warranted.

Advanced colorectal cancer (CRC) is often accompanied by development of liver metastases (LMs) and skeletal muscle wasting (i.e., cachexia). Despite plaguing the majority of CRC patients, cachexia remains unresolved. By using mice injected with Colon-26 mouse tumors, either subcutaneously (s.c.; C26) or intrasplenically to mimic hepatic dissemination of cancer cells (mC26), here we aimed to further characterize functional, molecular, and metabolic effects on skeletal muscle and examine whether LMs exacerbate CRC-induced cachexia. C26-derived LMs were associated with progressive loss of body weight, as well as with significant reductions in skeletal muscle size and strength, in line with reduced phosphorylation of markers of protein anabolism and enhanced protein catabolism. mC26 hosts showed prevalence of fibers with glycolytic metabolism and enhanced lipid accumulation, consistent with abnormalities of mitochondrial homeostasis and energy metabolism. In a comparison with mice bearing s.c. C26, cachexia appeared exacerbated in the mC26 hosts, as also supported by differentially expressed pathways within skeletal muscle. Overall, our model recapitulates the cachectic phenotype of metastatic CRC and reveals that formation of LMs resulting from CRC exacerbate cancer-induced skeletal muscle wasting by promoting differential gene expression signatures.

Colorectal cancer (CRC) is a leading cause of cancer-related death, and the prevalence of CRC in young adults is on the rise, making this a largescale clinical concern. Advanced CRC patients often present with liver metastases (LM) and an increased incidence of cachexia, i.e., musculoskeletal wasting. Despite its high incidence in CRC patients, cachexia remains an unresolved issue, and animal models for the study of CRC cachexia, in particular, metastatic CRC cachexia, remain limited; therefore, we aimed to establish a new model of metastatic CRC cachexia. C57BL/6 male mice (8 weeks old) were subcutaneously (MC38) or intrasplenically injected (mMC38) with MC38 murine CRC cells to disseminate LM, while experimental controls received saline (n = 5–8/group). The growth of subcutaneous MC38 tumors was accompanied by a reduction in skeletal muscle mass (−16%; quadriceps muscle), plantarflexion force (−22%) and extensor digitorum longus (EDL) contractility (−20%) compared to experimental controls. Meanwhile, the formation of MC38 LM (mMC38) led to heighted reductions in skeletal muscle mass (−30%; quadriceps), plantarflexion force (−28%) and EDL contractility (−35%) compared to sham-operated controls, suggesting exacerbated cachexia associated with LM. Moreover, both MC38 and mMC38 tumor hosts demonstrated a marked loss of bone indicated by reductions in trabecular (Tb.BV/TV: −49% in MC38, and −46% in mMC38) and cortical (C.BV/TV: −12% in MC38, and −8% in mMC38) bone. Cell culture experiments revealed that MC38 tumor-derived factors directly promote myotube wasting (−18%) and STAT3 phosphorylation (+5-fold), while the pharmacologic blockade of STAT3 signaling was sufficient to preserve myotube atrophy in the presence of MC38 cells (+21%). Overall, these results reinforce the notion that the formation of LM heightens cachexia in an experimental model of CRC.

Background: SerpinB3 (SB3) is a hypoxia and hypoxia-inducible factor (HIF)-2α-dependent cysteine-protease inhibitor up-regulated in hepatocellular carcinoma (HCC), released by cancer cells and able to stimulate proliferation and epithelial-to-mesenchymal-transition. Methods: In the study we employed transgenic and knock out SerpinB3 mice, liver cancer cell line, human HCC specimens, and mice receiving diethyl-nitrosamine (DEN) administration plus choline-deficient L-amino acid refined (CDAA) diet (DEN/CDAA protocol). Results: We provide detailed and mechanistic evidence that SB3 can act as a paracrine mediator able to affect the behavior of surrounding cells by differentially up-regulating, in normoxic conditions, HIF-1α and HIF-2α. SB3 acts by (i) up-regulating HIF-1α transcription, facilitating cell survival in a harsh microenvironment and promoting angiogenesis, (ii) increasing HIF-2α stabilization via direct/selective NEDDylation, promoting proliferation of liver cancer cells, and favoring HCC progression. Moreover (iii) the highest levels of NEDD8-E1 activating enzyme (NAE1) mRNA were detected in a subclass of HCC patients expressing the highest levels of HIF-2α transcripts; (iv) mice undergoing DEN/CDAA carcinogenic protocol showed a positive correlation between SB3 and HIF-2α transcripts with the highest levels of NAE1 mRNA detected in nodules expressing the highest levels of HIF-2α transcripts. Conclusions: These data outline either HIF-2α and NEDDylation as two novel putative therapeutic targets to interfere with the procarcinogenic role of SerpinB3 in the development of HCC.