Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways.

Rafael Barreto,Francesco Novelli,Teresa A Zimmers,Frank A Witzmann,Andrea Bonetto,Giorgia Mandili

doi:10.3389/fphys.2016.00472

Abstract

Cachexia represents one of the primary complications of colorectal cancer due to its effects on depletion of muscle and fat. Evidence suggests that chemotherapeutic regimens, such as Folfiri, contribute to cachexia-related symptoms. The purpose of the present study was to investigate the cachexia signature in different conditions associated with severe muscle wasting, namely Colon-26 (C26) and Folfiri-associated cachexia. Using a quantitative LC-MS/MS approach, we identified significant changes in 386 proteins in the quadriceps muscle of Folfiri-treated mice, and 269 proteins differentially expressed in the C26 hosts (p < 0.05; −1.5 ≥ fold change ≥ +1.5). Comparative analysis isolated 240 proteins that were modulated in common, with a large majority (218) that were down-regulated in both experimental settings. Interestingly, metabolic (47.08%) and structural (21.25%) proteins were the most represented. Pathway analysis revealed mitochondrial dysfunctions in both experimental conditions, also consistent with reduced expression of mediators of mitochondrial fusion (OPA-1, mitofusin-2), fission (DRP-1) and biogenesis (Cytochrome C, PGC-1α). Alterations of oxidative phosphorylation within the TCA cycle, fatty acid metabolism, and Ca2+ signaling were also detected. Overall, the proteomic signature in the presence of both chemotherapy and cancer suggests the activation of mechanisms associated with movement disorders, necrosis, muscle cell death, muscle weakness and muscle damage. Conversely, this is consistent with the inhibition of pathways that regulate nucleotide and fatty acid metabolism, synthesis of ATP, muscle and heart function, as well as ROS scavenging. Interestingly, strong up-regulation of pro-inflammatory acute-phase proteins and a more coordinated modulation of mitochondrial and lipidic metabolisms were observed in the muscle of the C26 hosts that were different from the Folfiri-treated animals. In conclusion, our results suggest that both cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. These data support the undertaking of combination strategies that aim to both counteract tumor growth and reduce chemotherapy side effects.

Highlights

According to the American Cancer Society, colorectal cancer represents the third leading cause of cancer-related deaths in the United States (American Cancer Society, 2015)
We recently reported that Folfox and Folfiri, which are chemotherapeutics utilized for the treatment of solid tumors, may contribute to the development of cachexia and muscle weakness by promoting oxidative stress-associated mitogen-activated protein kinase (MAPK) activation and by affecting the muscle mitochondrial
In order to limit the variability across the different animal models, both tumor hosts and animals treated with chemotherapy were sacrificed when muscle loss was comparable and resembling a condition of severe cachexia, as previously shown (Bonetto et al, 2011)

Summary

Introduction

According to the American Cancer Society, colorectal cancer represents the third leading cause of cancer-related deaths in the United States (American Cancer Society, 2015). Colorectal cancer therapy frequently includes treatment with 5-fluorouracil (5-FU), Leucovorin (LV) and CPT-11, a combination known as Folfiri. Among the several side effects frequently associated with the administration of Folfiri, increased fatigue represents one of the most common (Montagnani et al, 2011). A major contributor of colorectal cancer morbidity and mortality, cachexia is primarily responsible for body and muscle weight loss and correlates with tumor burden, increased pro-inflammatory cytokine levels, fatigue, and reduced response to chemo- and radio-therapy (Ravasco et al, 2007; Bapuji and Sawatzky, 2010; Fearon et al, 2012). We reported that blocking muscle wasting can prolong life even in the absence of effects on tumor growth (Benny Klimek et al, 2010). Targeting cachexia per se could improve outcomes and enhance tumor-free survival

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