Abstract
Patients with cancer cachexia (CCX) suffer from muscle wasting, which is often but not always accompanied by selective loss of myosin. Here we examined the effects of CCX on muscle mass and myosin heavy chain (MyHC) expression in denervated (DEN) muscles, especially focusing on the protein synthesis and degradation pathways. Male CD2F1 mice were randomly divided into control (CNT) and CCX groups and their left sciatic nerve was transected. CCX was induced by an intraperitoneal injection of colon 26 cells. After 14 days, the serum concentration of IL-6 and corticosteroid was higher in CCX mice than in CNT mice. The combination of CCX with DEN (CCX + DEN) resulted in a marked reduction of the gastrocnemius muscle weight (−69%) that was significantly lower than DEN (−53%) or CCX (−36%) alone. CCX had no effect on MyHC content, but it elicited a preferential MyHC loss when combined with DEN. The expression levels of autophagy markers cathepsin D and LC3BII/I ratio were markedly higher in the CCX + DEN group than in the CNT + DEN and the CCX groups. Paradoxically, there was an increase in protein synthesis rate and phosphorylation levels of p70S6K and rpS6, markers of mTORC1 signaling, in the CNT + DEN group, and these molecular alterations were inhibited in the CCX + DEN group. Our data indicate that CCX aggravates muscle atrophy in DEN muscles by inducing seletive loss of myosin, which involves inactivity dependent mechanisms that is likely to be a consequence of increased autophagy-mediated protein breakdown coupled with impaired protein synthesis.
Highlights
Cancer cachexia (CCX) is a multifactorial syndrome characterized by decreased skeletal muscle and adipose tissue mass (Tisdale, 2002)
Similar results were obtained in DEN muscles; the weight for the Gas, plantaris, and soleus muscles was reduced by 46, 44, and 39% in the CNT + DEN group compared to the CNT group, respectively (P < 0.05)
The weight for the Gas, plantaris, and soleus muscle in the CCX + DEN group was decreased by 69, 64, and 69% compared to the CNT group, respectively (P < 0.05), and was significantly lower than that of the CNT + DEN and the CCX groups (P < 0.05), indicating that the impacts of combined cachexia and inactivity on the regulation of muscle mass are additive
Summary
Cancer cachexia (CCX) is a multifactorial syndrome characterized by decreased skeletal muscle and adipose tissue mass (Tisdale, 2002). CCX is profound in patients with gastrointestinal, lung, and pancreatic cancers, with about one-thirds of patients losing more than 5% of their baseline body weight (Dewys et al, 1980). This affects quality of life of the patients due to muscle weakness and fatigue and has been associated with increased susceptibility to chemotherapy toxicity (Andreyev et al, 1998). Myosin Loss in Denervation With Cachexia understanding the cellular mechanisms behind the loss of muscle mass during CCX is highly significant from a clinical point of view
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