Induction of muscle protein degradation by a tumour factor

Abstract

Summary An antigen of apparent molecular weight of 24000, reactive with a murine monoclonal antibody, has been isolated from a cachexia-inducing tumour (MAC 16) and has been shown to initiate muscle protein degradation in vitro using isolated soleus muscle. Administration of this material to female NMRI mice (20 g) produced a pronounced depression in body weight (2.72 ± 0.14 g; P<0.005 from control) over a 24 h period. This weight loss was attenuated in mice pretreated with the monoclonal antibody (0.06 + 0.26 g over 24 h) and occurred without a reduction in food and water intake. There was no change in body water composition, and the major contribution to the decrease in body weight was a decrease in the non-fat carcass dry weight (mainly lean body mass). The plasma levels of glucose and most amino acids were also significantly depressed. The decrease in lean body mass was accounted for by an increase (by 50%) in protein degradation and a decrease (by 50%) in protein synthesis in gastrocnemius muscle. Protein degradation was significantly decreased and protein synthesis increased to control values in mice pretreated with the monoclonal antibody. Protein degradation initiated in vitro with the proteolysis-inducing factor was abolished in mice pretreated with eicosapentaenoic acid (EPA), which had been shown to prevent muscle wastage in mice bearing the MAC16 tumour. Protein degradation was associated with a significant elevation of prostaglandin E2 production by isolated soleus muscle, which was inhibited by both the monoclonal antibody and EPA. These results suggest that this material may be the humoral factor mediating changes in skeletal muscle protein homeostasis during the process of cancer cachexia in animals bearing the MAC16 tumour, and could potentially be involved in other cases of cachexia.

Effect of a tumour-produced lipid-mobilizing factor on protein synthesis and degradation

“…This process has been attributed to tumour production of PIF, which inhibits protein synthesis and increases protein catabolism in skeletal muscle (Todorov et al, 1996;Lorite et al, 1997). However, the present study shows that LMF, also produced by cachexia-inducing tumours, appears to oppose the action of PIF by increasing protein synthesis and decreasing protein degradation in muscle.…”

“…Protein synthesis was determined by the incorporation of L-[4-3 H] phenylalanine into protein during a 2 h incubation, and the rate of protein synthesis was calculated by dividing the amount of protein bound radioactivity by the amount of acid soluble radioactivity. Protein catabolism was determined by the tyrosine release assay as described (Lorite et al, 1997). Tyrosine release from soleus muscles was determined during a 2 h incubation in Krebs-Henseleit buffer containing 6 mM D-glucose, 1.2 mg ml -1 bovine serum albumin and 130 µg ml -1 cycloheximide.…”

Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-κB activation

“…Muscle mass in cancer cachexia is strongly regulated by a tumour produced sulphated glycoprotein, proteolysis-inducing factor (PIF), which inhibits protein synthesis and stimulates protein degradation (Lorite et al, 1997). The effect on protein degradation is due to an increased gene and protein expression of the key components of the ubiquitin -proteasome proteolytic pathway (Lorite et al, 2001).…”

Angiotensin II directly induces muscle protein catabolism through the ubiquitin–proteasome proteolytic pathway and may play a role in cancer cachexia

“…In all cases, loss of fat-free mass involves only skeletal muscle and not visceral tissues, and is reflected in an increased morbidity and mortality. In cancer cachexia, the mechanism for the selective depletion of skeletal muscle is thought to involve tumour factors, such as proteolysisinducing factor (PIF), which inhibits protein synthesis and increases protein degradation in skeletal muscle, without affecting visceral protein reserves (Lorite et al, 1997). Studies in other wasting conditions suggest that other factors may be involved.…”