Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase.
Atrophy of skeletal muscle is due to a depression in protein synthesis and an increase in degradation. Studies in vitro have suggested that activation of the dsRNA-dependent protein kinase (PKR) may be responsible for these changes in protein synthesis and degradation. In order to evaluate whether this is also applicable to cancer cachexia the action of a PKR inhibitor on the development of cachexia has been studied in mice bearing the MAC16 tumour. Treatment of animals with the PKR inhibitor (5 mg kg(-1)) significantly reduced levels of phospho-PKR in muscle down to that found in non-tumour-bearing mice, and effectively attenuated the depression of body weight, with increased muscle mass, and also inhibited tumour growth. There was an increase in protein synthesis in skeletal muscle, which paralleled a decrease in eukaryotic initiation factor 2alpha phosphorylation. Protein degradation rates in skeletal muscle were also significantly decreased, as was proteasome activity levels and expression. Myosin levels were increased up to values found in non-tumour-bearing animals. Proteasome expression correlated with a decreased nuclear accumulation of nuclear factor-kappaB (NF-kappaB). The PKR inhibitor also significantly inhibited tumour growth, although this appeared to be a separate event from the effect on muscle wasting. These results suggest that inhibition of the autophosphorylation of PKR may represent an appropriate target for the attenuation of muscle atrophy in cancer cachexia.
Eley
H L
HL
Nutritional Biomedicine, School of Life and Health Sciences, Aston University Biomedical Science, Birmingham B4 7ET, UK.
Russell
S T
ST
Tisdale
M J
MJ
D000818:Animals; D002100:Cachexia / Q000188:drug therapy*; D004247:DNA / Q000378:metabolism; D008297:Male; D051379:Mice; D009133:Muscular Atrophy / Q000188:drug therapy*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011506:Proteins / Q000378:metabolism; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011506:Proteins; D004247:DNA; D019892:eIF-2 Kinase