Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase
| Autor: | Steven T. Russell, Helen L. Eley, Michael J. Tisdale |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Cachexia Protein degradation Biology Mice eIF-2 Kinase Atrophy muscle protein degradation Internal medicine Myosin medicine Animals Phosphorylation Protein kinase A Protein Kinase Inhibitors NF-kappa B Proteins Skeletal muscle DNA medicine.disease dsRNA-dependent protein kinase Protein kinase R inhibition Muscle atrophy Muscular Atrophy Endocrinology medicine.anatomical_structure Oncology medicine.symptom Translational Therapeutics muscle protein synthesis cancer cachexia |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| DOI: | 10.1038/sj.bjc.6603704 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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