Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase

Eley, H., Russell, S.T. and Tisdale, M.J. (2007). Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase. British Journal of Cancer, 96 (8), pp. 1216-1222.

Abstract

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 2α 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-κB (NF-κB). 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. © 2007 Cancer Research UK.

Publication DOI: https://doi.org/10.1038/sj.bjc.6603704
Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences
Additional Information: © 2007 Cancer Research UK Creative Commons Attribution-NonCommercial-Share-Alike 3.0 licence, subject to the conditions listed at http://creativecommons.org/licences/by-nc-sa/3.0/
Uncontrolled Keywords: cancer cachexia,dsRNA-dependent protein kinase,inhibition,muscle protein degradation,muscle protein synthesis,Cancer Research,Oncology
Full Text Link: http://www.nature.com/bjc/journal/v96/n8/full/6603704a.html
Related URLs: http://www.scopus.com/inward/record.url?scp=34247236209&partnerID=8YFLogxK (Scopus URL)
Published Date: 2007-03-27
Authors: Eley, H.
Russell, S.T.
Tisdale, M.J.

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