Is there a common mechanism linking muscle wasting in various disease types?
OBJECTIVE
There have been a number of recent developments in our understanding of the cellular mechanisms leading to muscle atrophy, which are likely to be of major importance in the design of therapeutic agents.


RESULTS
Muscle atrophy in a range of conditions is thought to be due to an increased expression of the ubiquitin-proteasome proteolytic pathway. The main transcription factors involved in muscle atrophy are nuclear factor-kappaB and the forkhead type transcription factors, as determined from experiments with transgenic mice. Catabolic agents such as cytokines, proteolysis-inducing factor and angiotensin II induce activation of nuclear factor-kappaB through an increase in reactive oxygen species, causing an increased gene expression of proteasome subunits and the ubiquitin ligase MuRF1. Glucocorticoids cause activation of forkhead type transcription factors possibly through an increase in expression of myostatin, which leads to an increased expression of the E3 ligase atrogin-1/MAFbx and cathepsin L. Forkhead type transcription factors is regulated by its state of phosphorylation induced by Akt, while activation of nuclear factor-kappaB requires reactive oxygen species and activation of the dsRNA-dependent protein kinase. Activation of dsRNA-dependent protein kinase also inhibits translational initiation of protein synthesis through phosphorylation of eukaryotic initiation factor 2 on the alpha-subunit.


CONCLUSIONS
These results suggest a common mechanism leading to muscle atrophy, which has important implications in the clinical treatment of wasting diseases.
Tisdale
Michael J
MJ
D000818:Animals; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex