Identification of pathways controlling muscle protein metabolism in uremia and other catabolic conditions

Purpose of review Major progress has been made in defining two key steps that mediate muscle protein degradation in kidney disease and other catabolic conditions. These advances are identified and discussed. Recent findings Activation of caspase-3 in muscle was discovered to be the initial step in breaking down the complex structure of myofibrils. Caspase-3 cleaves the complex structure, yielding substrate proteins and protein fragments that are degraded by the ubiquitin-proteasome system. Activation of caspase-3 occurs when insulin receptor substrate-1 associated phosphaticlylinositol 3 kinase activity is suppressed in different models of catabolic conditions. The E3 ubiquitin ligases, MAFbx (also called atrogin-1) and MuRF1, were previously shown to play an essential role in muscle wasting. Several reports show that the insulin receptor substrate-1-associated phosphaticlylincisitol 3 kinase/Akt pathway activates forkhead transcription factors to increase expression of MAFbx/atrogin-1 and MuRF1. This response induces muscle protein wasting. In addition, chronic activation of the transcription factor, nuclear factor-kappa B, induces muscle atrophy. Summary The insulin-like growth factor-1/insulin receptor substrate-1 -associated phosphaticlylinositol 3 kinase/Akt cellular signaling pathway coordinately regulates two proteolytic pathways, caspase-3 and the ubiquitin ligases MAFbx/ atrogin-1 and MuRF1 to control muscle protein degradation. These pathways represent therapeutic targets in diseases that cause muscle wasting.