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 phosphatidylinositol 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 phosphatidylinositol 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-kappaB, induces muscle atrophy.
Summary: The insulin-like growth factor-1/insulin receptor substrate-1-associated phosphatidylinositol 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.