Less is more: how protein degradation regulates muscle development.

Abstract

The organization of sarcomeric structures during muscle development involves regulated multistep assembly pathways. The myosin assembly factor UNC-45 functions both as a molecular chaperone and as an Hsp90 co-chaperone for myosin throughout muscle thick-filament formation. Consequently, mutations in unc-45 result in paralyzed worms with severe myofibril disorganization in striated body wall muscles. Our data suggest that functional muscle formation in Caenorhabditis elegans is linked to ubiquitin-dependent UNC-45 turnover, regulated by the E3 enzymes UFD-2 and CHN-1 in cooperation with the ubiquitin-selective chaperone CDC-48 (also known as p97 in human). Missense mutations in the gene encoding p97 are known to cause a dominant, late-onset hereditary inclusion body myopathy. Remarkably, we identified a conserved role of CDC-48/p97 in the process of myofiber differentiation and maintenance, which appears to have important implications for understanding defects in muscle formation and maintenance during pathological conditions.