In vitro and in vivo models for studying muscle differentiation and regeneration: unravelling the role of the ubiquitin-ligase Ozz-E3 and its substrates

Ozz is the substrate-binding component of a RING-type ubiquitin ligase complex, which comprises Elongin B/C, Rbx1 and Cullin 5 (Nastasi et al., 2004). Ozz expression is muscle-specific and upregulated during muscle fiber differentiation, but downregulated in muscle atrophy. Ozz null-mutants exhibit defects in myofibrillogenesis and muscle fiber differentiation. The role of Ozz toward the membrane-associated pool of ß-catenin has been well characterized (Nastasi et al., 2004). Our recent results demonstrated that Ozz binding to the embryonic isoform of the myosin heavy chain, within muscle sarcomeres, marks it for disassembly and proteolytic degradation. This event facilitates the exchange of adult for embryonic isoforms during muscle maturation. The multifunctional adaptor protein ALG-2 interacting protein X or 1 (ALIX/AIP1) is an additional Ozz-E3 substrate, and plays an active role in the regulation of actin filament dynamic and cell migration in differentiating muscle cells.