Abstract
The development of striated muscle in vertebrates requires the assembly of contractile myofibrils, consisting of highly ordered bundles of protein filaments. Myofibril formation occurs by the stepwise addition of complex proteins, a process that is mediated by a variety of molecular chaperones and quality control factors. Most notably, myosin of the thick filament requires specialized chaperone activity during late myofibrillogenesis, including that of Hsp90 and its cofactor, Unc45b. Unc45b has been proposed to act exclusively as an adaptor molecule, stabilizing interactions between Hsp90 and myosin; however, recent discoveries in zebrafish and C. elegans suggest the possibility of an earlier role for Unc45b during myofibrillogenesis. This role may involve functional control of nonmuscle myosins during the earliest stages of myogenesis, when premyofibril scaffolds are first formed from dynamic cytoskeletal actin. This paper will outline several lines of evidence that converge to build a model for Unc45b activity during early myofibrillogenesis.
Highlights
The field of regenerative medicine represents the dawn of a transformative era, as embryonic stem cell treatments move into clinical trials after many years of laboratory research
The organization of sarcomeric protein complexes during early myoblast differentiation remains poorly understood, and many factors involved in the process have been identified, the specific order of events that leads from proliferating myoblasts to differentiated myotubes with mature myofibrils is not clear
Integrin-extracellular matrix (ECM) interactions and subsequent costamere formation are implicated as the initial steps in establishing the periodicity of regularly-spaced sarcomeres
Summary
The field of regenerative medicine represents the dawn of a transformative era, as embryonic stem cell treatments move into clinical trials after many years of laboratory research. The first successful surgeries involving complex, stem-cellderived muscular organs have recently been reported [1, 2], and these treatments are promising for the regeneration of muscle and connective tissue [3, 4]. Myogenesis must involve highly specific and regulated steps of protein folding and assembly, involving both general and myocyte-specific molecular chaperones, cochaperones, scaffolds, and intermediate structures This is coupled with dynamic turnover of proteins through proteasome-mediated degradation, resulting in a system of development and repair that allows complex assembly without protein aggregation. Over the past two decades, several models have been proposed of the earliest stages of myofibrillogenesis, focused on the stepwise nucleation and incorporation of sarcomere components, beginning with stress-fiber-like structures in differentiating myoblasts
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