Abstract 923: Flatline - A Novel Transcriptional Regulator Controls Myofibrillogenesis
Coordinate renewal of sarcomeric units is essential to all muscle tissue. However, gene programs that regulate cardiac and skeletal muscle myofibrillogenesis are only poorly understood, but of great clinical importance, since many cardiac and skeletal muscle diseases are associated with defective sarcomerogenesis. To define novel genetic components of muscle myofibrillogenesis we performed a forward genetic mutagenesis screen in zebrafish and isolated the recessive mutant flatline (fla), which displays disturbed heart and skeletal muscle function. Strikingly, thick and thin filament assembly is completely impaired in fla mutant heart and fast-type skeletal muscle tissue, whereas slow-type skeletal muscle fibres show normal myofibrillar arrays. By positional cloning, gene-knock-down and rescue experiments we show that the fla mutant phenotype is due to loss of mBop gene function. mBop, which we find to be restrictively expressed in heart and fast-type skeletal muscle cells, is a novel transcriptional co-factor with histone methyltransferase activity. Using micro-array cDNA expression analysis (zebrafish 14k chip), we find in heart and skeletal muscle tissue of fla mutants a group of RNAs encoding muscle-specific chaperone proteins severely up-regulated, implicating an essential function of mBop in regulating transcription of these factors. Furthermore, we find expression of thick and thin filament proteins almost completely absent in fla, whereas RNA levels for these proteins are unaltered, implicating that chaperone-mediated protein degradation might be the major molecular trigger for disturbed myofibrillo-genesis in fla. In conclusion, characterization of fla mutant zebrafish reveals for the first time an essential role of mBop in heart and skeletal muscle function. Our findings suggest a key-regulatory role of mBop in controlling expression of chaperones in muscle tissue, which are known factors essential for the assembly but also the targeted renewal of myofibrills. Accordingly, modulation of mBop transcriptional activity might be a novel therapeutic strategy to enforce muscle strength in heart failure and myopathies.