Characterization and investigation of zebrafish models of filamin-related myofibrillar myopathy.
Myofibrillar myopathies are a group of muscle disorders characterized by the disintegration of skeletal muscle fibers and formation of sarcomeric protein aggregates. All the proteins known to be involved in myofibrillar myopathies localize to a region of the sarcomere known as the Z-disk, the site at which defects are first observed. Given the common cellular phenotype observed in this group of disorders, it is thought that there is a common mechanism of pathology. Mutations in filamin C, which has several proposed roles in the development and function of skeletal muscle, can result in filamin-related myofibrillar myopathy. The lack of a suitable animal model system has limited investigation into the mechanism of pathology in this disease and the role of filamin C in muscle development. Here, we characterize stretched out (sot), a zebrafish filamin Cb mutant, together with targeted knockdown of zebrafish filamin Ca, revealing fiber dissolution and formation of protein aggregates strikingly similar to those seen in filamin-related myofibrillar myopathies. Through knockdown of both zebrafish filamin C homologues, we demonstrate that filamin C is not required for fiber specification and that fiber damage is a consequence of muscle activity. The remarkable similarities in the myopathology between our models and filamin-related myofibrillar myopathy makes them suitable for the study of these diseases and provides unique opportunities for the investigation of the function of filamin C in muscle and development of therapies.
School of Biological Sciences, Monash University, Melbourne 3800, Australia.
Avnika A
AA
Ruparelia
Mo
M
Zhao
Peter D
PD
Currie
Robert J
RJ
Bryson-Richardson
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D019521:Body Patterning / Q000235:genetics; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000378:metabolism / Q000473:pathology; D064448:Filamins; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D008040:Genetic Linkage; D006801:Humans; D016013:Likelihood Functions; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D009119:Muscle Contraction; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000196:embryology / Q000235:genetics*; D016296:Mutagenesis; D009218:Myosins / Q000378:metabolism; D010641:Phenotype; D010802:Phylogeny; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
D018389:Codon, Nonsense; D064448:Filamins; C577432:Flncb protein, zebrafish; D008840:Microfilament Proteins; D020033:Protein Isoforms; D029961:Zebrafish Proteins; D009218:Myosins