Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 4073 - 4083 |
| Number of pages | 11 |
| Journal | Human Molecular Genetics |
| Volume | 21 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - 2012 |
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Characterization and investigation of zebrafish models of filamin-related myofibrillar myopathy. / Ruparelia, Avnika; Zhao, Mo; Currie, Peter David; Bryson-Richardson, Robert James.
In: Human Molecular Genetics, Vol. 21, No. 18, 2012, p. 4073 - 4083.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Characterization and investigation of zebrafish models of filamin-related myofibrillar myopathy
AU - Ruparelia, Avnika
AU - Zhao, Mo
AU - Currie, Peter David
AU - Bryson-Richardson, Robert James
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
UR - http://hmg.oxfordjournals.org/content/21/18/4073.full.pdf+html
U2 - 10.1093/hmg/dds231
DO - 10.1093/hmg/dds231
M3 - Article
VL - 21
SP - 4073
EP - 4083
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 18
ER -