title: Severe protein aggregate myopathy in a knockout mouse model points to an essential role of cofilin2 in sarcomeric actin exchange and muscle maintenance.
abstract: Mutations in the human actin depolymerizing factor cofilin2 result in an autosomal dominant form of nemaline myopathy. Here, we report on the targeted ablation of murine cofilin2, which leads to a severe skeletal muscle specific phenotype within the first two weeks after birth. Apart from skeletal muscle, cofilin2 is also expressed in heart and CNS, however the pathology was restricted to skeletal muscle. The two close family members of cofilin2 - ADF and cofilin1 - were co-expressed in muscle, but unable to compensate for the loss of cofilin2. While primary myofibril assembly and muscle development were unaffected in cofilin2 mutant mice, progressive muscle degeneration was observed between postnatal days 3 and 7. Muscle pathology was characterized by sarcoplasmic protein aggregates, fiber size disproportion, mitochondrial abnormalities and internal nuclei. The observed muscle pathology differed from nemaline myopathy, but showed combined features of actin-associated myopathy and myofibrillar myopathy. In cofilin2 mutant mice, the postnatal expression pattern and turnover of sarcomeric α-actin isoforms were altered. Levels of smooth muscle α-actin were increased and remained high in developing muscles, suggesting that cofilin2 plays a crucial role during the exchange of α-actin isoforms during the early postnatal remodeling of the sarcomere.
authors.affiliation: University of Bonn, Institute of Genetics, Cell Migration Unit, Germany.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Gurniak
authors.affiliation: University of Erlangen, Institute of Neuropathology, Germany.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chevessier
authors.affiliation: University of Bonn, Institute of Genetics, Cell Migration Unit, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Jokwitz
authors.affiliation: Institut Pasteur, Département d'Immunologie, Laboratoire Anticorps en Thérapie et Pathologie, Inserm, U.760, 75015 Paris, France.
authors.forename: Friederike
authors.initials: F
authors.lastname: Jönsson
authors.affiliation: EMBL Monterotondo, Italy.
authors.forename: Emerald
authors.initials: E
authors.lastname: Perlas
authors.affiliation: University of Bonn, Institute of Cellular and Molecular Botany, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Richter
authors.affiliation: University of Bonn, Institute of Genetics, Cell Migration Unit, Germany.
authors.forename: Gabi
authors.initials: G
authors.lastname: Matern
authors.affiliation: University of Bonn, Institute of Genetics, Cell Migration Unit, Germany.
authors.forename: Pietro Pilo
authors.initials: PP
authors.lastname: Boyl
authors.affiliation: University of Geneva, Department of Pathology and Immunology, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Chaponnier
authors.affiliation: University of Bonn, Institute of Cell Biology, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Fürst
authors.affiliation: University of Erlangen, Institute of Neuropathology, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Schröder
authors.affiliation: University of Bonn, Institute of Genetics, Cell Migration Unit, Germany. Electronic address: w.witke@uni-bonn.de.
authors.forename: Walter
authors.initials: W
authors.lastname: Witke
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D051340:Cofilin 2 / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000235:genetics / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D009130:Muscle, Smooth / Q000254:growth & development / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D066329:Protein Aggregates / Q000235:genetics*; D012518:Sarcomeres / Q000378:metabolism*
chemical_list: D000199:Actins; C495816:Cfl2 protein, mouse; D051340:Cofilin 2; D066329:Protein Aggregates
keywords: Actin isoform exchange; Cofilin2; Muscle development; Protein aggregate myopathy; Sarcomere structure