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Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member
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Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member
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Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member
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Journal Article
Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member
2018
Overview
Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in MYH7 encoding slow/β-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the α-helical rod domain of MYH7 are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative MYH7 mutation (K1729del), we have developed a Drosophila melanogaster model of Laing distal myopathy by genomic engineering of the Drosophila Mhc locus. Homozygous MhcK1728del
animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only MhcK1728del
in indirect flight and jump muscles, and heterozygous MhcK1728del
animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of MhcK1728del
mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous MhcK1728del
larvae also demonstrated structural and functional impairments in heart muscle, which were not observed in heterozygous animals, indicating a dose-dependent effect of the mutated allele. The impaired jump and flight ability and the myopathy of indirect flight and leg muscles associated with MhcK1728del
were fully suppressed by expression of Abba/Thin, an E3-ligase that is essential for maintaining sarcomere integrity. This model of Laing distal myopathy in Drosophila recapitulates certain morphological phenotypic features seen in Laing distal myopathy patients with the recurrent K1729del mutation. Our observations that Abba/Thin modulates these phenotypes suggest that manipulation of Abba/Thin activity levels may be beneficial in Laing distal myopathy.
Publisher
National Academy of Sciences
Subject
/ Animals
/ Distal Myopathies - genetics
/ Distal Myopathies - metabolism
/ Distal Myopathies - pathology
/ Drosophila Proteins - genetics
/ Drosophila Proteins - metabolism
/ Flight
/ Heart
/ Humans
/ Insects
/ journal of applied physiology
/ Larvae
/ Muscles
/ Mutation
/ myh7
/ Myopathy
/ Myosin
/ Myosin Heavy Chains - genetics
/ Myosin Heavy Chains - metabolism
/ p493
/ Proteins
/ Science & Technology - Other Topics
/ storage
/ Structure-function relationships
/ Tripartite Motif Proteins - biosynthesis
/ Tripartite Motif Proteins - genetics
/ v77
