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Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member

Journal article
Authors Martin Dahl-Halvarsson
M. Olive
Malgorzata Pokrzywa
K. Ejeskar
Ruth H. Palmer
Anne Uv
H. Tajsharghi
Published in Proceedings of the National Academy of Sciences of the United States of America
Volume 115
Issue 28
Pages E6566-E6575
ISSN 0027-8424
Publication year 2018
Published at Institute of Biomedicine, Department of Pathology
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages E6566-E6575
Language en
Keywords myosin myopathy, Laing distal myopathy, myosin, Drosophila, Abba/Thin, skeletal-muscle atrophy, heavy-chain gene, distal myopathy, storage, myopathy, mutations, myh7, cardiomyopathy, expression, melanogaster, stability, Science & Technology - Other Topics, hiaffino s, 1994, journal of applied physiology, v77, p493
Subject categories Pathology


Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in MYH7 encoding slow/beta-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the alpha-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.

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Utskriftsdatum: 2019-10-18