Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness
| Autor: | Girish C. Melkani, Yang Wang, Anju Melkani, Sanford I. Bernstein, William A. Kronert, Anthony Cammarato, Jennifer A. Suggs |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Myofilament Contracture Molecular Sequence Data macromolecular substances Biology Protein Structure Secondary Myositis Inclusion Body Animals Genetically Modified 03 medical and health sciences Myosin head 0302 clinical medicine Myofibrils Myosin medicine Animals Humans Amino Acid Sequence Protein Structure Quaternary Molecular Biology Actin Conserved Sequence 030304 developmental biology Inclusion Bodies 0303 health sciences Muscle Weakness Ophthalmoplegia Myosin Heavy Chains Protein Stability Homozygote Temperature Autosomal dominant trait Muscle weakness Cell Biology Articles Actins Cell biology Kinetics Drosophila melanogaster Biochemistry Cell Biology of Disease Mutation MYH7 Mutant Proteins Ca(2+) Mg(2+)-ATPase medicine.symptom Myofibril 030217 neurology & neurosurgery Locomotion |
| Zdroj: | Molecular Biology of the Cell |
| ISSN: | 1939-4586 1059-1524 |
| Popis: | A Drosophila model of myosin-based inclusion body myopathy type 3 is presented. Muscle function, ATPase activity, and actin sliding velocity were dramatically reduced. The mutant myosin is prone to aggregate, likely accounting for the observed cytoplasmic inclusions and disorganized muscle filaments reminiscent of the human disease. Hereditary myosin myopathies are characterized by variable clinical features. Inclusion body myopathy 3 (IBM-3) is an autosomal dominant disease associated with a missense mutation (E706K) in the myosin heavy chain IIa gene. Adult patients experience progressive muscle weakness. Biopsies reveal dystrophic changes, rimmed vacuoles with cytoplasmic inclusions, and focal disorganization of myofilaments. We constructed a transgene encoding E706K myosin and expressed it in Drosophila (E701K) indirect flight and jump muscles to establish a novel homozygous organism with homogeneous populations of fast IBM-3 myosin and muscle fibers. Flight and jump abilities were severely reduced in homozygotes. ATPase and actin sliding velocity of the mutant myosin were depressed >80% compared with wild-type myosin. Light scattering experiments and electron microscopy revealed that mutant myosin heads bear a dramatic propensity to collapse and aggregate. Thus E706K (E701K) myosin appears far more labile than wild-type myosin. Furthermore, mutant fly fibers exhibit ultrastructural hallmarks seen in patients, including cytoplasmic inclusions containing aberrant proteinaceous structures and disorganized muscle filaments. Our Drosophila model reveals the unambiguous consequences of the IBM-3 lesion on fast muscle myosin and fibers. The abnormalities observed in myosin function and muscle ultrastructure likely contribute to muscle weakness observed in our flies and patients. |
| Databáze: | OpenAIRE |
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