Abstract |
While mutations in the myosin subfragment 1 motor domain can directly disrupt the generation and transmission of force along myofibrils and lead to myopathy, the mechanism whereby mutations in the myosin rod influences mechanical function is less clear. Here, we used a combination of various imaging techniques and molecular dynamics simulations to test the hypothesis that perturbations in the myosin rod can disturb normal sarcomeric uniformity and, like motor domain lesions, would influence force production and propagation. We show that disrupting the rod can alter its nanomechanical properties and, in vivo, can drive asymmetric myofilament and sarcomere formation. Our imaging results indicate that myosin rod mutations likely disturb production and/or propagation of contractile force. This provides a unifying theory where common pathological cascades accompany both myosin motor and specific rod domain mutations. Finally, we suggest that sarcomeric inhomogeneity, caused by asymmetric thick filaments, could be a useful index of myopathic dysfunction.
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Authors | Anthony Cammarato, Xiaochuan Edward Li, Mary C Reedy, Chi F Lee, William Lehman, Sanford I Bernstein |
Journal | Journal of molecular biology
(J Mol Biol)
Vol. 414
Issue 4
Pg. 477-84
(Dec 09 2011)
ISSN: 1089-8638 [Electronic] Netherlands |
PMID | 22037585
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier Ltd. All rights reserved. |
Chemical References |
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Topics |
- Humans
- Models, Molecular
- Motor Endplate
(genetics, physiology)
- Muscle Contraction
- Muscular Diseases
(genetics, pathology, physiopathology)
- Mutation
- Myosin Subfragments
(chemistry, genetics, physiology, ultrastructure)
- Sarcomeres
(chemistry, genetics, physiology, ultrastructure)
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