Journal
JOURNAL OF STRUCTURAL BIOLOGY
Volume 170, Issue 2, Pages 334-343Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jsb.2009.11.013
Keywords
Nemaline myopathy; Nebulin; Muscle weakness; Cross-bridge cycling; Thin filament length
Funding
- Dutch Organization for Scientific Research [NIH RO1 AR053897, NIH R01 AR044345]
- Muscular Dystrophy Association (USA) [MDA3971]
- Lee and Penny Anderson Family Foundation
- Joshua Frase Foundation
- [NIH-P30-HD18655]
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Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is clinically characterized by muscle weakness. However, the mechanisms underlying this weakness are poorly understood. Here, we studied the contractile phenotype of skeletal muscle from NM patients with nebulin mutations (NEM2). SDS-PAGE and Western blotting studies revealed markedly reduced nebulin protein levels in muscle from NM patients, whereas levels of other thin filament-based proteins were not significantly altered. Muscle mechanics studies indicated significantly reduced calcium sensitivity of force generation in NM muscle fibers compared to control fibers. In addition, we found slower rate constant of force redevelopment, as well as increased tension cost, in NM compared to control fibers, indicating that in NM muscle the rate of cross-bridge attachment is reduced, whereas the rate of cross-bridge detachment is increased. The resulting reduced fraction of force generating cross-bridges is expected to greatly impair the force generating capacity of muscle from NM patients. Thus, the present study provides important novel insights into the pathogenesis of muscle weakness in nebulin-based NM. (C) 2009 Elsevier Inc. All rights reserved.
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