Human Molecular Genetics Advance Access originally published online on April 4, 2009
Human Molecular Genetics 2009 18(13):2359-2369; doi:10.1093/hmg/ddp168
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency
1 Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85724, USA 2 Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam 1081 BT, The Netherlands 3 Institute for Integrative Pathophysiology, University Hospital Mannheim, Mannheim 68131, Germany 4 Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
* To whom correspondence should be addressed. Tel: +1 5206263641; Fax: +1 5206267600; Email: granzier{at}email.arizona.edu
Received January 22, 2009; Revised March 18, 2009; Accepted April 2, 2009
Nemaline myopathy (NM) is the most common non-dystrophic congenital myopathy. Clinically the most important feature of NM is muscle weakness; however, the mechanisms underlying this weakness are poorly understood. Here, we studied the muscular phenotype of NM patients with a well-defined nebulin mutation (NM-NEB), using a multidisciplinary approach to study thin filament length regulation and muscle contractile performance. SDS–PAGE and western blotting revealed greatly reduced nebulin levels in skeletal muscle of NM-NEB patients, with the most prominent reduction at nebulin’s N-terminal end. Muscle mechanical studies indicated 
60% reduced force generating capacity of NM-NEB muscle and a leftward-shift of the force–sarcomere length relation in NM-NEB muscle fibers. This indicates that the mechanism for the force reduction is likely to include shorter and non-uniform thin filament lengths in NM-NEB muscle compared with control muscle. Immunofluorescence confocal microscopy and electron microscopy studies indicated that average thin filament length is reduced from 1.3 µm in control muscle to 0.75 µm in NM-NEB muscle. Thus, the present study is the first to show a distinct genotype-functional phenotype correlation in patients with NM due to a nebulin mutation, and provides evidence for the notion that dysregulated thin filament length contributes to muscle weakness in NM patients with nebulin mutations. Furthermore, a striking similarity between the contractile and structural phenotypes of nebulin-deficient mouse muscle and human NM-NEB muscle was observed, indicating that the nebulin knockout model is well suited for elucidating the functional basis of muscle weakness in NM and for the development of treatment strategies.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Chandra, R. Mamidi, S. Ford, C. Hidalgo, C. Witt, C. Ottenheijm, S. Labeit, and H. Granzier Nebulin Alters Cross-bridge Cycling Kinetics and Increases Thin Filament Activation: A NOVEL MECHANISM FOR INCREASING TENSION AND REDUCING TENSION COST J. Biol. Chem., November 6, 2009; 284(45): 30889 - 30896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kontrogianni-Konstantopoulos, M. A. Ackermann, A. L. Bowman, S. V. Yap, and R. J. Bloch Muscle Giants: Molecular Scaffolds in Sarcomerogenesis Physiol Rev, October 1, 2009; 89(4): 1217 - 1267. [Abstract] [Full Text] [PDF]
|
|