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Article

  • The EMBO Journal (2006) 25, 3843 - 3855
  • doi:10.1038/sj.emboj.7601242

Published online: 10 August 2006

Nebulin regulates thin filament length, contractility, and Z-disk structure in vivo

Christian C Witt1, Christoph Burkart1, Dietmar Labeit1, Mark McNabb2, Yiming Wu2, Henk Granzier2 and Siegfried Labeit1

  1. Institute for Anaesthesiology and Intensive Care, University Hospital Mannheim, Mannheim, Germany
  2. Department of VCAPP, Washington State University Pullman, WA, USA

Correspondence to:

Siegfried Labeit, Institute for Anaesthesiology and Intensive Care, University Clinic Mannheim, Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany. Tel.: +49 621 3831625; Fax: +49 621 3831971; E-mail: Siegfried.Labeit@anaes.ma.uni-heidelberg.de

Received 10 January 2006; Accepted 26 June 2006

The precise assembly of the highly organized filament systems found in muscle is critically important for its function. It has been hypothesized that nebulin, a giant filamentous protein extending along the entire length of the thin filament, provides a blueprint for muscle thin filament assembly. To test this hypothesis, we generated a KO mouse model to investigate nebulin functions in vivo. Nebulin KO mice assemble thin filaments of reduced lengths and approx15% of their Z-disks are abnormally wide. Our data demonstrate that nebulin functions in vivo as a molecular ruler by specifying pointed- and barbed-end thin filament capping. Consistent with the shorter thin filament length of nebulin deficient mice, maximal active tension was significantly reduced in KO animals. Phenotypically, the murine model recapitulates human nemaline myopathy (NM), that is, the formation of nemaline rods combined with severe skeletal muscle weakness. The myopathic changes in the nebulin KO model include depressed contractility, loss of myopalladin from the Z-disk, and dysregulation of genes involved in calcium homeostasis and glycogen metabolism; features potentially relevant for understanding human NM.

  • Keywords:

    • nebulin,
    • nemaline myopathy,
    • thin filament,
    • titin,
    • Z-disk