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

Christian C. Witt, Christoph Burkart, Dietmar Labeit, Mark McNabb, Yiming Wu, Henk Granzier, Siegfried Labeit

Research output: Contribution to journalArticlepeer-review

180 Scopus citations

Abstract

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 ∼15% 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.

Original languageEnglish (US)
Pages (from-to)3843-3855
Number of pages13
JournalEMBO Journal
Volume25
Issue number16
DOIs
StatePublished - Aug 23 2006
Externally publishedYes

Keywords

  • Nebulin
  • Nemaline myopathy
  • Thin filament
  • Titin
  • Z-disk

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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