title: Nebulin regulates thin filament length, contractility, and Z-disk structure in vivo.
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 approximately 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.
authors.affiliation: Institute for Anaesthesiology and Intensive Care, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Witt
authors.forename: Christoph
authors.initials: C
authors.lastname: Burkart
authors.forename: Dietmar
authors.initials: D
authors.lastname: Labeit
authors.forename: Mark
authors.initials: M
authors.lastname: McNabb
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wu
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D017696:Myopathies, Nemaline / Q000378:metabolism / Q000473:pathology; D012518:Sarcomeres / Q000502:physiology
chemical_list: D009124:Muscle Proteins; C035620:nebulin; D002118:Calcium