Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency

Coen A C Ottenheijm, Christian C. Witt, Ger J. Stienen, Siegfried Labeit, Alan H. Beggs, Hendrikus "Henk" Granzier

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2359-2369
Number of pages11
JournalHuman Molecular Genetics
Volume18
Issue number13
DOIs
StatePublished - 2009

Fingerprint

Nemaline Myopathies
Muscle Weakness
Muscles
nebulin
Mutation
Myotonia Congenita
Phenotype
Sarcomeres
Genetic Association Studies

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency. / Ottenheijm, Coen A C; Witt, Christian C.; Stienen, Ger J.; Labeit, Siegfried; Beggs, Alan H.; Granzier, Hendrikus "Henk".

In: Human Molecular Genetics, Vol. 18, No. 13, 2009, p. 2359-2369.

Research output: Contribution to journalArticle

Ottenheijm, Coen A C ; Witt, Christian C. ; Stienen, Ger J. ; Labeit, Siegfried ; Beggs, Alan H. ; Granzier, Hendrikus "Henk". / Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 13. pp. 2359-2369.
@article{1ad9d6d9036a47018eed054339e2a0d1,
title = "Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency",
abstract = "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.",
author = "Ottenheijm, {Coen A C} and Witt, {Christian C.} and Stienen, {Ger J.} and Siegfried Labeit and Beggs, {Alan H.} and Granzier, {Hendrikus {"}Henk{"}}",
year = "2009",
doi = "10.1093/hmg/ddp168",
language = "English (US)",
volume = "18",
pages = "2359--2369",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "13",

}

TY - JOUR

T1 - Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency

AU - Ottenheijm, Coen A C

AU - Witt, Christian C.

AU - Stienen, Ger J.

AU - Labeit, Siegfried

AU - Beggs, Alan H.

AU - Granzier, Hendrikus "Henk"

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=67249115136&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67249115136&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddp168

DO - 10.1093/hmg/ddp168

M3 - Article

C2 - 19346529

AN - SCOPUS:67249115136

VL - 18

SP - 2359

EP - 2369

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 13

ER -