Changes in cross-bridge cycling underlie muscle weakness in patients with tropomyosin 3-based myopathy

Coen A C Ottenheijm, Michael W. Lawlor, Ger J M Stienen, Hendrikus "Henk" Granzier, Alan H. Beggs

Research output: Contribution to journalArticle

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Abstract

Nemaline myopathy, the most common non-dystrophic congenital myopathy, is caused by mutations in six genes, all of which encode thin-filament proteins, including NEB (nebulin) and TPM3 (α tropomyosin). In contrast to the mechanisms underlying weakness in NEB-based myopathy, which are related to loss of thin-filament functions normally exerted by nebulin, the pathogenesis of muscle weakness in patients with TPM3 mutations remains largely unknown. Here, we tested the hypothesis that the contractile phenotype of TPM3-based myopathy is different from that of NEB-based myopathy and that this phenotype is a direct consequence of the loss of the specific functions normally exerted by tropomyosin. To test this hypothesis, we used a multidisciplinary approach, including muscle fiber mechanics and confocal and electron microscopy to characterize the structural and functional phenotype of muscle fibers from five patients with TPM3-based myopathy and compared this with that of unaffected control subjects. Our findings demonstrate that patients with TPM3-based myopathy display a contractile phenotype that is very distinct from that of patients with NEB-based myopathy. Whereas both show severe myofilament-based muscle weakness, the contractile dysfunction in TPM3-based myopathy is largely explained by changes in cross-bridge cycling kinetics, but not by the dysregulation of sarcomeric thin-filament length that plays a prominent role in NEBbased myopathy. Interestingly, the loss of force-generating capacity in TPM3-based myopathy appears to be compensated by enhanced thin-filament activation. These findings provide a scientific basis for differential therapeutics aimed at restoring contractile performance in patients with TPM3-based versus NEB-based myopathy.

Original languageEnglish (US)
Article numberddr084
Pages (from-to)2015-2025
Number of pages11
JournalHuman Molecular Genetics
Volume20
Issue number10
DOIs
StatePublished - May 2011

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Tropomyosin
Muscle Weakness
Muscular Diseases
Phenotype
Nemaline Myopathies
Myotonia Congenita
Muscles
Mutation
Myofibrils
Mechanics
Confocal Microscopy
nebulin
Electron Microscopy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Changes in cross-bridge cycling underlie muscle weakness in patients with tropomyosin 3-based myopathy. / Ottenheijm, Coen A C; Lawlor, Michael W.; Stienen, Ger J M; Granzier, Hendrikus "Henk"; Beggs, Alan H.

In: Human Molecular Genetics, Vol. 20, No. 10, ddr084, 05.2011, p. 2015-2025.

Research output: Contribution to journalArticle

Ottenheijm, Coen A C ; Lawlor, Michael W. ; Stienen, Ger J M ; Granzier, Hendrikus "Henk" ; Beggs, Alan H. / Changes in cross-bridge cycling underlie muscle weakness in patients with tropomyosin 3-based myopathy. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 10. pp. 2015-2025.
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