Altered myofilament function depresses force generation in patients with nebulin-based nemaline myopathy (NEM2)

Coen A.C. Ottenheijm, Pleuni Hooijman, Elizabeth T. DeChene, Ger J. Stienen, Alan H. Beggs, Henk Granzier

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is clinically characterized by muscle weakness. However, the mechanisms underlying this weakness are poorly understood. Here, we studied the contractile phenotype of skeletal muscle from NM patients with nebulin mutations (NEM2). SDS-PAGE and Western blotting studies revealed markedly reduced nebulin protein levels in muscle from NM patients, whereas levels of other thin filament-based proteins were not significantly altered. Muscle mechanics studies indicated significantly reduced calcium sensitivity of force generation in NM muscle fibers compared to control fibers. In addition, we found slower rate constant of force redevelopment, as well as increased tension cost, in NM compared to control fibers, indicating that in NM muscle the rate of cross-bridge attachment is reduced, whereas the rate of cross-bridge detachment is increased. The resulting reduced fraction of force generating cross-bridges is expected to greatly impair the force generating capacity of muscle from NM patients. Thus, the present study provides important novel insights into the pathogenesis of muscle weakness in nebulin-based NM.

Original languageEnglish (US)
Pages (from-to)334-343
Number of pages10
JournalJournal of Structural Biology
Volume170
Issue number2
DOIs
StatePublished - May 2010

Keywords

  • Cross-bridge cycling
  • Muscle weakness
  • Nebulin
  • Nemaline myopathy
  • Thin filament length

ASJC Scopus subject areas

  • Structural Biology

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