English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background  Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is characterized by generalized skeletal muscle weakness, often from birth. To date, no therapy exists that enhances the contractile strength of muscles of NM patients. Mutations in  NEB , encoding the giant protein nebulin, are the most common cause of NM. The pathophysiology of muscle weakness in NM patients with  NEB  mutations ( NEB -NM) includes a lower calcium-sensitivity of force generation. We propose that the lower calcium-sensitivity of force generation in  NEB -NM offers a therapeutic target. Levosimendan is a calcium sensitizer that is approved for use in humans and has been developed to target cardiac muscle fibers. It exerts its effect through binding to slow skeletal/cardiac troponin C. As slow skeletal/cardiac troponin C is also the dominant troponin C isoform in  slow-twitch skeletal  muscle fibers, we hypothesized that levosimendan improves slow-twitch muscle fiber strength at submaximal levels of activation in patients with  NEB -NM.    Methods  To test whether levosimendan affects force production, permeabilized slow-twitch muscle fibers isolated from biopsies of  NEB -NM patients and controls were exposed to levosimendan and the force response was measured.    Results  No effect of levosimendan on muscle fiber force in  NEB -NM and control skeletal muscle fibers was found, both at a submaximal calcium level using incremental levosimendan concentrations, and at incremental calcium concentrations in the presence of levosimendan. In contrast, levosimendan did significantly increase the calcium-sensitivity of force in human single cardiomyocytes. Protein analysis confirmed that the slow skeletal/cardiac troponin C isoform was present in the skeletal muscle fibers tested.    Conclusions  These findings indicate that levosimendan does not improve the contractility in human skeletal muscle fibers, and do not provide rationale for using levosimendan as a therapeutic to restore muscle weakness in  NEB -NM patients. We stress the importance of searching for compounds that improve the calcium-sensitivity of force generation of slow-twitch muscle fibers. Such compounds provide an appealing approach to restore muscle force in patients with  NEB -NM, and also in patients with other neuromuscular disorders.    Electronic supplementary material  The online version of this article (doi:10.1186/s13395-015-0037-7) contains supplementary material, which is available to authorized users.

Effect of levosimendan on the contractility of muscle fibers from nemaline myopathy patients with mutations in the nebulin gene