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

Josine M. de Winter, Barbara Joureau, Vasco Sequeira, Nigel F. Clarke, Jolanda van der Velden, Ger J M Stienen, Hendrikus "Henk" Granzier, Alan H. Beggs, Coen A C Ottenheijm

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalSkeletal Muscle
DOIs
StateAccepted/In press - Apr 28 2015

Fingerprint

Nemaline Myopathies
Muscles
Mutation
Slow-Twitch Muscle Fibers
Troponin C
Genes
Skeletal Muscle Fibers
Calcium
Muscle Weakness
Muscle Strength
Protein Isoforms
simendan
nebulin
Calcium Compounds
Myotonia Congenita
Cardiac Myocytes

Keywords

  • Calcium-sensitizer
  • Levosimendan
  • Muscle force
  • Muscle mechanics
  • Nebulin
  • Nemaline myopathy

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Orthopedics and Sports Medicine

Cite this

de Winter, J. M., Joureau, B., Sequeira, V., Clarke, N. F., van der Velden, J., Stienen, G. J. M., ... Ottenheijm, C. A. C. (Accepted/In press). Effect of levosimendan on the contractility of muscle fibers from nemaline myopathy patients with mutations in the nebulin gene. Skeletal Muscle, 1-10. https://doi.org/10.1186/s13395-015-0037-7

Effect of levosimendan on the contractility of muscle fibers from nemaline myopathy patients with mutations in the nebulin gene. / de Winter, Josine M.; Joureau, Barbara; Sequeira, Vasco; Clarke, Nigel F.; van der Velden, Jolanda; Stienen, Ger J M; Granzier, Hendrikus "Henk"; Beggs, Alan H.; Ottenheijm, Coen A C.

In: Skeletal Muscle, 28.04.2015, p. 1-10.

Research output: Contribution to journalArticle

de Winter, JM, Joureau, B, Sequeira, V, Clarke, NF, van der Velden, J, Stienen, GJM, Granzier, HH, Beggs, AH & Ottenheijm, CAC 2015, 'Effect of levosimendan on the contractility of muscle fibers from nemaline myopathy patients with mutations in the nebulin gene', Skeletal Muscle, pp. 1-10. https://doi.org/10.1186/s13395-015-0037-7
de Winter, Josine M. ; Joureau, Barbara ; Sequeira, Vasco ; Clarke, Nigel F. ; van der Velden, Jolanda ; Stienen, Ger J M ; Granzier, Hendrikus "Henk" ; Beggs, Alan H. ; Ottenheijm, Coen A C. / Effect of levosimendan on the contractility of muscle fibers from nemaline myopathy patients with mutations in the nebulin gene. In: Skeletal Muscle. 2015 ; pp. 1-10.
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AU - Clarke, Nigel F.

AU - van der Velden, Jolanda

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AU - Ottenheijm, Coen A C

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N2 - 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.

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