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

Persistent Link:
http://hdl.handle.net/10150/610333
Title:
Effect of levosimendan on the contractility of muscle fibers from nemaline myopathy patients with mutations in the nebulin gene
Author:
de Winter, J. M.; Joureau, B.; Sequeira, V.; Clarke, N. F.; van der Velden, J.; Stienen, G. J.; Granzier, H.; Beggs, A. H.; Ottenheijm, C. A.
Affiliation:
Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdam; INMR, The Children's Hospital at Westmead and Discipline of Paediatrics & Child Health, University of Sydney; Department of Physics and Astronomy, Faculty of Science, VU University; Department of Cellular and Molecular Medicine, University of Arizona; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School
Issue Date:
2015
Publisher:
BioMed Central
Citation:
de Winter et al. Skeletal Muscle (2015) 5:12 DOI 10.1186/s13395-015-0037-7
Journal:
Skeletal Muscle
Rights:
© 2015 de Winter et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
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.
EISSN:
2044-5040
PubMed ID:
25949787
PubMed Central ID:
PMC4422316
DOI:
10.1186/s13395-015-0037-7 [doi]
Keywords:
Calcium-sensitizer; Levosimendan; Muscle force; Muscle mechanics; Nebulin; Nemaline myopathy
Version:
Final published version
Additional Links:
http://skeletalmusclejournal.biomedcentral.com/articles/10.1186/s13395-015-0037-7

Full metadata record

DC FieldValue Language
dc.contributor.authorde Winter, J. M.en
dc.contributor.authorJoureau, B.en
dc.contributor.authorSequeira, V.en
dc.contributor.authorClarke, N. F.en
dc.contributor.authorvan der Velden, J.en
dc.contributor.authorStienen, G. J.en
dc.contributor.authorGranzier, H.en
dc.contributor.authorBeggs, A. H.en
dc.contributor.authorOttenheijm, C. A.en
dc.date.accessioned2016-05-20T09:04:28Z-
dc.date.available2016-05-20T09:04:28Z-
dc.date.issued2015en
dc.identifier.citationde Winter et al. Skeletal Muscle (2015) 5:12 DOI 10.1186/s13395-015-0037-7en
dc.identifier.pmid25949787en
dc.identifier.doi10.1186/s13395-015-0037-7 [doi]en
dc.identifier.urihttp://hdl.handle.net/10150/610333-
dc.description.abstractBACKGROUND: 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.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://skeletalmusclejournal.biomedcentral.com/articles/10.1186/s13395-015-0037-7en
dc.rights© 2015 de Winter et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)en
dc.subjectCalcium-sensitizeren
dc.subjectLevosimendanen
dc.subjectMuscle forceen
dc.subjectMuscle mechanicsen
dc.subjectNebulinen
dc.subjectNemaline myopathyen
dc.titleEffect of levosimendan on the contractility of muscle fibers from nemaline myopathy patients with mutations in the nebulin geneen
dc.typeArticleen
dc.identifier.eissn2044-5040en
dc.contributor.departmentDepartment of Physiology, Institute for Cardiovascular Research, VU University Medical Center Amsterdamen
dc.contributor.departmentINMR, The Children's Hospital at Westmead and Discipline of Paediatrics & Child Health, University of Sydneyen
dc.contributor.departmentDepartment of Physics and Astronomy, Faculty of Science, VU Universityen
dc.contributor.departmentDepartment of Cellular and Molecular Medicine, University of Arizonaen
dc.contributor.departmentDivision of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical Schoolen
dc.identifier.journalSkeletal Muscleen
dc.identifier.pmcidPMC4422316en
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen

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