Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations

Josine Marieke de Winter, Danielle Buck, Carlos Hidalgo, Jeffrey R. Jasper, Fady I. Malik, Nigel F. Clarke, Ger J M Stienen, Michael W. Lawlor, Alan H. Beggs, Coen A C Ottenheijm, Hendrikus "Henk" Granzier

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: Nemaline myopathy-the most common non-dystrophic congenital myopathy-is caused by mutations in thin filament genes, of which the nebulin gene is the most frequently affected one. The nebulin gene codes for the giant sarcomeric protein nebuli which plays a crucial role in skeletal muscle contractile performance. Muscle weakness is a hallmark feature of nemaline myopathy patients with nebulin mutations, and is caused by changes in contractile protein function, including a lower calcium-sensitivity of force generation. To date no therapy exists to treat muscle weakness in nemaline myopathy. Here, we studied the ability of the novel fast skeletal muscle troponin activator, CK- 2066260, to augment force generation at submaximal calcium levels in muscle cells from nemaline myopathy patients with nebulin mutations. Methods: Contractile protein function was determined in permeabilised muscle cells isolated from frozen patient biopsies. The effect of 5 μM CK-2066260 on force production was assessed. Results: Nebulin protein concentrations were severely reduced in muscle cells from these patients compared to controls, while myofibrillar ultrastructure was largely preserved. Both maximal active tension and the calciumsensitivity of force generation were lower in patients compared to controls. Importantly, CK-2066260 greatly increased the calcium-sensitivity of force generation- without affecting the cooperativity of activation-in patients to levels that exceed those observed in untreated control muscle. Conclusions: Fast skeletal troponin activation is a therapeutic mechanism to augment contractile protein function in nemaline myopathy patients with nebulin mutations and with other neuromuscular diseases.

Original languageEnglish (US)
Pages (from-to)383-392
Number of pages10
JournalJournal of Medical Genetics
Volume50
Issue number6
DOIs
StatePublished - 2013

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Nemaline Myopathies
Troponin
Muscles
Mutation
Contractile Proteins
Muscle Cells
Muscle Weakness
Calcium
Skeletal Muscle
Myotonia Congenita
Genes
Neuromuscular Diseases
nebulin
Proteins
Biopsy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations. / de Winter, Josine Marieke; Buck, Danielle; Hidalgo, Carlos; Jasper, Jeffrey R.; Malik, Fady I.; Clarke, Nigel F.; Stienen, Ger J M; Lawlor, Michael W.; Beggs, Alan H.; Ottenheijm, Coen A C; Granzier, Hendrikus "Henk".

In: Journal of Medical Genetics, Vol. 50, No. 6, 2013, p. 383-392.

Research output: Contribution to journalArticle

de Winter, JM, Buck, D, Hidalgo, C, Jasper, JR, Malik, FI, Clarke, NF, Stienen, GJM, Lawlor, MW, Beggs, AH, Ottenheijm, CAC & Granzier, HH 2013, 'Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations', Journal of Medical Genetics, vol. 50, no. 6, pp. 383-392. https://doi.org/10.1136/jmedgenet-2012-101470
de Winter, Josine Marieke ; Buck, Danielle ; Hidalgo, Carlos ; Jasper, Jeffrey R. ; Malik, Fady I. ; Clarke, Nigel F. ; Stienen, Ger J M ; Lawlor, Michael W. ; Beggs, Alan H. ; Ottenheijm, Coen A C ; Granzier, Hendrikus "Henk". / Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations. In: Journal of Medical Genetics. 2013 ; Vol. 50, No. 6. pp. 383-392.
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AU - Buck, Danielle

AU - Hidalgo, Carlos

AU - Jasper, Jeffrey R.

AU - Malik, Fady I.

AU - Clarke, Nigel F.

AU - Stienen, Ger J M

AU - Lawlor, Michael W.

AU - Beggs, Alan H.

AU - Ottenheijm, Coen A C

AU - Granzier, Hendrikus "Henk"

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N2 - Background: Nemaline myopathy-the most common non-dystrophic congenital myopathy-is caused by mutations in thin filament genes, of which the nebulin gene is the most frequently affected one. The nebulin gene codes for the giant sarcomeric protein nebuli which plays a crucial role in skeletal muscle contractile performance. Muscle weakness is a hallmark feature of nemaline myopathy patients with nebulin mutations, and is caused by changes in contractile protein function, including a lower calcium-sensitivity of force generation. To date no therapy exists to treat muscle weakness in nemaline myopathy. Here, we studied the ability of the novel fast skeletal muscle troponin activator, CK- 2066260, to augment force generation at submaximal calcium levels in muscle cells from nemaline myopathy patients with nebulin mutations. Methods: Contractile protein function was determined in permeabilised muscle cells isolated from frozen patient biopsies. The effect of 5 μM CK-2066260 on force production was assessed. Results: Nebulin protein concentrations were severely reduced in muscle cells from these patients compared to controls, while myofibrillar ultrastructure was largely preserved. Both maximal active tension and the calciumsensitivity of force generation were lower in patients compared to controls. Importantly, CK-2066260 greatly increased the calcium-sensitivity of force generation- without affecting the cooperativity of activation-in patients to levels that exceed those observed in untreated control muscle. Conclusions: Fast skeletal troponin activation is a therapeutic mechanism to augment contractile protein function in nemaline myopathy patients with nebulin mutations and with other neuromuscular diseases.

AB - Background: Nemaline myopathy-the most common non-dystrophic congenital myopathy-is caused by mutations in thin filament genes, of which the nebulin gene is the most frequently affected one. The nebulin gene codes for the giant sarcomeric protein nebuli which plays a crucial role in skeletal muscle contractile performance. Muscle weakness is a hallmark feature of nemaline myopathy patients with nebulin mutations, and is caused by changes in contractile protein function, including a lower calcium-sensitivity of force generation. To date no therapy exists to treat muscle weakness in nemaline myopathy. Here, we studied the ability of the novel fast skeletal muscle troponin activator, CK- 2066260, to augment force generation at submaximal calcium levels in muscle cells from nemaline myopathy patients with nebulin mutations. Methods: Contractile protein function was determined in permeabilised muscle cells isolated from frozen patient biopsies. The effect of 5 μM CK-2066260 on force production was assessed. Results: Nebulin protein concentrations were severely reduced in muscle cells from these patients compared to controls, while myofibrillar ultrastructure was largely preserved. Both maximal active tension and the calciumsensitivity of force generation were lower in patients compared to controls. Importantly, CK-2066260 greatly increased the calcium-sensitivity of force generation- without affecting the cooperativity of activation-in patients to levels that exceed those observed in untreated control muscle. Conclusions: Fast skeletal troponin activation is a therapeutic mechanism to augment contractile protein function in nemaline myopathy patients with nebulin mutations and with other neuromuscular diseases.

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