Mutation-specific effects on thin filament length in thin filament myopathy

Josine M de Winter, Barbara Joureau, Eun Jeong Lee, Balázs Kiss, Michaela Yuen, Vandana A. Gupta, Christopher T. Pappas, Carol Gregorio, Ger J M Stienen, Simon Edvardson, Carina Wallgren-Pettersson, Vilma Lotta Lehtokari, Katarina Pelin, Edoardo Malfatti, Norma B. Romero, Baziel G van Engelen, Nicol C. Voermans, Sandra Donkervoort, C. G. Bönnemann, Nigel F. ClarkeAlan H. Beggs, Hendrikus "Henk" Granzier, Coen A C Ottenheijm

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objective: Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation. Methods: We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. Results: Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force-sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin-thick filament overlap. Interpretation: These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths.

Original languageEnglish (US)
JournalAnnals of Neurology
DOIs
StateAccepted/In press - 2016

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Muscular Diseases
Sarcomeres
Mutation
Muscles
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Muscle Weakness
Muscle Strength
Knockout Mice
Confocal Microscopy
Skeletal Muscle
Genotype
Proteins

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Winter, J. M. D., Joureau, B., Lee, E. J., Kiss, B., Yuen, M., Gupta, V. A., ... Ottenheijm, C. A. C. (Accepted/In press). Mutation-specific effects on thin filament length in thin filament myopathy. Annals of Neurology. https://doi.org/10.1002/ana.24654

Mutation-specific effects on thin filament length in thin filament myopathy. / Winter, Josine M de; Joureau, Barbara; Lee, Eun Jeong; Kiss, Balázs; Yuen, Michaela; Gupta, Vandana A.; Pappas, Christopher T.; Gregorio, Carol; Stienen, Ger J M; Edvardson, Simon; Wallgren-Pettersson, Carina; Lehtokari, Vilma Lotta; Pelin, Katarina; Malfatti, Edoardo; Romero, Norma B.; Engelen, Baziel G van; Voermans, Nicol C.; Donkervoort, Sandra; Bönnemann, C. G.; Clarke, Nigel F.; Beggs, Alan H.; Granzier, Hendrikus "Henk"; Ottenheijm, Coen A C.

In: Annals of Neurology, 2016.

Research output: Contribution to journalArticle

Winter, JMD, Joureau, B, Lee, EJ, Kiss, B, Yuen, M, Gupta, VA, Pappas, CT, Gregorio, C, Stienen, GJM, Edvardson, S, Wallgren-Pettersson, C, Lehtokari, VL, Pelin, K, Malfatti, E, Romero, NB, Engelen, BGV, Voermans, NC, Donkervoort, S, Bönnemann, CG, Clarke, NF, Beggs, AH, Granzier, HH & Ottenheijm, CAC 2016, 'Mutation-specific effects on thin filament length in thin filament myopathy', Annals of Neurology. https://doi.org/10.1002/ana.24654
Winter, Josine M de ; Joureau, Barbara ; Lee, Eun Jeong ; Kiss, Balázs ; Yuen, Michaela ; Gupta, Vandana A. ; Pappas, Christopher T. ; Gregorio, Carol ; Stienen, Ger J M ; Edvardson, Simon ; Wallgren-Pettersson, Carina ; Lehtokari, Vilma Lotta ; Pelin, Katarina ; Malfatti, Edoardo ; Romero, Norma B. ; Engelen, Baziel G van ; Voermans, Nicol C. ; Donkervoort, Sandra ; Bönnemann, C. G. ; Clarke, Nigel F. ; Beggs, Alan H. ; Granzier, Hendrikus "Henk" ; Ottenheijm, Coen A C. / Mutation-specific effects on thin filament length in thin filament myopathy. In: Annals of Neurology. 2016.
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AU - Winter, Josine M de

AU - Joureau, Barbara

AU - Lee, Eun Jeong

AU - Kiss, Balázs

AU - Yuen, Michaela

AU - Gupta, Vandana A.

AU - Pappas, Christopher T.

AU - Gregorio, Carol

AU - Stienen, Ger J M

AU - Edvardson, Simon

AU - Wallgren-Pettersson, Carina

AU - Lehtokari, Vilma Lotta

AU - Pelin, Katarina

AU - Malfatti, Edoardo

AU - Romero, Norma B.

AU - Engelen, Baziel G van

AU - Voermans, Nicol C.

AU - Donkervoort, Sandra

AU - Bönnemann, C. G.

AU - Clarke, Nigel F.

AU - Beggs, Alan H.

AU - Granzier, Hendrikus "Henk"

AU - Ottenheijm, Coen A C

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N2 - Objective: Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation. Methods: We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. Results: Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force-sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin-thick filament overlap. Interpretation: These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths.

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