Mutation-specific effects on thin filament length in thin filament myopathy
Josine M. de Winter MS
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorBarbara Joureau MS
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorEun-Jeong Lee PhD
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Search for more papers by this authorBalázs Kiss MD, PhD
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Search for more papers by this authorMichaela Yuen PhD
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Westmead, New South Wales, Australia
Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia
Search for more papers by this authorVandana A. Gupta PhD
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA
Search for more papers by this authorChristopher T. Pappas PhD
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Search for more papers by this authorCarol C. Gregorio PhD
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Search for more papers by this authorGer J. M. Stienen PhD
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Department of Physics and Astronomy, VU University, Amsterdam, the Netherlands
Search for more papers by this authorSimon Edvardson MD
Pediatric Neurology Unit, Hadassah University Hospital, Jerusalem, Israel
Search for more papers by this authorCarina Wallgren-Pettersson MD, PhD
Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland
Search for more papers by this authorVilma-Lotta Lehtokari PhD
Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland
Search for more papers by this authorKatarina Pelin PhD
Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland
Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki, Finland
Search for more papers by this authorEdoardo Malfatti MD, PhD
Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France
Search for more papers by this authorNorma B. Romero MD, PhD
Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France
Search for more papers by this authorBaziel G. van Engelen MD, PhD
Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands
Search for more papers by this authorNicol C. Voermans MD, PhD
Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands
Search for more papers by this authorSandra Donkervoort MS, CGC
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorC. G. Bönnemann MD
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorNigel F. Clarke MD, PhD
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Westmead, New South Wales, Australia
Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia
Dr Nigel F. Clarke is deceased.
Search for more papers by this authorAlan H. Beggs PhD
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA
Search for more papers by this authorHenk Granzier PhD
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Search for more papers by this authorCorresponding Author
Coen A. C. Ottenheijm PhD
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Address correspondence to Dr Ottenheijm, Department of Physiology, VU University Medical Center, 1081 BT Amsterdam, the Netherlands. E-mail: [email protected]Search for more papers by this authorJosine M. de Winter MS
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorBarbara Joureau MS
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorEun-Jeong Lee PhD
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Search for more papers by this authorBalázs Kiss MD, PhD
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Search for more papers by this authorMichaela Yuen PhD
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Westmead, New South Wales, Australia
Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia
Search for more papers by this authorVandana A. Gupta PhD
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA
Search for more papers by this authorChristopher T. Pappas PhD
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Search for more papers by this authorCarol C. Gregorio PhD
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Search for more papers by this authorGer J. M. Stienen PhD
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Department of Physics and Astronomy, VU University, Amsterdam, the Netherlands
Search for more papers by this authorSimon Edvardson MD
Pediatric Neurology Unit, Hadassah University Hospital, Jerusalem, Israel
Search for more papers by this authorCarina Wallgren-Pettersson MD, PhD
Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland
Search for more papers by this authorVilma-Lotta Lehtokari PhD
Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland
Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland
Search for more papers by this authorKatarina Pelin PhD
Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland
Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki, Finland
Search for more papers by this authorEdoardo Malfatti MD, PhD
Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France
Search for more papers by this authorNorma B. Romero MD, PhD
Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France
Search for more papers by this authorBaziel G. van Engelen MD, PhD
Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands
Search for more papers by this authorNicol C. Voermans MD, PhD
Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands
Search for more papers by this authorSandra Donkervoort MS, CGC
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorC. G. Bönnemann MD
Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD
Search for more papers by this authorNigel F. Clarke MD, PhD
Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Westmead, New South Wales, Australia
Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia
Dr Nigel F. Clarke is deceased.
Search for more papers by this authorAlan H. Beggs PhD
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA
Search for more papers by this authorHenk Granzier PhD
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Search for more papers by this authorCorresponding Author
Coen A. C. Ottenheijm PhD
Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ
Address correspondence to Dr Ottenheijm, Department of Physiology, VU University Medical Center, 1081 BT Amsterdam, the Netherlands. E-mail: [email protected]Search for more papers by this authorAbstract
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. Ann Neurol 2016;79:959–969
Supporting Information
Additional supporting information can be found in the online version of this article.
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