AustralieFrV1, PubMed, Curation, bibRecord, 002724

Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.

Identifieur interne : 002724 ( PubMed/Curation ); précédent : 002723; suivant : 002725

Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.

Auteurs : Michaela Yuen [Australie] ; Sandra T. Cooper [Australie] ; Steve B. Marston [Royaume-Uni] ; Kristen J. Nowak [Australie] ; Elyshia Mcnamara [Australie] ; Nancy Mokbel [Liban] ; Biljana Ilkovski [Australie] ; Gianina Ravenscroft [Australie] ; John Rendu [France] ; Josine M. De Winter [Pays-Bas] ; Lars Klinge [Allemagne] ; Alan H. Beggs [États-Unis] ; Kathryn N. North [Australie] ; Coen A C. Ottenheijm [Pays-Bas] ; Nigel F. Clarke [Australie]

Source :

Human molecular genetics [ 1460-2083 ] ; 2015.

RBID : pubmed:26307083

Descripteurs français

KwdFr :
- Actines (génétique), Actines (métabolisme), Adolescent, Adulte, Adulte d'âge moyen, Amyotrophie (génétique), Amyotrophie (métabolisme), Calcium (métabolisme), Contraction musculaire (physiologie), Enfant, Enfant d'âge préscolaire, Faiblesse musculaire (génétique), Faiblesse musculaire (métabolisme), Femelle, Fibres musculaires à contraction lente (métabolisme), Humains, Isoformes de protéines, Maladies musculaires (génétique), Maladies musculaires (métabolisme), Mutation, Myosines (génétique), Myosines (métabolisme), Mâle, Nourrisson, Tropomyosine (génétique), Tropomyosine (métabolisme).
MESH :
- génétique : Actines, Amyotrophie, Faiblesse musculaire, Maladies musculaires, Myosines, Tropomyosine.
- métabolisme : Actines, Amyotrophie, Calcium, Faiblesse musculaire, Fibres musculaires à contraction lente, Maladies musculaires, Myosines, Tropomyosine.
- physiologie : Contraction musculaire.
- Adolescent, Adulte, Adulte d'âge moyen, Enfant, Enfant d'âge préscolaire, Femelle, Humains, Isoformes de protéines, Mutation, Mâle, Nourrisson.

English descriptors

KwdEn :
- Actins (genetics), Actins (metabolism), Adolescent, Adult, Calcium (metabolism), Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Muscle Contraction (physiology), Muscle Fibers, Slow-Twitch (metabolism), Muscle Weakness (genetics), Muscle Weakness (metabolism), Muscular Atrophy (genetics), Muscular Atrophy (metabolism), Muscular Diseases (genetics), Muscular Diseases (metabolism), Mutation, Myosins (genetics), Myosins (metabolism), Protein Isoforms, Tropomyosin (genetics), Tropomyosin (metabolism).
MESH :
- chemical , genetics : Actins, Myosins, Tropomyosin.
- chemical , metabolism : Actins, Calcium, Myosins, Tropomyosin.
- genetics : Muscle Weakness, Muscular Atrophy, Muscular Diseases.
- metabolism : Muscle Fibers, Slow-Twitch, Muscle Weakness, Muscular Atrophy, Muscular Diseases.
- physiology : Muscle Contraction.
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Middle Aged, Mutation, Protein Isoforms.

Abstract

Dominant mutations in TPM3, encoding α-tropomyosinslow, cause a congenital myopathy characterized by generalized muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in 12 TPM3-myopathy patients. We confirm that slow myofibre hypotrophy is a diagnostic hallmark of TPM3-myopathy, and is commonly accompanied by skewing of fibre-type ratios (either slow or fast fibre predominance). Patient muscle contained normal ratios of the three tropomyosin isoforms and normal fibre-type expression of myosins and troponins. Using 2D-PAGE, we demonstrate that mutant α-tropomyosinslow was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosinslow likely impacts actin-tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosinslow (R168C) to filamentous actin. Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca(2+)] (pCa 4.5), patient slow fibres produced only 63% of the contractile force produced in control slow fibres and had reduced acto-myosin cross-bridge cycling kinetics. Importantly, due to reduced Ca(2+)-sensitivity, at sub-saturating [Ca(2+)] (pCa 6, levels typically released during in vivo contraction) patient slow fibres produced only 26% of the force generated by control slow fibres. Thus, weakness in TPM3-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca(2+)], and impaired acto-myosin cross-bridge cycling kinetics. Fast myofibres are spared; however, they appear to be unable to compensate for slow fibre dysfunction. Abnormal Ca(2+)-sensitivity in TPM3-myopathy patients suggests Ca(2+)-sensitizing drugs may represent a useful treatment for this condition.

DOI: 10.1093/hmg/ddv334
PubMed: 26307083

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<author><name sortKey="Rendu, John" sort="Rendu, John" uniqKey="Rendu J" first="John" last="Rendu">John Rendu</name>
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<author><name sortKey="De Winter, Josine M" sort="De Winter, Josine M" uniqKey="De Winter J" first="Josine M" last="De Winter">Josine M. De Winter</name>
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<author><name sortKey="Klinge, Lars" sort="Klinge, Lars" uniqKey="Klinge L" first="Lars" last="Klinge">Lars Klinge</name>
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<author><name sortKey="Beggs, Alan H" sort="Beggs, Alan H" uniqKey="Beggs A" first="Alan H" last="Beggs">Alan H. Beggs</name>
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<country xml:lang="fr">États-Unis</country>
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</affiliation>
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<author><name sortKey="North, Kathryn N" sort="North, Kathryn N" uniqKey="North K" first="Kathryn N" last="North">Kathryn N. North</name>
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<wicri:regionArea>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia, Murdoch Children's Research Institute, the Royal Children's Hospital, Parkville, Australia and Department of Paediatrics, University of Melbourne, Melbourne</wicri:regionArea>
</affiliation>
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<author><name sortKey="Ottenheijm, Coen A C" sort="Ottenheijm, Coen A C" uniqKey="Ottenheijm C" first="Coen A C" last="Ottenheijm">Coen A C. Ottenheijm</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam</wicri:regionArea>
</affiliation>
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<author><name sortKey="Clarke, Nigel F" sort="Clarke, Nigel F" uniqKey="Clarke N" first="Nigel F" last="Clarke">Nigel F. Clarke</name>
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<country xml:lang="fr">Australie</country>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.</title>
<author><name sortKey="Yuen, Michaela" sort="Yuen, Michaela" uniqKey="Yuen M" first="Michaela" last="Yuen">Michaela Yuen</name>
<affiliation wicri:level="1"><nlm:affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia, michaela.kreissl@sydney.edu.au.</nlm:affiliation>
<country wicri:rule="url">Australie</country>
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</affiliation>
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<author><name sortKey="Cooper, Sandra T" sort="Cooper, Sandra T" uniqKey="Cooper S" first="Sandra T" last="Cooper">Sandra T. Cooper</name>
<affiliation wicri:level="1"><nlm:affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney</wicri:regionArea>
</affiliation>
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<author><name sortKey="Marston, Steve B" sort="Marston, Steve B" uniqKey="Marston S" first="Steve B" last="Marston">Steve B. Marston</name>
<affiliation wicri:level="1"><nlm:affiliation>National Heart and Lung Institute, Imperial College London, London, UK.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>National Heart and Lung Institute, Imperial College London, London</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nowak, Kristen J" sort="Nowak, Kristen J" uniqKey="Nowak K" first="Kristen J" last="Nowak">Kristen J. Nowak</name>
<affiliation wicri:level="1"><nlm:affiliation>Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mcnamara, Elyshia" sort="Mcnamara, Elyshia" uniqKey="Mcnamara E" first="Elyshia" last="Mcnamara">Elyshia Mcnamara</name>
<affiliation wicri:level="1"><nlm:affiliation>Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mokbel, Nancy" sort="Mokbel, Nancy" uniqKey="Mokbel N" first="Nancy" last="Mokbel">Nancy Mokbel</name>
<affiliation wicri:level="1"><nlm:affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Faculty of Health Sciences, St. George Health Complex, The University of Balamand, Beirut, Lebanon.</nlm:affiliation>
<country xml:lang="fr">Liban</country>
<wicri:regionArea>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Faculty of Health Sciences, St. George Health Complex, The University of Balamand, Beirut</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ilkovski, Biljana" sort="Ilkovski, Biljana" uniqKey="Ilkovski B" first="Biljana" last="Ilkovski">Biljana Ilkovski</name>
<affiliation wicri:level="1"><nlm:affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ravenscroft, Gianina" sort="Ravenscroft, Gianina" uniqKey="Ravenscroft G" first="Gianina" last="Ravenscroft">Gianina Ravenscroft</name>
<affiliation wicri:level="1"><nlm:affiliation>Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rendu, John" sort="Rendu, John" uniqKey="Rendu J" first="John" last="Rendu">John Rendu</name>
<affiliation wicri:level="1"><nlm:affiliation>Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.</nlm:affiliation>
<country xml:lang="fr">France</country>
<wicri:regionArea>Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire, Centre Hospitalier Universitaire de Grenoble, Grenoble</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="De Winter, Josine M" sort="De Winter, Josine M" uniqKey="De Winter J" first="Josine M" last="De Winter">Josine M. De Winter</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Klinge, Lars" sort="Klinge, Lars" uniqKey="Klinge L" first="Lars" last="Klinge">Lars Klinge</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Faculty of Medicine, Georg August University, Göttingen, Germany.</nlm:affiliation>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Faculty of Medicine, Georg August University, Göttingen</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Beggs, Alan H" sort="Beggs, Alan H" uniqKey="Beggs A" first="Alan H" last="Beggs">Alan H. Beggs</name>
<affiliation wicri:level="1"><nlm:affiliation>Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="North, Kathryn N" sort="North, Kathryn N" uniqKey="North K" first="Kathryn N" last="North">Kathryn N. North</name>
<affiliation wicri:level="1"><nlm:affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia, Murdoch Children's Research Institute, the Royal Children's Hospital, Parkville, Australia and Department of Paediatrics, University of Melbourne, Melbourne, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia, Murdoch Children's Research Institute, the Royal Children's Hospital, Parkville, Australia and Department of Paediatrics, University of Melbourne, Melbourne</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ottenheijm, Coen A C" sort="Ottenheijm, Coen A C" uniqKey="Ottenheijm C" first="Coen A C" last="Ottenheijm">Coen A C. Ottenheijm</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.</nlm:affiliation>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Clarke, Nigel F" sort="Clarke, Nigel F" uniqKey="Clarke N" first="Nigel F" last="Clarke">Nigel F. Clarke</name>
<affiliation wicri:level="1"><nlm:affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney</wicri:regionArea>
</affiliation>
</author>
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<series><title level="j">Human molecular genetics</title>
<idno type="eISSN">1460-2083</idno>
<imprint><date when="2015" type="published">2015</date>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Actins (genetics)</term>
<term>Actins (metabolism)</term>
<term>Adolescent</term>
<term>Adult</term>
<term>Calcium (metabolism)</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>Female</term>
<term>Humans</term>
<term>Infant</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Muscle Contraction (physiology)</term>
<term>Muscle Fibers, Slow-Twitch (metabolism)</term>
<term>Muscle Weakness (genetics)</term>
<term>Muscle Weakness (metabolism)</term>
<term>Muscular Atrophy (genetics)</term>
<term>Muscular Atrophy (metabolism)</term>
<term>Muscular Diseases (genetics)</term>
<term>Muscular Diseases (metabolism)</term>
<term>Mutation</term>
<term>Myosins (genetics)</term>
<term>Myosins (metabolism)</term>
<term>Protein Isoforms</term>
<term>Tropomyosin (genetics)</term>
<term>Tropomyosin (metabolism)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Actines (génétique)</term>
<term>Actines (métabolisme)</term>
<term>Adolescent</term>
<term>Adulte</term>
<term>Adulte d'âge moyen</term>
<term>Amyotrophie (génétique)</term>
<term>Amyotrophie (métabolisme)</term>
<term>Calcium (métabolisme)</term>
<term>Contraction musculaire (physiologie)</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Faiblesse musculaire (génétique)</term>
<term>Faiblesse musculaire (métabolisme)</term>
<term>Femelle</term>
<term>Fibres musculaires à contraction lente (métabolisme)</term>
<term>Humains</term>
<term>Isoformes de protéines</term>
<term>Maladies musculaires (génétique)</term>
<term>Maladies musculaires (métabolisme)</term>
<term>Mutation</term>
<term>Myosines (génétique)</term>
<term>Myosines (métabolisme)</term>
<term>Mâle</term>
<term>Nourrisson</term>
<term>Tropomyosine (génétique)</term>
<term>Tropomyosine (métabolisme)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Actins</term>
<term>Myosins</term>
<term>Tropomyosin</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Actins</term>
<term>Calcium</term>
<term>Myosins</term>
<term>Tropomyosin</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Muscle Weakness</term>
<term>Muscular Atrophy</term>
<term>Muscular Diseases</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Actines</term>
<term>Amyotrophie</term>
<term>Faiblesse musculaire</term>
<term>Maladies musculaires</term>
<term>Myosines</term>
<term>Tropomyosine</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Muscle Fibers, Slow-Twitch</term>
<term>Muscle Weakness</term>
<term>Muscular Atrophy</term>
<term>Muscular Diseases</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Actines</term>
<term>Amyotrophie</term>
<term>Calcium</term>
<term>Faiblesse musculaire</term>
<term>Fibres musculaires à contraction lente</term>
<term>Maladies musculaires</term>
<term>Myosines</term>
<term>Tropomyosine</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Contraction musculaire</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Muscle Contraction</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Adolescent</term>
<term>Adult</term>
<term>Child</term>
<term>Child, Preschool</term>
<term>Female</term>
<term>Humans</term>
<term>Infant</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Mutation</term>
<term>Protein Isoforms</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Adolescent</term>
<term>Adulte</term>
<term>Adulte d'âge moyen</term>
<term>Enfant</term>
<term>Enfant d'âge préscolaire</term>
<term>Femelle</term>
<term>Humains</term>
<term>Isoformes de protéines</term>
<term>Mutation</term>
<term>Mâle</term>
<term>Nourrisson</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Dominant mutations in TPM3, encoding α-tropomyosinslow, cause a congenital myopathy characterized by generalized muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in 12 TPM3-myopathy patients. We confirm that slow myofibre hypotrophy is a diagnostic hallmark of TPM3-myopathy, and is commonly accompanied by skewing of fibre-type ratios (either slow or fast fibre predominance). Patient muscle contained normal ratios of the three tropomyosin isoforms and normal fibre-type expression of myosins and troponins. Using 2D-PAGE, we demonstrate that mutant α-tropomyosinslow was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosinslow likely impacts actin-tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosinslow (R168C) to filamentous actin. Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca(2+)] (pCa 4.5), patient slow fibres produced only 63% of the contractile force produced in control slow fibres and had reduced acto-myosin cross-bridge cycling kinetics. Importantly, due to reduced Ca(2+)-sensitivity, at sub-saturating [Ca(2+)] (pCa 6, levels typically released during in vivo contraction) patient slow fibres produced only 26% of the force generated by control slow fibres. Thus, weakness in TPM3-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca(2+)], and impaired acto-myosin cross-bridge cycling kinetics. Fast myofibres are spared; however, they appear to be unable to compensate for slow fibre dysfunction. Abnormal Ca(2+)-sensitivity in TPM3-myopathy patients suggests Ca(2+)-sensitizing drugs may represent a useful treatment for this condition.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26307083</PMID>
<DateCreated><Year>2015</Year>
<Month>10</Month>
<Day>23</Day>
</DateCreated>
<DateCompleted><Year>2016</Year>
<Month>09</Month>
<Day>12</Day>
</DateCompleted>
<DateRevised><Year>2017</Year>
<Month>09</Month>
<Day>22</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1460-2083</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>24</Volume>
<Issue>22</Issue>
<PubDate><Year>2015</Year>
<Month>Nov</Month>
<Day>15</Day>
</PubDate>
</JournalIssue>
<Title>Human molecular genetics</Title>
<ISOAbbreviation>Hum. Mol. Genet.</ISOAbbreviation>
</Journal>
<ArticleTitle>Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.</ArticleTitle>
<Pagination><MedlinePgn>6278-92</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1093/hmg/ddv334</ELocationID>
<Abstract><AbstractText>Dominant mutations in TPM3, encoding α-tropomyosinslow, cause a congenital myopathy characterized by generalized muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in 12 TPM3-myopathy patients. We confirm that slow myofibre hypotrophy is a diagnostic hallmark of TPM3-myopathy, and is commonly accompanied by skewing of fibre-type ratios (either slow or fast fibre predominance). Patient muscle contained normal ratios of the three tropomyosin isoforms and normal fibre-type expression of myosins and troponins. Using 2D-PAGE, we demonstrate that mutant α-tropomyosinslow was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosinslow likely impacts actin-tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosinslow (R168C) to filamentous actin. Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca(2+)] (pCa 4.5), patient slow fibres produced only 63% of the contractile force produced in control slow fibres and had reduced acto-myosin cross-bridge cycling kinetics. Importantly, due to reduced Ca(2+)-sensitivity, at sub-saturating [Ca(2+)] (pCa 6, levels typically released during in vivo contraction) patient slow fibres produced only 26% of the force generated by control slow fibres. Thus, weakness in TPM3-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca(2+)], and impaired acto-myosin cross-bridge cycling kinetics. Fast myofibres are spared; however, they appear to be unable to compensate for slow fibre dysfunction. Abnormal Ca(2+)-sensitivity in TPM3-myopathy patients suggests Ca(2+)-sensitizing drugs may represent a useful treatment for this condition.</AbstractText>
<CopyrightInformation>© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yuen</LastName>
<ForeName>Michaela</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia, michaela.kreissl@sydney.edu.au.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Cooper</LastName>
<ForeName>Sandra T</ForeName>
<Initials>ST</Initials>
<AffiliationInfo><Affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Marston</LastName>
<ForeName>Steve B</ForeName>
<Initials>SB</Initials>
<AffiliationInfo><Affiliation>National Heart and Lung Institute, Imperial College London, London, UK.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Nowak</LastName>
<ForeName>Kristen J</ForeName>
<Initials>KJ</Initials>
<AffiliationInfo><Affiliation>Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>McNamara</LastName>
<ForeName>Elyshia</ForeName>
<Initials>E</Initials>
<AffiliationInfo><Affiliation>Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Mokbel</LastName>
<ForeName>Nancy</ForeName>
<Initials>N</Initials>
<AffiliationInfo><Affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Faculty of Health Sciences, St. George Health Complex, The University of Balamand, Beirut, Lebanon.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ilkovski</LastName>
<ForeName>Biljana</ForeName>
<Initials>B</Initials>
<AffiliationInfo><Affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ravenscroft</LastName>
<ForeName>Gianina</ForeName>
<Initials>G</Initials>
<AffiliationInfo><Affiliation>Harry Perkins Institute of Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rendu</LastName>
<ForeName>John</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>de Winter</LastName>
<ForeName>Josine M</ForeName>
<Initials>JM</Initials>
<AffiliationInfo><Affiliation>Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Klinge</LastName>
<ForeName>Lars</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Faculty of Medicine, Georg August University, Göttingen, Germany.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Beggs</LastName>
<ForeName>Alan H</ForeName>
<Initials>AH</Initials>
<AffiliationInfo><Affiliation>Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>North</LastName>
<ForeName>Kathryn N</ForeName>
<Initials>KN</Initials>
<AffiliationInfo><Affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia, Murdoch Children's Research Institute, the Royal Children's Hospital, Parkville, Australia and Department of Paediatrics, University of Melbourne, Melbourne, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ottenheijm</LastName>
<ForeName>Coen A C</ForeName>
<Initials>CA</Initials>
<AffiliationInfo><Affiliation>Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Clarke</LastName>
<ForeName>Nigel F</ForeName>
<Initials>NF</Initials>
<AffiliationInfo><Affiliation>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Westmead, Australia, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>FS/12/24/29568</GrantID>
<Agency>British Heart Foundation</Agency>
<Country>United Kingdom</Country>
</Grant>
<Grant><GrantID>RG/11/20/29266</GrantID>
<Agency>British Heart Foundation</Agency>
<Country>United Kingdom</Country>
</Grant>
</GrantList>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2015</Year>
<Month>08</Month>
<Day>24</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>England</Country>
<MedlineTA>Hum Mol Genet</MedlineTA>
<NlmUniqueID>9208958</NlmUniqueID>
<ISSNLinking>0964-6906</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000199">Actins</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D020033">Protein Isoforms</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C498783">TPM3 protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D014335">Tropomyosin</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 3.6.4.1</RegistryNumber>
<NameOfSubstance UI="D009218">Myosins</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>SY7Q814VUP</RegistryNumber>
<NameOfSubstance UI="D002118">Calcium</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
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<MeshHeadingList><MeshHeading><DescriptorName UI="D000199" MajorTopicYN="N">Actins</DescriptorName>
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<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
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   |texte=   Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.
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	Serveur d'exploration sur les relations entre la France et l'Australie
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Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.

Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.

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