Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres
Identifieur interne : 002980 ( Ncbi/Merge ); précédent : 002979; suivant : 002981Muscle 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 [Australie, 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 [ 0964-6906 ] ; 2015.
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
Url:
DOI: 10.1093/hmg/ddv334
PubMed: 26307083
PubMed Central: 4614700
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PMC:4614700Le document en format XML
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Nowak</name><affiliation wicri:level="1"><nlm:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af5"><addr-line>Faculty of Health Sciences, St. George Health Complex</addr-line>,<institution>The University of Balamand</institution>,<addr-line>Beirut</addr-line>,<country>Lebanon</country>,</nlm:aff><country xml:lang="fr">Liban</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af6"><addr-line>Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire</addr-line>,<institution>Centre Hospitalier Universitaire de Grenoble</institution>,<addr-line>Grenoble</addr-line>,<country>France</country>,</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af7"><addr-line>Department of Physiology</addr-line>,<institution>Institute for Cardiovascular Research, VU University Medical Center</institution>,<addr-line>Amsterdam</addr-line>,<country>The Netherlands</country>,</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af8"><addr-line>Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Faculty of Medicine</addr-line>,<institution>Georg August University</institution>,<addr-line>Göttingen</addr-line>,<country>Germany</country>,</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af9"><addr-line>Division of Genetics and Genomics, The Manton Center for Orphan Disease Research</addr-line>,<institution>Boston Children's Hospital, Harvard Medical School</institution>,<addr-line>Boston, MA</addr-line>,<country>USA</country>,</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="North, Kathryn N" sort="North, Kathryn N" uniqKey="North K" first="Kathryn N." last="North">Kathryn N. 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C." last="Ottenheijm">Coen A. C. Ottenheijm</name><affiliation wicri:level="1"><nlm:aff id="af7"><addr-line>Department of Physiology</addr-line>,<institution>Institute for Cardiovascular Research, VU University Medical Center</institution>,<addr-line>Amsterdam</addr-line>,<country>The Netherlands</country>,</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26307083</idno><idno type="pmc">4614700</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614700</idno><idno type="RBID">PMC:4614700</idno><idno type="doi">10.1093/hmg/ddv334</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000191</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000191</idno><idno type="wicri:Area/Pmc/Curation">000191</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000191</idno><idno type="wicri:Area/Pmc/Checkpoint">000E49</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000E49</idno><idno type="wicri:source">PubMed</idno><idno type="wicri:Area/PubMed/Corpus">002793</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002793</idno><idno type="wicri:Area/PubMed/Curation">002724</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002724</idno><idno type="wicri:Area/PubMed/Checkpoint">002724</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">002724</idno><idno type="wicri:Area/Ncbi/Merge">002980</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Muscle weakness in <italic>TPM3</italic>-myopathy is due to reduced Ca<sup>2+</sup>-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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><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:aff id="af3"><institution>National Heart and Lung Institute, Imperial College London</institution>,<addr-line>London</addr-line>,<country>UK</country>,</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af5"><addr-line>Faculty of Health Sciences, St. George Health Complex</addr-line>,<institution>The University of Balamand</institution>,<addr-line>Beirut</addr-line>,<country>Lebanon</country>,</nlm:aff><country xml:lang="fr">Liban</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af6"><addr-line>Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire</addr-line>,<institution>Centre Hospitalier Universitaire de Grenoble</institution>,<addr-line>Grenoble</addr-line>,<country>France</country>,</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af7"><addr-line>Department of Physiology</addr-line>,<institution>Institute for Cardiovascular Research, VU University Medical Center</institution>,<addr-line>Amsterdam</addr-line>,<country>The Netherlands</country>,</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af8"><addr-line>Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Faculty of Medicine</addr-line>,<institution>Georg August University</institution>,<addr-line>Göttingen</addr-line>,<country>Germany</country>,</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af9"><addr-line>Division of Genetics and Genomics, The Manton Center for Orphan Disease Research</addr-line>,<institution>Boston Children's Hospital, Harvard Medical School</institution>,<addr-line>Boston, MA</addr-line>,<country>USA</country>,</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff wicri:cut=" and" id="af10"><institution>Murdoch Children's Research Institute, the Royal Children's Hospital</institution>,<addr-line>Parkville</addr-line>,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af11"><addr-line>Department of Paediatrics</addr-line>,<institution>University of Melbourne</institution>,<addr-line>Melbourne</addr-line>,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af7"><addr-line>Department of Physiology</addr-line>,<institution>Institute for Cardiovascular Research, VU University Medical Center</institution>,<addr-line>Amsterdam</addr-line>,<country>The Netherlands</country>,</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><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"><p>Dominant mutations in <italic>TPM3</italic>, encoding α-tropomyosin<sub>slow</sub>, cause a congenital myopathy characterized by generalized muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in 12 <italic>TPM3</italic>-myopathy patients. We confirm that slow myofibre hypotrophy is a diagnostic hallmark of <italic>TPM3</italic>-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-tropomyosin<sub>slow</sub> was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosin<sub>slow</sub> likely impacts actin–tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosin<sub>slow</sub> (R168C) to filamentous actin. Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca<sup>2+</sup>] (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<sup>2+</sup>-sensitivity, at sub-saturating [Ca<sup>2+</sup>] (pCa 6, levels typically released during <italic>in vivo</italic> contraction) patient slow fibres produced only 26% of the force generated by control slow fibres. Thus, weakness in <italic>TPM3</italic>-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca<sup>2+</sup>], 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<sup>2+</sup>-sensitivity in <italic>TPM3</italic>-myopathy patients suggests Ca<sup>2+</sup>-sensitizing drugs may represent a useful treatment for this condition.</p></div></front></TEI><double pmid="26307083"><pmc><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Muscle weakness in <italic>TPM3</italic>-myopathy is due to reduced Ca<sup>2+</sup>-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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><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:aff id="af3"><institution>National Heart and Lung Institute, Imperial College London</institution>,<addr-line>London</addr-line>,<country>UK</country>,</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af5"><addr-line>Faculty of Health Sciences, St. George Health Complex</addr-line>,<institution>The University of Balamand</institution>,<addr-line>Beirut</addr-line>,<country>Lebanon</country>,</nlm:aff><country xml:lang="fr">Liban</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af6"><addr-line>Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire</addr-line>,<institution>Centre Hospitalier Universitaire de Grenoble</institution>,<addr-line>Grenoble</addr-line>,<country>France</country>,</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af7"><addr-line>Department of Physiology</addr-line>,<institution>Institute for Cardiovascular Research, VU University Medical Center</institution>,<addr-line>Amsterdam</addr-line>,<country>The Netherlands</country>,</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af8"><addr-line>Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Faculty of Medicine</addr-line>,<institution>Georg August University</institution>,<addr-line>Göttingen</addr-line>,<country>Germany</country>,</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af9"><addr-line>Division of Genetics and Genomics, The Manton Center for Orphan Disease Research</addr-line>,<institution>Boston Children's Hospital, Harvard Medical School</institution>,<addr-line>Boston, MA</addr-line>,<country>USA</country>,</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff wicri:cut=" and" id="af10"><institution>Murdoch Children's Research Institute, the Royal Children's Hospital</institution>,<addr-line>Parkville</addr-line>,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af11"><addr-line>Department of Paediatrics</addr-line>,<institution>University of Melbourne</institution>,<addr-line>Melbourne</addr-line>,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af7"><addr-line>Department of Physiology</addr-line>,<institution>Institute for Cardiovascular Research, VU University Medical Center</institution>,<addr-line>Amsterdam</addr-line>,<country>The Netherlands</country>,</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26307083</idno><idno type="pmc">4614700</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614700</idno><idno type="RBID">PMC:4614700</idno><idno type="doi">10.1093/hmg/ddv334</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000191</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000191</idno><idno type="wicri:Area/Pmc/Curation">000191</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000191</idno><idno type="wicri:Area/Pmc/Checkpoint">000E49</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000E49</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Muscle weakness in <italic>TPM3</italic>-myopathy is due to reduced Ca<sup>2+</sup>-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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><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:aff id="af3"><institution>National Heart and Lung Institute, Imperial College London</institution>,<addr-line>London</addr-line>,<country>UK</country>,</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af5"><addr-line>Faculty of Health Sciences, St. George Health Complex</addr-line>,<institution>The University of Balamand</institution>,<addr-line>Beirut</addr-line>,<country>Lebanon</country>,</nlm:aff><country xml:lang="fr">Liban</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af4"><addr-line>Harry Perkins Institute of Medical Research and the Centre for Medical Research</addr-line>,<institution>University of Western Australia</institution>,<addr-line>Nedlands</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af6"><addr-line>Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire</addr-line>,<institution>Centre Hospitalier Universitaire de Grenoble</institution>,<addr-line>Grenoble</addr-line>,<country>France</country>,</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af7"><addr-line>Department of Physiology</addr-line>,<institution>Institute for Cardiovascular Research, VU University Medical Center</institution>,<addr-line>Amsterdam</addr-line>,<country>The Netherlands</country>,</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af8"><addr-line>Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, Faculty of Medicine</addr-line>,<institution>Georg August University</institution>,<addr-line>Göttingen</addr-line>,<country>Germany</country>,</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af9"><addr-line>Division of Genetics and Genomics, The Manton Center for Orphan Disease Research</addr-line>,<institution>Boston Children's Hospital, Harvard Medical School</institution>,<addr-line>Boston, MA</addr-line>,<country>USA</country>,</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff wicri:cut=" and" id="af10"><institution>Murdoch Children's Research Institute, the Royal Children's Hospital</institution>,<addr-line>Parkville</addr-line>,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af11"><addr-line>Department of Paediatrics</addr-line>,<institution>University of Melbourne</institution>,<addr-line>Melbourne</addr-line>,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af7"><addr-line>Department of Physiology</addr-line>,<institution>Institute for Cardiovascular Research, VU University Medical Center</institution>,<addr-line>Amsterdam</addr-line>,<country>The Netherlands</country>,</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea># see nlm:aff country strict</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:aff id="af1"><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2"><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Dominant mutations in <italic>TPM3</italic>, encoding α-tropomyosin<sub>slow</sub>, cause a congenital myopathy characterized by generalized muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in 12 <italic>TPM3</italic>-myopathy patients. We confirm that slow myofibre hypotrophy is a diagnostic hallmark of <italic>TPM3</italic>-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-tropomyosin<sub>slow</sub> was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosin<sub>slow</sub> likely impacts actin–tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosin<sub>slow</sub> (R168C) to filamentous actin. Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca<sup>2+</sup>] (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<sup>2+</sup>-sensitivity, at sub-saturating [Ca<sup>2+</sup>] (pCa 6, levels typically released during <italic>in vivo</italic> contraction) patient slow fibres produced only 26% of the force generated by control slow fibres. Thus, weakness in <italic>TPM3</italic>-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca<sup>2+</sup>], 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<sup>2+</sup>-sensitivity in <italic>TPM3</italic>-myopathy patients suggests Ca<sup>2+</sup>-sensitizing drugs may represent a useful treatment for this condition.</p></div></front></TEI></pmc><pubmed><TEI><teiHeader><fileDesc><titleStmt><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="4"><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><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</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><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="4"><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><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region><settlement type="city">Sydney</settlement></placeName><orgName type="university">Université de Sydney</orgName></affiliation></author><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="3"><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><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></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><wicri:noRegion>Nedlands</wicri:noRegion></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><wicri:noRegion>Nedlands</wicri:noRegion></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><wicri:noRegion>Beirut</wicri:noRegion></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><wicri:noRegion>Westmead</wicri:noRegion></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><wicri:noRegion>Nedlands</wicri:noRegion></affiliation></author><author><name sortKey="Rendu, John" sort="Rendu, John" uniqKey="Rendu J" first="John" last="Rendu">John Rendu</name><affiliation wicri:level="3"><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><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></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="3"><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><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></affiliation></author><author><name sortKey="Klinge, Lars" sort="Klinge, Lars" uniqKey="Klinge L" first="Lars" last="Klinge">Lars Klinge</name><affiliation wicri:level="3"><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><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="4"><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><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region><settlement type="city">Sydney</settlement></placeName><orgName type="university">Université de Sydney</orgName></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="3"><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><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></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="4"><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><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region><settlement type="city">Sydney</settlement></placeName><orgName type="university">Université de Sydney</orgName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:26307083</idno><idno type="pmid">26307083</idno><idno type="doi">10.1093/hmg/ddv334</idno><idno type="wicri:Area/PubMed/Corpus">002793</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002793</idno><idno type="wicri:Area/PubMed/Curation">002724</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002724</idno><idno type="wicri:Area/PubMed/Checkpoint">002724</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">002724</idno></publicationStmt><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="4"><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><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</wicri:regionArea><orgName type="university">Université de Sydney</orgName><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region></placeName></affiliation></author><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="4"><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><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region><settlement type="city">Sydney</settlement></placeName><orgName type="university">Université de Sydney</orgName></affiliation></author><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="3"><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><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></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><wicri:noRegion>Nedlands</wicri:noRegion></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><wicri:noRegion>Nedlands</wicri:noRegion></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><wicri:noRegion>Beirut</wicri:noRegion></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><wicri:noRegion>Westmead</wicri:noRegion></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><wicri:noRegion>Nedlands</wicri:noRegion></affiliation></author><author><name sortKey="Rendu, John" sort="Rendu, John" uniqKey="Rendu J" first="John" last="Rendu">John Rendu</name><affiliation wicri:level="3"><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><placeName><region type="region">Auvergne-Rhône-Alpes</region><region type="old region">Rhône-Alpes</region><settlement type="city">Grenoble</settlement></placeName></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="3"><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><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></affiliation></author><author><name sortKey="Klinge, Lars" sort="Klinge, Lars" uniqKey="Klinge L" first="Lars" last="Klinge">Lars Klinge</name><affiliation wicri:level="3"><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><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Göttingen</settlement></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="4"><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><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region><settlement type="city">Sydney</settlement></placeName><orgName type="university">Université de Sydney</orgName></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="3"><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><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></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="4"><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><placeName><settlement type="city">Sydney</settlement><region type="état">Nouvelle-Galles du Sud</region><settlement type="city">Sydney</settlement></placeName><orgName type="university">Université de Sydney</orgName></affiliation></author></analytic><series><title level="j">Human molecular genetics</title><idno type="eISSN">1460-2083</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><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></double></record>Pour manipuler ce document sous Unix (Dilib)
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