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<record><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><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></affiliation><affiliation><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></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><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></affiliation><affiliation><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></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><nlm:aff id="af3"><institution>National Heart and Lung Institute, Imperial College London</institution>,<addr-line>London</addr-line>,<country>UK</country>,</nlm:aff></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><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></affiliation></author><author><name sortKey="Mcnamara, Elyshia" sort="Mcnamara, Elyshia" uniqKey="Mcnamara E" first="Elyshia" last="Mcnamara">Elyshia Mcnamara</name><affiliation><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></affiliation></author><author><name sortKey="Mokbel, Nancy" sort="Mokbel, Nancy" uniqKey="Mokbel N" first="Nancy" last="Mokbel">Nancy Mokbel</name><affiliation><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></affiliation><affiliation><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></affiliation></author><author><name sortKey="Ilkovski, Biljana" sort="Ilkovski, Biljana" uniqKey="Ilkovski B" first="Biljana" last="Ilkovski">Biljana Ilkovski</name><affiliation><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></affiliation></author><author><name sortKey="Ravenscroft, Gianina" sort="Ravenscroft, Gianina" uniqKey="Ravenscroft G" first="Gianina" last="Ravenscroft">Gianina Ravenscroft</name><affiliation><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></affiliation></author><author><name sortKey="Rendu, John" sort="Rendu, John" uniqKey="Rendu J" first="John" last="Rendu">John Rendu</name><affiliation><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></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><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></affiliation></author><author><name sortKey="Klinge, Lars" sort="Klinge, Lars" uniqKey="Klinge L" first="Lars" last="Klinge">Lars Klinge</name><affiliation><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></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><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></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><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></affiliation><affiliation><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></affiliation><affiliation><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></affiliation><affiliation><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></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><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></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><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></affiliation><affiliation><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></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></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><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></affiliation><affiliation><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></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><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></affiliation><affiliation><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></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><nlm:aff id="af3"><institution>National Heart and Lung Institute, Imperial College London</institution>,<addr-line>London</addr-line>,<country>UK</country>,</nlm:aff></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><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></affiliation></author><author><name sortKey="Mcnamara, Elyshia" sort="Mcnamara, Elyshia" uniqKey="Mcnamara E" first="Elyshia" last="Mcnamara">Elyshia Mcnamara</name><affiliation><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></affiliation></author><author><name sortKey="Mokbel, Nancy" sort="Mokbel, Nancy" uniqKey="Mokbel N" first="Nancy" last="Mokbel">Nancy Mokbel</name><affiliation><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></affiliation><affiliation><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></affiliation></author><author><name sortKey="Ilkovski, Biljana" sort="Ilkovski, Biljana" uniqKey="Ilkovski B" first="Biljana" last="Ilkovski">Biljana Ilkovski</name><affiliation><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></affiliation></author><author><name sortKey="Ravenscroft, Gianina" sort="Ravenscroft, Gianina" uniqKey="Ravenscroft G" first="Gianina" last="Ravenscroft">Gianina Ravenscroft</name><affiliation><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></affiliation></author><author><name sortKey="Rendu, John" sort="Rendu, John" uniqKey="Rendu J" first="John" last="Rendu">John Rendu</name><affiliation><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></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><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></affiliation></author><author><name sortKey="Klinge, Lars" sort="Klinge, Lars" uniqKey="Klinge L" first="Lars" last="Klinge">Lars Klinge</name><affiliation><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></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><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></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><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></affiliation><affiliation><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></affiliation><affiliation><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></affiliation><affiliation><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></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><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></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><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></affiliation><affiliation><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></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 article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Hum Mol Genet</journal-id><journal-id journal-id-type="iso-abbrev">Hum. Mol. Genet</journal-id><journal-id journal-id-type="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title-group><journal-title>Human Molecular Genetics</journal-title></journal-title-group><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26307083</article-id><article-id pub-id-type="pmc">4614700</article-id><article-id pub-id-type="doi">10.1093/hmg/ddv334</article-id><article-id pub-id-type="publisher-id">ddv334</article-id><article-categories><subj-group subj-group-type="heading"><subject>Articles</subject></subj-group></article-categories><title-group><article-title>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</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Yuen</surname><given-names>Michaela</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Cooper</surname><given-names>Sandra T.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Marston</surname><given-names>Steve B.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Nowak</surname><given-names>Kristen J.</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>McNamara</surname><given-names>Elyshia</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Mokbel</surname><given-names>Nancy</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Ilkovski</surname><given-names>Biljana</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ravenscroft</surname><given-names>Gianina</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Rendu</surname><given-names>John</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>de Winter</surname><given-names>Josine M.</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Klinge</surname><given-names>Lars</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Beggs</surname><given-names>Alan H.</given-names></name><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>North</surname><given-names>Kathryn N.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="aff" rid="af10">10</xref><xref ref-type="aff" rid="af11">11</xref></contrib><contrib contrib-type="author"><name><surname>Ottenheijm</surname><given-names>Coen A.C.</given-names></name><xref ref-type="aff" rid="af7">7</xref><xref ref-type="author-notes" rid="AN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Clarke</surname><given-names>Nigel F.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="aff" rid="af2">2</xref><xref ref-type="author-notes" rid="AN1">†</xref></contrib><aff id="af1"><label>1</label><institution>Institute for Neuroscience and</institution><institution>Muscle Research, The Children's Hospital at Westmead</institution>,<addr-line>Westmead</addr-line>,<country>Australia</country>,</aff><aff id="af2"><label>2</label><addr-line>Discipline of Paediatrics and Child Health</addr-line>,<institution>University of Sydney</institution>,<addr-line>Sydney</addr-line>,<country>Australia</country>,</aff><aff id="af3"><label>3</label><institution>National Heart and Lung Institute, Imperial College London</institution>,<addr-line>London</addr-line>,<country>UK</country>,</aff><aff id="af4"><label>4</label><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>,</aff><aff id="af5"><label>5</label><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>,</aff><aff id="af6"><label>6</label><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>,</aff><aff id="af7"><label>7</label><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>,</aff><aff id="af8"><label>8</label><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>,</aff><aff id="af9"><label>9</label><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>,</aff><aff id="af10"><label>10</label><institution>Murdoch Children's Research Institute, the Royal Children's Hospital</institution>,<addr-line>Parkville</addr-line>,<country>Australia</country> and</aff><aff id="af11"><label>11</label><addr-line>Department of Paediatrics</addr-line>,<institution>University of Melbourne</institution>,<addr-line>Melbourne</addr-line>,<country>Australia</country></aff></contrib-group><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. Tel: +61 298451495; Fax: +61 298453489; Email: <email>michaela.kreissl@sydney.edu.au</email></corresp><fn id="AN1" fn-type="con"><label>†</label><p>The authors wish it to be known that, in their opinion, the last two authors should be regarded as joint last authors.</p></fn></author-notes><pub-date pub-type="ppub"><day>15</day><month>11</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>24</day><month>8</month><year>2015</year></pub-date><volume>24</volume><issue>22</issue><fpage>6278</fpage><lpage>6292</lpage><history><date date-type="received"><day>28</day><month>5</month><year>2015</year></date><date date-type="rev-recd"><day>20</day><month>7</month><year>2015</year></date><date date-type="accepted"><day>10</day><month>8</month><year>2015</year></date></history><permissions><copyright-statement>© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com</copyright-statement><copyright-year>2015</copyright-year></permissions><self-uri content-type="pdf" xlink:href="ddv334.pdf"></self-uri><abstract><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></abstract><funding-group><award-group id="funding-1"><funding-source>National Health and Medical Research Council of Australia</funding-source><award-id>APP571287</award-id><award-id>APP1022707</award-id><award-id>APP1048816</award-id><award-id>APP1035955</award-id></award-group><award-group id="funding-2"><funding-source>National Institutes of Health (USA)</funding-source><award-id>R01 HD075802</award-id></award-group><award-group id="funding-3"><funding-source>Australian Resource Council Future Fellowship</funding-source><award-id>FT100100734</award-id></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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