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http://purl.uniprot.org/citations/26307083http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/26307083http://www.w3.org/2000/01/rdf-schema#comment"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."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.org/dc/terms/identifier"doi:10.1093/hmg/ddv334"xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Yuen M."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Beggs A.H."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"North K.N."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Ravenscroft G."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Clarke N.F."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Cooper S.T."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Ilkovski B."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Marston S.B."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Nowak K.J."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Klinge L."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Rendu J."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"McNamara E."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Ottenheijm C.A."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"de Winter J.M."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/author"Mokbel N."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/date"2015"xsd:gYear
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/name"Hum Mol Genet"xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/pages"6278-6292"xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/title"Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres."xsd:string
http://purl.uniprot.org/citations/26307083http://purl.uniprot.org/core/volume"24"xsd:string
http://purl.uniprot.org/citations/26307083http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/26307083
http://purl.uniprot.org/citations/26307083http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/26307083
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