Myofibrillar instability exacerbated by acute exercise in filaminopathy
| العنوان: | Myofibrillar instability exacerbated by acute exercise in filaminopathy |
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| المؤلفون: | Anne-C. Plank, Peter F.M. van der Ven, Ursula Schlötzer-Schrehardt, Lucie Wolf, Frédéric Chevessier, Dieter O. Fürst, Andreas Unger, Zacharias Orfanos, A. Maerkens, Matthias Vorgerd, Stephan von Hörsten, Julia Schuld, Rudolf A. Kley, Rolf Schröder, Wolfgang A. Linke, Katrin Marcus |
| المصدر: | Human Molecular Genetics. 24:7207-7220 |
| بيانات النشر: | Oxford University Press (OUP), 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Pathology, medicine.medical_specialty, Genotype, Filamins, Cardiomyopathy, Protein aggregation, Biology, Filamin, medicine.disease_cause, Muscular Dystrophies, Lesion, Mice, Muscular Diseases, Myofibrils, Medizinische Fakultät, Genetics, medicine, Animals, ddc:610, FLNC, Muscle, Skeletal, Molecular Biology, Genetics (clinical), Mutation, Muscle weakness, General Medicine, medicine.disease, Microscopy, Electron, Phenotype, medicine.symptom, Myofibril |
| الوصف: | Filamin C (FLNC) mutations in humans cause myofibrillar myopathy (MFM) and cardiomyopathy, characterized by protein aggregation and myofibrillar degeneration. We generated the first patient-mimicking knock-in mouse harbouring the most common disease-causing filamin C mutation (p.W2710X). These heterozygous mice developed muscle weakness and myofibrillar instability, with formation of filamin C- and Xin-positive lesions streaming between Z-discs. These lesions, which are distinct from the classical MFM protein aggregates by their morphology and filamentous appearance, were greatly increased in number upon acute physical exercise in the mice. This pathology suggests that mutant filamin influences the mechanical stability of myofibrillar Z-discs, explaining the muscle weakness in mice and humans. Re-evaluation of biopsies from MFM-filaminopathy patients with different FLNC mutations revealed a similar, previously unreported lesion pathology, in addition to the classical protein aggregates, and suggested that structures previously interpreted as aggregates may be in part sarcomeric lesions. We postulate that these lesions define preclinical disease stages, preceding the formation of protein aggregates. |
| وصف الملف: | application/pdf |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f112b89cf194271c8dbce82877a50791Test https://doi.org/10.1093/hmg/ddv421Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f112b89cf194271c8dbce82877a50791 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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