Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies

Caroline Ramspacher, Emily Steed, Francesco Boselli, Rita Ferreira, Nathalie Faggianelli, Stéphane Roth, Coralie Spiegelhalter, Nadia Messaddeq, Le Trinh, Michael Liebling, Nikhil Chacko, Federico Tessadori, Jeroen Bakkers, Jocelyn Laporte, Karim Hnia, Julien Vermot

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

Desminopathies belong to a family of muscle disorders called myofibrillar myopathies that are caused by Desmin mutations and lead to protein aggregates in muscle fibers. To date, the initial pathological steps of desminopathies and the impact of desmin aggregates in the genesis of the disease are unclear. Using live, high-resolution microscopy, we show that Desmin loss of function and Desmin aggregates promote skeletal muscle defects and alter heart biomechanics. In addition, we show that the calcium dynamics associated with heart contraction are impaired and are associated with sarcoplasmic reticulum dilatation as well as abnormal subcellular distribution of Ryanodine receptors. Our results demonstrate that desminopathies are associated with perturbed excitation-contraction coupling machinery and that aggregates are more detrimental than Desmin loss of function. Additionally, we show that pharmacological inhibition of aggregate formation and Desmin knockdown revert these phenotypes. Our data suggest alternative therapeutic approaches and further our understanding of the molecular determinants modulating Desmin aggregate formation.

Originele taal-2Engels
Pagina's (van-tot)1564-76
Aantal pagina's13
TijdschriftCell Reports
Volume11
Nummer van het tijdschrift10
DOI's
StatusGepubliceerd - 16 jun 2015

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