TY - JOUR
T1 - Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies
AU - Ramspacher, Caroline
AU - Steed, Emily
AU - Boselli, Francesco
AU - Ferreira, Rita
AU - Faggianelli, Nathalie
AU - Roth, Stéphane
AU - Spiegelhalter, Coralie
AU - Messaddeq, Nadia
AU - Trinh, Le
AU - Liebling, Michael
AU - Chacko, Nikhil
AU - Tessadori, Federico
AU - Bakkers, Jeroen
AU - Laporte, Jocelyn
AU - Hnia, Karim
AU - Vermot, Julien
PY - 2015/6/16
Y1 - 2015/6/16
N2 - 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. Desminopathies are myopathies and cardiomyopathies associated with Desmin mutations leading to protein aggregates. Ramspacher et al. demonstrate that altered Desmin function or expression affect the EC coupling machinery and calcium dynamics. They show that aggregates are more toxic than the loss of function and can be rescued by knockdown and pharmacological treatment.
AB - 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. Desminopathies are myopathies and cardiomyopathies associated with Desmin mutations leading to protein aggregates. Ramspacher et al. demonstrate that altered Desmin function or expression affect the EC coupling machinery and calcium dynamics. They show that aggregates are more toxic than the loss of function and can be rescued by knockdown and pharmacological treatment.
UR - http://www.scopus.com/inward/record.url?scp=84937631803&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.05.010
DO - 10.1016/j.celrep.2015.05.010
M3 - Article
C2 - 26051936
AN - SCOPUS:84937631803
SN - 2211-1247
VL - 11
SP - 1564
EP - 1576
JO - Cell Reports [E]
JF - Cell Reports [E]
IS - 10
ER -