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

doi:10.1016/j.celrep.2015.05.010

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

36 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1564-76
Number of pages	13
Journal	Cell Reports
Volume	11
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2015.05.010
Publication status	Published - 16 Jun 2015

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10.1016/j.celrep.2015.05.010

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Ramspacher, C., Steed, E., Boselli, F., Ferreira, R., Faggianelli, N., Roth, S., Spiegelhalter, C., Messaddeq, N., Trinh, L., Liebling, M., Chacko, N., Tessadori, F., Bakkers, J., Laporte, J., Hnia, K., & Vermot, J. (2015). Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies. Cell Reports, 11(10), 1564-76. https://doi.org/10.1016/j.celrep.2015.05.010

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

abstract = "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.",

author = "Caroline Ramspacher and Emily Steed and Francesco Boselli and Rita Ferreira and Nathalie Faggianelli and St{\'e}phane Roth and Coralie Spiegelhalter and Nadia Messaddeq and Le Trinh and Michael Liebling and Nikhil Chacko and Federico Tessadori and Jeroen Bakkers and Jocelyn Laporte and Karim Hnia and Julien Vermot",

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Ramspacher, C, Steed, E, Boselli, F, Ferreira, R, Faggianelli, N, Roth, S, Spiegelhalter, C, Messaddeq, N, Trinh, L, Liebling, M, Chacko, N, Tessadori, F , Bakkers, J, Laporte, J, Hnia, K & Vermot, J 2015, 'Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies', Cell Reports, vol. 11, no. 10, pp. 1564-76. https://doi.org/10.1016/j.celrep.2015.05.010

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.

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.

U2 - 10.1016/j.celrep.2015.05.010

DO - 10.1016/j.celrep.2015.05.010

M3 - Article

C2 - 26051936

SN - 2211-1247

VL - 11

SP - 1564

EP - 1576

JO - Cell Reports

JF - Cell Reports

IS - 10

ER -

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

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