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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ramspacher
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Emily
authors.initials: E
authors.lastname: Steed
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Francesco
authors.initials: F
authors.lastname: Boselli
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Ferreira
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Faggianelli
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Roth
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Spiegelhalter
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.affiliation: Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Trinh
authors.affiliation: Department of Electrical and Computer Engineering, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Liebling
authors.affiliation: Department of Electrical and Computer Engineering, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Chacko
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht 3584 CT, the Netherlands.
authors.forename: Federico
authors.initials: F
authors.lastname: Tessadori
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht 3584 CT, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bakkers
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Hnia
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France. Electronic address: julien@igbmc.fr.
authors.forename: Julien
authors.initials: J
authors.lastname: Vermot
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D003893:Desmin / Q000235:genetics* / Q000378:metabolism*; D006321:Heart / Q000502:physiology*; D006801:Humans; D018482:Muscle, Skeletal / Q000502:physiology*; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D015027:Zebrafish
chemical_list: D003893:Desmin