DesR349P Mutation Results in Ultrastructural Disruptions and Compromise of Skeletal Muscle Biomechanics Already at Preclinical Stages in Young Mice before the Onset of Protein Aggregation

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Details zur Publikation

Autor(en): Diermeier S, Haug M, Reischl B, Buttgereit A, Schürmann S, Spörrer M, Goldmann W, Fabry B, Elhimine F, Stehle R, Pfitzer G, Winter L, Clemen C, Schröder R, Friedrich O
Zeitschrift: Biophysical Journal
Verlag: Elsevier (Cell Press) / Biophysical Society
Jahr der Veröffentlichung: 2016
Band: 110
Heftnummer: 3
Seitenbereich: 303A-303A
ISSN: 0006-3495
Sprache: Englisch


Abstract

Mutations in the extra-sarcomeric protein desmin give rise to protein aggregate
myopathies that interfere with cellular function. The R350P mutation is
the most common human desminopathy. A murine DesR349P model of human
DesR350P desminopathy was previously engineered. In this study, we
followed the hypothesis of whether muscle cytoarchitecture and
biomechanical properties are already altered in preclinical stages of
R349P desminopathy. We applied non-linear second harmonic generation
(SHG) and 2-photon fluorescence morphometry analysis to single fibres of
fast- and slow-twitch muscle to analyze sarcomeric architecture and
nuclear morphology. We found a vast disruption of the lateral sarcomere
lattice (indicated by large ‘vernier’ densities) and myofibrillar
angular deviations (indicated by cosine angle sums) in single DesR349P
fibres. Homozygous fibres were more severely affected than heterozygous.
The former showed a marked nuclear pathology with spheric nuclei,
increased nuclear number and density. For biomechanics, we assessed
active and passive properties. Axial stiffness of DesR349P muscle was
much increased, both in fibre and myofibrillar homozygous bundles.
Lateral stiffness of the membrane complex in myoblasts was increased in
cells heterozygous for DesR349P while homozygous were similar to wt.
Caffeine-induced force was compromised in heterozygous fibre bundles but
increased in homozygous bundles. This was explained by a marked shift
of myofibrillar Ca2+ sensitivity: heterozygous bundles being less sensitive but homozygous more sensitive to Ca2+.
This points towards a specific compensatory mechanism in homozygous
mutation to cope with otherwise compromised force production already at
preclinical stages of desminopathy. Our findings provide a very first
complete picture to explain compromised force in heterozygous DesR350P
patients: increased muscle stiffness, higher susceptibility towards
stretch-induced injury, disrupted myofibrillar alignment and compromised
active force production.


FAU-Autoren / FAU-Herausgeber

Buttgereit, Andreas Dr.
Lehrstuhl für Medizinische Biotechnologie
Fabry, Ben Prof. Dr.
Lehrstuhl für Biophysik
Friedrich, Oliver Prof. Dr. Dr.
Lehrstuhl für Medizinische Biotechnologie
Goldmann, Wolfgang Prof.
Lehrstuhl für Biophysik
Haug, Michael
Lehrstuhl für Medizinische Biotechnologie
Reischl, Barbara
Lehrstuhl für Medizinische Biotechnologie
Schröder, Rolf Prof. Dr.
Professur für Neuropathologie
Schürmann, Sebastian Dr. rer. nat.
Lehrstuhl für Medizinische Biotechnologie
Spörrer, Marina
Lehrstuhl für Biophysik


Autor(en) der externen Einrichtung(en)
Universität Köln


Zitierweisen

APA:
Diermeier, S., Haug, M., Reischl, B., Buttgereit, A., Schürmann, S., Spörrer, M.,... Friedrich, O. (2016). DesR349P Mutation Results in Ultrastructural Disruptions and Compromise of Skeletal Muscle Biomechanics Already at Preclinical Stages in Young Mice before the Onset of Protein Aggregation. Biophysical Journal, 110(3), 303A-303A. https://dx.doi.org/10.1016/j.bpj.2015.11.1629

MLA:
Diermeier, Stefanie, et al. "DesR349P Mutation Results in Ultrastructural Disruptions and Compromise of Skeletal Muscle Biomechanics Already at Preclinical Stages in Young Mice before the Onset of Protein Aggregation." Biophysical Journal 110.3 (2016): 303A-303A.

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Zuletzt aktualisiert 2018-30-11 um 12:10