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Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
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2006 (Engelska)Ingår i: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 16, nr 11, s. 782-791Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The pathogenic events leading to the progressive muscle weakness in patients with a E706K mutation in the head of the myosin heavy chain (MyHC) IIa were analyzed at the muscle cell and motor protein levels. Contractile properties were measured in single muscle fiber segments using the skinned fiber preparation and a single muscle fiber in vitro motility assay. A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level. At the single muscle fiber level, on the other hand, a general decrease was observed in the number of preparations where the specific criteria for acceptance were fulfilled irrespective of MyHC isoform expression. Our results provide evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle cells irrespective of MyHC isoform expression.

Ort, förlag, år, upplaga, sidor
2006. Vol. 16, nr 11, s. 782-791
Nyckelord [en]
myosin heavy chain mutation, skinned muscle fibers, in vitro motility, shortening velocity, specific tension
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-82938DOI: 10.1016/j.nmd.2006.07.023ISI: 000242494400009PubMedID: 17005402OAI: oai:DiVA.org:uu-82938DiVA, id: diva2:110845
Tillgänglig från: 2006-11-29 Skapad: 2006-11-29 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
Ingår i avhandling
1. Celluar and Molecular Mechanisms Underlying Regulation of Skeletal Muscle Contraction in Health and Disease
Öppna denna publikation i ny flik eller fönster >>Celluar and Molecular Mechanisms Underlying Regulation of Skeletal Muscle Contraction in Health and Disease
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Morphological changes, genetic modifications, and cell functional alterations are not always parallel. Therefore, assessment of skeletal muscle function is an integral part of the etiological approach. The general objective of this thesis was to look into the cellular and molecular events occurring in skeletal muscle contraction in healthy and diseased condition, using a single fiber preparation and a single fiber in vitro motility assay, in an attempt to approach the underlying mechanisms from different physiological angles. In a body size related muscle contractility study, scaling of actin filament sliding speed and its temperature sensitivity has been investigated in mammals covering a 5,500-fold difference in body mass. A profound temperature dependence of actin filament sliding speed over myosin head was demonstrated irrespective of MyHC isoform expression and species. However, the expected body size related scaling within orthologus myosin isoforms between species failed to be maintained at any temperature over 5,500-fold range in body mass, with the larger species frequently having faster in vitro motility speeds than the smaller species. This suggest that apart from the MyHC iso-form expression, other factors such as thin filament proteins and myofilament lattice spacing, may contribute to the scaling related regulation of skeletal muscle contractility. A study of a novel R133W β-tropomyosin mutation on regulation of skeletal muscle contraction in the skinned single fiber prepration and single fiber in vitro motility assay suggested that the mutation induced alteration in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin binding state, resulting in overall muscle weakness in the absence of muscle wasting. A study on a type IIa MyHC isoform missense mutation at the motor protein level demonstrated a significant negative effect on the function of the IIa MyHC isoform while other myosin isoforms had normal function. This provides evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle irrespective of MyHC isoform expression.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2010. s. 88
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 562
Nyckelord
Scaling, myosin heavy chain, in vitro motility assay, myopathy
Nationell ämneskategori
Fysiologi
Forskningsämne
Neurovetenskap
Identifikatorer
urn:nbn:se:uu:diva-123005 (URN)978-91-554-7812-4 (ISBN)
Disputation
2010-05-25, Enghoffssalen, Ing 50 Akademiska Sjukhuset, Uppsala, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2010-05-04 Skapad: 2010-04-22 Senast uppdaterad: 2018-01-12

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Li, MingxinLarsson, Lars

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