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Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. (Clinical Neurophysiology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
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2007 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 581, no 3, 1283-1292 p.Article in journal (Refereed) Published
Abstract [en]

A novel R133W β-tropomyosin (β-Tm) mutation, associated with muscle weakness and distal limb deformities, has recently been identified in a woman and her daughter. The muscle weakness was not accompanied by progressive muscle wasting or histopathological abnormalities in tibialis anterior muscle biopsy specimens. The aim of the present study was to explore the mechanisms underlying the impaired muscle function in patients with the β-Tm mutation. Maximum force normalized to fibre cross-sectional area (specific force, SF), maximum velocity of unloaded shortening (V0), apparent rate constant of force redevelopment (ktr) and force–pCa relationship were evaluated in single chemically skinned muscle fibres from the two patients carrying the β-Tm mutation and from healthy control subjects. Significant differences in regulation of muscle contraction were observed in the type I fibres: a lower SF (P < 0.05) and ktr (P < 0.01), and a faster V0 (P < 0.05). The force–pCa relationship did not differ between patient and control fibres, indicating an unaltered Ca2+ activation of contractile proteins. Collectively, these results indicate a slower cross-bridge attachment rate and a faster detachment rate caused by the R133W β-Tm mutation. It is suggested that the R133W β-Tm mutation induces 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.

Place, publisher, year, edition, pages
2007. Vol. 581, no 3, 1283-1292 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-12417DOI: 10.1113/jphysiol.2007.129759ISI: 000247174700035OAI: oai:DiVA.org:uu-12417DiVA: diva2:40186
Available from: 2007-12-17 Created: 2007-12-17 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Celluar and Molecular Mechanisms Underlying Regulation of Skeletal Muscle Contraction in Health and Disease
Open this publication in new window or tab >>Celluar and Molecular Mechanisms Underlying Regulation of Skeletal Muscle Contraction in Health and Disease
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 88 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 562
Keyword
Scaling, myosin heavy chain, in vitro motility assay, myopathy
National Category
Physiology
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-123005 (URN)978-91-554-7812-4 (ISBN)
Public defence
2010-05-25, Enghoffssalen, Ing 50 Akademiska Sjukhuset, Uppsala, 13:00 (English)
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Available from: 2010-05-04 Created: 2010-04-22 Last updated: 2010-05-18

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Ochala, JulienLi, MingxinLarsson, Lars

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