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Celluar and Molecular Mechanisms Underlying Regulation of Skeletal Muscle Contraction in Health and Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
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. , p. 88
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 562
Keywords [en]
Scaling, myosin heavy chain, in vitro motility assay, myopathy
National Category
Physiology
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-123005ISBN: 978-91-554-7812-4 (print)OAI: oai:DiVA.org:uu-123005DiVA, id: diva2:311646
Public defence
2010-05-25, Enghoffssalen, Ing 50 Akademiska Sjukhuset, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2010-05-04 Created: 2010-04-22 Last updated: 2018-01-12
List of papers
1. Scaling of Motility Speed and Its Temperature Sensitivity in Mammals Representing a 5,500-fold Difference in Body Size
Open this publication in new window or tab >>Scaling of Motility Speed and Its Temperature Sensitivity in Mammals Representing a 5,500-fold Difference in Body Size
(English)Article in journal (Refereed) Submitted
National Category
Physiology
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-123004 (URN)
Note
kommer att kompletterasAvailable from: 2010-04-22 Created: 2010-04-22 Last updated: 2018-01-12Bibliographically approved
2. Human skeletal muscle myosin function at physiological and non-physiological temperatures
Open this publication in new window or tab >>Human skeletal muscle myosin function at physiological and non-physiological temperatures
2006 (English)In: Acta Physiol, Vol. 186, p. 151-158Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-78355 (URN)
Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2011-01-11
3. Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres
Open this publication in new window or tab >>Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres
Show others...
2007 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 581, no 3, p. 1283-1292Article 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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-12417 (URN)10.1113/jphysiol.2007.129759 (DOI)000247174700035 ()
Available from: 2007-12-17 Created: 2007-12-17 Last updated: 2017-12-11Bibliographically approved
4. Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)
Open this publication in new window or tab >>Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)
Show others...
2006 (English)In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 16, no 11, p. 782-791Article in journal (Refereed) 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.

Keywords
myosin heavy chain mutation, skinned muscle fibers, in vitro motility, shortening velocity, specific tension
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-82938 (URN)10.1016/j.nmd.2006.07.023 (DOI)000242494400009 ()17005402 (PubMedID)
Available from: 2006-11-29 Created: 2006-11-29 Last updated: 2017-12-14Bibliographically approved

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