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Defective regulation of contractile function in muscle fibres carrying an E41K beta-tropomyosin mutation.

Journal article
Authors Julien Ochala
Meishan Li
Monica Ohlsson
Anders Oldfors
Lars Larsson
Published in The Journal of physiology
Volume 586
Issue Pt 12
Pages 2993-3004
ISSN 1469-7793
Publication year 2008
Published at Institute of Biomedicine, Department of Pathology
Pages 2993-3004
Language en
Keywords Adaptation, Physiological, genetics, Adult, Aged, Female, Gene Expression Regulation, genetics, Genotype, Humans, Models, Genetic, Muscle Contraction, genetics, Muscle Fibers, Skeletal, Muscle, Skeletal, physiopathology, Mutation, Myopathies, Structural, Congenital, pathology, physiopathology, Tropomyosin, genetics
Subject categories Cell and Molecular Biology


A novel E41K beta-tropomyosin (beta-Tm) mutation, associated with congenital myopathy and muscle weakness, was recently identified in a woman and her daughter. In both patients, muscle weakness was coupled with muscle fibre atrophy. It remains unknown, however, whether the E41K beta-Tm mutation directly affects regulation of muscle contraction, contributing to the muscle weakness. To address this question, we studied a broad range of contractile characteristics in skinned muscle fibres from the two patients and eight healthy controls. Results showed decreases (i) in speed of contraction at saturated Ca(2+) concentration (apparent rate constant of force redevelopment (k(tr)) and unloaded shortening speed (V(0))); and (ii) in contraction sensitivity to Ca(2+) concentration, in fibres from patients compared with controls, suggesting that the mutation has a negative effect on contractile function, contributing to the muscle weakness. To investigate whether these negative impacts are reversible, we exposed skinned muscle fibres to the Ca(2+) sensitizer EMD 57033. In fibres from patients, 30 mum of EMD 57033 (i) had no effect on speed of contraction (k(tr) and V(0)) at saturated Ca(2+) concentration but (ii) increased Ca(2+) sensitivity of contraction, suggesting a potential therapeutic approach in patients carrying the E41K beta-Tm mutation.

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