Defective regulation of contractile function in muscle fibres carrying an E41K beta-tropomyosin mutation.
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.
Ochala
Julien
J
Department of Neuroscience, Clinical Neurophysiology, University Hospital, Entrance 85, 3rd floor, SE-751 85 Uppsala, Sweden. julien.ochala@neurofys.uu.se
Li
Meishan
M
Ohlsson
Monica
M
Oldfors
Anders
A
Larsson
Lars
L
D000222:Adaptation, Physiological / Q000235:genetics; D000328:Adult; D000368:Aged; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D009119:Muscle Contraction / Q000235:genetics*; D018485:Muscle Fibers, Skeletal; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000473:pathology / Q000503:physiopathology*; D014335:Tropomyosin / Q000235:genetics*
D014335:Tropomyosin