Defective regulation of contractile function in muscle fibres carrying an E41K β‐tropomyosin mutation

Abstract

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.