Muscle fibres carrying the E41K beta-Tm mutation showed decreased speed of contraction and Ca(2+) sensitivity compared to controls, with Ca(2+) sensitivity being reversible by EMD 57033.
Case-Control (n=10)
The E41K beta-Tm mutation impairs muscle contractile function by decreasing contraction speed and Ca(2+) sensitivity, but the latter can be improved with the Ca(2+) sensitizer EMD 57033, suggesting a potential therapeutic approach.
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 et al. (Fri,) conducted a case-control in Congenital myopathy and muscle weakness (n=10). E41K beta-Tm mutation vs. Healthy controls was evaluated on Speed of contraction and contraction sensitivity to Ca(2+) concentration. Muscle fibres carrying the E41K beta-Tm mutation showed decreased speed of contraction and Ca(2+) sensitivity compared to controls, with Ca(2+) sensitivity being reversible by EMD 57033.