Impaired excitation-contraction coupling in muscle fibres from the dynamin2R465W mouse model of centronuclear myopathy

Abstract

Mutations in the gene encoding dynamin 2 (DNM2) are responsible for autosomal dominant centronuclear myopathy (AD-CNM). We studied the functional properties of Ca²⁺ signalling and excitation-contraction (EC) coupling in muscle fibres isolated from a knock-in (KI) mouse model of the disease, using confocal imaging and voltage-clamp. The transverse-tubule network organization looked unaltered in the diseased fibres but its density was reduced by ∼10% as compared to that in control fibres. The density of Ca²⁺ current through CaV1.1 channels and the rate of voltage-activated sarcoplasmic reticulum Ca²⁺ release were reduced by ∼60% and 30%, respectively, in KI vs. control fibres. In addition, Ca²⁺ release in the KI fibres reached its peak value 10–50 ms later than in control ones. Activation of Ca²⁺ transients along the longitudinal axis of the fibres was more heterogeneous in the KI than in the control fibres, the difference being exacerbated at intermediate membrane voltages. KI fibres exhibited spontaneous Ca²⁺ release events which were virtually absent from control fibres. Overall results demonstrate that Ca²⁺ signalling and EC coupling exhibit a number of dysfunctions that are likely to contribute to muscle weakness in DNM2-related AD-CNM.

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