Disrupted T-tubular network accounts for asynchronous calcium release in MTM1 deficient skeletal muscle.

KEY POINTS: Myotubular myopathy is a fatal disease due to genetic deficiency in the phosphoinositide phosphatase MTM1. Although causes are known and corresponding gene-therapy strategies are developed, there is no mechanistic understanding of the disease-associated muscle function failure. Resolving this issue is of primary interest both for fundamental knowledge of how MTM1 is critical for healthy muscle function but also for establishing the related cellular mechanisms most primarily or stringently affected by the disease, and thus of potential interest as therapy targets. The mathematical modelling approach used in the present work proves that the disease-associated alteration of the plasma membrane invagination network is sufficient to explain dysfunctions of excitation-contraction coupling, providing the first integrated quantitative framework explaining the associated contraction failure.

ABSTRACT: In mammalian skeletal muscle propagation of surface membrane depolarization into the interior of the muscle fibre along the transverse (T-) tubular network is essential for the synchronized release of calcium from the sarcoplasmic reticulum (SR) via Ryanodine receptors (RyR) in response to the conformational change in the voltage-sensor dihydropyridine receptors. Deficiency in 3-phosphoinositide phosphatase myotubularin (MTM1) has been reported that disruption of T-tubules results in impaired SR calcium release. Here confocal calcium transients recorded in muscle fibres of MTM1-deficient mice were compared to results from a model where propagation of the depolarization along the T-tubules was modelled mathematically with disruptions in the network assumed to modify the access and transmembrane resistances as well as the capacitance. If, in simulations, T-tubules were assumed to be partially or completely inaccessible to the depolarization and RyR at these points to be prime for calcium-induced calcium release, all features of measured SR calcium release could be reproduced. We conclude that the inappropriate propagation of the depolarization into the fibre interior is the initial critical cause of severely impaired SR calcium release in MTM1 deficiency, while Ca2+ -triggered opening of RyRs provides an alleviating support to the diseased process. Abstract figure legend In mammalian skeletal muscle the surface membrane depolarization propagates into the interior of the muscle fibre along the transverse (T-) tubular network and synchronizes the release of calcium from the sarcoplasmic reticulum (SR) via Ryanodine receptors (RyR). Deficiency in 3-phosphoinositide phosphatase myotubularin (MTM1) results in the disruption of the T-tubules and the appearance of delayed SR calcium release. Calcium transients recorded in muscle fibres of MTM1-deficient mice were compared to results when the propagation of the depolarization along the T-tubules was modelled mathematically. If T-tubules were assumed to be partially or completely inaccessible to the depolarization all features of measured SR calcium release could be reproduced. Thus the inappropriate propagation of the depolarization into the fibre interior is the initial critical cause of severely impaired SR calcium release in MTM1 deficiency, while Ca2+ -triggered opening of RyRs provides an alleviating support to the diseased process. This article is protected by copyright. All rights reserved.