Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène, Lyon, France.
J Physiol. 2023 Jan;601(1):99-121. doi: 10.1113/JP283650. Epub 2022 Dec 8.
In mammalian skeletal muscle, the 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 (RyRs) in response to the conformational change in the voltage-sensor dihydropyridine receptors. Deficiency in 3-phosphoinositide phosphatase myotubularin (MTM1) has been reported to disrupt T-tubules, resulting in impaired SR calcium release. Here confocal calcium transients recorded in muscle fibres of MTM1-deficient mice were compared with the 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 resistance as well as the capacitance. If, in simulations, T-tubules were assumed to be partially or completely inaccessible to the depolarization and RyRs at these points to be prime for calcium-induced calcium release, all the 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 the Ca -triggered opening of RyRs provides an alleviating support to the diseased process. KEY POINTS: Myotubular myopathy is a fatal disease due to genetic deficiency in the phosphoinositide phosphatase MTM1. Although the causes are known and corresponding gene therapy strategies are being developed, there is no mechanistic understanding of the disease-associated muscle function failure. Resolving this issue is of primary interest not only for a fundamental understanding 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, which are 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 the dysfunctions of excitation-contraction coupling, providing the first integrated quantitative framework that explains the associated contraction failure.
在哺乳动物的骨骼肌中，沿着横向（T）管状网络将表面膜去极化传播到肌肉纤维内部对于通过ryanodine 受体（RyRs）从肌浆网（SR）同步释放钙是必不可少的，这是对电压传感器二氢吡啶受体构象变化的响应。已经报道 3-磷酸肌醇磷酸酶肌小管素（MTM1）的缺乏会破坏 T 小管，导致 SR 钙释放受损。在这里，与数学建模模拟 T 小管中去极化传播的模型结果进行了比较，该模型假设网络中断会改变进入和跨膜电阻以及电容。如果在模拟中，T 小管被假设为部分或完全无法到达去极化，并且这些点处的 RyRs 易于钙诱导的钙释放，则可以重现测量的 SR 钙释放的所有特征。我们得出结论，去极化向纤维内部的不当传播是 MTM1 缺乏中严重损害 SR 钙释放的初始关键原因，而 Ca 触发的 RyRs 开放为疾病过程提供了缓解支持。关键点：肌小管肌病是一种致命疾病，由磷酸肌醇磷酸酶 MTM1 的遗传缺陷引起。尽管原因已知，并且正在开发相应的基因治疗策略，但对与疾病相关的肌肉功能衰竭没有机制上的理解。解决这个问题不仅对于深入了解 MTM1 对健康肌肉功能的重要性具有首要意义，而且对于确定受疾病影响最严重或最严格的相关细胞机制也具有首要意义，这些机制因此具有作为治疗靶点的潜力。本工作中使用的数学建模方法证明，质膜内陷网络的疾病相关改变足以解释兴奋-收缩偶联的功能障碍，提供了解释相关收缩失败的第一个综合定量框架。
