Nox4-RyR1-Nox2: Regulators of micro-domain signaling in skeletal muscle
Nox4-RyR1-Nox2: Regulators of micro-domain signaling in skeletal muscle
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DOI：
10.1016/j.redox.2020.101557
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发表时间：
2020-09-01
期刊：
影响因子：
11.4
通讯作者：
Rodney, George G.
中科院分区：
文献类型：
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作者：
Cully, Tanya R.;Rodney, George G.
骨骼肌最佳表现的能力可以受到静息时三叉神经连接间隙内Ca 2+调节的影响。由于氧化应激、损伤和信号级联的氧化还原调节的变化，活性氧影响肌肉性能。因此，了解骨骼肌三联体中ROS和Ca 2+信号之间的相互作用非常重要，因为它可以影响健康和患病肌肉的性能。在这里，我们的目的是研究如何在Ca 2+和氧化还原信号的连接空间微域的小鼠骨骼肌纤维内的变化改变这些复合物的稳态。营养不良mdx小鼠模型显示RyR 1 Ca 2+渗漏增加和NAD（P）H氧化酶2 ROS增加。这些改变使mdx小鼠成为了解ROS和Ca 2+处理如何相互影响的理想模型。我们假设升高的t-管Nox 2 ROS增加RyR 1 Ca 2+泄漏，导致细胞质Ca 2+增加，从而引发蛋白质降解和受损的细胞功能，如自噬和ER应激。我们发现，抑制Nox 2 ROS并没有减少RyR 1钙泄漏观察肌营养不良蛋白缺陷的骨骼肌。有趣的是，另一种NAD（P）H亚型Nox 4在不能产生Nox 2 ROS的小鼠中上调，并且当被抑制时减少RyR 1 Ca 2+泄漏。我们的研究结果支持了一个模型，其中Nox 4 ROS诱导RyR 1 Ca 2+泄漏，增加的连接空间[Ca 2 +]加剧了Nox 2 ROS;下游细胞过程破坏的累积效应最终导致肌肉或细胞性能降低。
The ability for skeletal muscle to perform optimally can be affected by the regulation of Ca2+ within the triadic junctional space at rest. Reactive oxygen species impact muscle performance due to changes in oxidative stress, damage and redox regulation of signaling cascades. The interplay between ROS and Ca2+ signaling at the triad of skeletal muscle is therefore important to understand as it can impact the performance of healthy and diseased muscle. Here, we aimed to examine how changes in Ca2+ and redox signaling within the junctional space micro-domain of the mouse skeletal muscle fibre alters the homeostasis of these complexes. The dystrophic mdx mouse model displays increased RyR1 Ca2+ leak and increased NAD(P)H Oxidase 2 ROS. These alterations make the mdx mouse an ideal model for understanding how ROS and Ca2+ handling impact each other. We hypothesised that elevated t-tubular Nox2 ROS increases RyR1 Ca2+ leak contributing to an increase in cytoplasmic Ca2+, which could then initiate protein degradation and impaired cellular functions such as autophagy and ER stress. We found that inhibiting Nox2 ROS did not decrease RyR1 Ca2+ leak observed in dystrophin-deficient skeletal muscle. Intriguingly, another NAD(P)H isoform, Nox4, is upregulated in mice unable to produce Nox2 ROS and when inhibited reduced RyR1 Ca2+ leak. Our findings support a model in which Nox4 ROS induces RyR1 Ca2+ leak and the increased junctional space [Ca2+] exacerbates Nox2 ROS; with the cumulative effect of disruption of downstream cellular processes that would ultimately contribute to reduced muscle or cellular performance.