Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
Redox Biol. 2020 Sep;36:101557. doi: 10.1016/j.redox.2020.101557. Epub 2020 May 26.
The ability for skeletal muscle to perform optimally can be affected by the regulation of Ca 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 Ca 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 Ca 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 Ca leak and increased NAD(P)H Oxidase 2 ROS. These alterations make the mdx mouse an ideal model for understanding how ROS and Ca handling impact each other. We hypothesised that elevated t-tubular Nox2 ROS increases RyR1 Ca leak contributing to an increase in cytoplasmic Ca, 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 Ca 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 Ca leak. Our findings support a model in which Nox4 ROS induces RyR1 Ca leak and the increased junctional space [Ca] exacerbates Nox2 ROS; with the cumulative effect of disruption of downstream cellular processes that would ultimately contribute to reduced muscle or cellular performance.
在休息时，三连接点空间内 Ca 的调节会影响骨骼肌的最佳性能。由于氧化应激、损伤和信号级联的氧化还原调节的变化，活性氧会影响肌肉性能。因此，了解骨骼肌三连接点处 ROS 和 Ca 信号之间的相互作用非常重要，因为它会影响健康和患病肌肉的性能。在这里，我们旨在研究钙和氧化还原信号在小鼠骨骼肌纤维连接点微域内的变化如何改变这些复合物的内稳态。dystrophin 缺陷型 mdx 小鼠模型显示 RyR1 Ca 渗漏增加和 NAD(P)H 氧化酶 2 ROS 增加。这些改变使 mdx 小鼠成为理解 ROS 和 Ca 处理如何相互影响的理想模型。我们假设，升高的 t-管状 Nox2 ROS 增加 RyR1 Ca 渗漏，导致细胞质 Ca 增加，从而引发蛋白降解和细胞功能受损，如自噬和 ER 应激。我们发现，抑制 Nox2 ROS 并不能减少在缺乏 dystrophin 的骨骼肌中观察到的 RyR1 Ca 渗漏。有趣的是，另一种 NAD(P)H 同工型 Nox4 在不能产生 Nox2 ROS 的小鼠中上调，当被抑制时，它会减少 RyR1 Ca 渗漏。我们的研究结果支持这样一种模型，即 Nox4 ROS 诱导 RyR1 Ca 渗漏，增加的连接点空间 [Ca] 加剧了 Nox2 ROS；其累积效应会破坏下游细胞过程，最终导致肌肉或细胞性能下降。
