Muscle-restricted Nox4 knockout partially corrects muscle contractility following spinal cord injury in mice.
Muscle-restricted Nox4 knockout partially corrects muscle contractility following spinal cord injury in mice.
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肌肉限制性 Nox4 敲除可部分纠正小鼠脊髓损伤后的肌肉收缩力。
DOI：
10.1101/2023.08.04.551985
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Cardozo,ChristopherP
中科院分区：
文献类型：
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作者：
Toro,CarlosA;DeGasperi,Rita;Aslan,Abdurrahman;Johnson,Nicholas;Siddiq,MustafaM;Chow,Christine;Zhao,Wei;Harlow,Lauren;Graham,Zachary;Liu,Xin-Hua;Sadoshima,Junichi;Iyengar,Ravi;Cardozo,ChristopherP
脊髓损伤（SCI）导致瘫痪区域的骨骼肌严重萎缩，并且每单位横截面积的肌肉产生的力降低。骨骼肌Ryanodine 1受体（RyR1）的氧化降低了收缩力，这是由于钙蛋白1与RyR1的结合减少以及RyR1的门控改变。RyR1氧化的一个原因是NADPH氧化酶4（Nox 4）。我们以前已经表明，在大鼠中，RyR1被氧化，并结合较少的钙蛋白1在脊髓损伤（SCI）后56天横断。在这里，我们使用了一个条件性敲除小鼠模型的Nox4在肌肉中，以调查的作用，Nox4在减少肌肉比力脊髓损伤后。与假手术对照组相比，SCI后对照小鼠的峰值抽搐力降低了42%，但与SCI对照组相比，SCI Nox 4条件性KO小鼠的峰值抽搐力增加了约43%，尽管其仍低于假手术对照组。与在大鼠中观察到的不同，脊髓损伤后，Nox 4的表达在腓肠肌中没有增加，并且钙蛋白1与RyR1的结合在该肌肉中没有减少。结果表明肌肉组织中的Nox 4表达与肌肉抽搐力的降低之间存在联系，但需要进一步研究以了解这种联系的机制基础。
Spinal cord injury (SCI) results in severe atrophy of skeletal muscle in paralyzed regions, and a decrease in the force generated by muscle per unit of cross-sectional area. Oxidation of skeletal muscle ryanodine 1 receptors (RyR1) reduces contractile force due to reduced binding of calstabin 1 to RyR1 together with altered gating of RyR1. One cause of RyR1 oxidation is NADPH oxidase 4 (Nox4). We have previously shown that in rats, RyR1 was oxidized and bound less calstabin 1 at 56 days after spinal cord injury (SCI) by transection. Here, we used a conditional knock-out mouse model of Nox4 in muscle to investigate the role of Nox4 in reduced muscle specific force after SCI. Peak twitch force in control mice after SCI was reduced by 42% compared to sham-operated controls but was increased by approximately 43% in SCI Nox4 conditional KO mice compared to SCI controls although it remained less than that for sham-operated controls. Unlike what observed in rats, after SCI the expression of Nox4 was not increased in gastrocnemius muscle and binding of calstabin 1 to RyR1 was not reduced in this muscle. The results suggest a link between Nox4 expression in muscle tissue and reduction in muscle twitch force, however further studies are needed to understand the mechanistic basis for this linkage.