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首页> 外文期刊>Journal of Cachexia, Sarcopenia and Muscle >Cardiac troponin T and fast skeletal muscle denervation in ageing
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Cardiac troponin T and fast skeletal muscle denervation in ageing

机译：衰老过程中的心肌肌钙蛋白T和快速骨骼肌失神经

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Abstract Background Ageing skeletal muscle undergoes chronic denervation, and the neuromuscular junction (NMJ), the key structure that connects motor neuron nerves with muscle cells, shows increased defects with ageing. Previous studies in various species have shown that with ageing, type II fast-twitch skeletal muscle fibres show more atrophy and NMJ deterioration than type I slow-twitch fibres. However, how this process is regulated is largely unknown. A better understanding of the mechanisms regulating skeletal muscle fibre-type specific denervation at the NMJ could be critical to identifying novel treatments for sarcopenia. Cardiac troponin T (cTnT), the heart muscle-specific isoform of TnT, is a key component of the mechanisms of muscle contraction. It is expressed in skeletal muscle during early development, after acute sciatic nerve denervation, in various neuromuscular diseases and possibly in ageing muscle. Yet the subcellular localization and function of cTnT in skeletal muscle is largely unknown. Methods Studies were carried out on isolated skeletal muscles from mice, vervet monkeys, and humans. Immunoblotting, immunoprecipitation, and mass spectrometry were used to analyse protein expression, real-time reverse transcription polymerase chain reaction was used to measure gene expression, immunofluorescence staining was performed for subcellular distribution assay of proteins, and electromyographic recording was used to analyse neurotransmission at the NMJ. Results Levels of cTnT expression in skeletal muscle increased with ageing in mice. In addition, cTnT was highly enriched at the NMJ region?￠????but mainly in the fast-twitch, not the slow-twitch, muscle of old mice. We further found that the protein kinase A (PKA) RI???± subunit was largely removed from, while PKA RII???± and RII???2 are enriched at, the NMJ?￠????again, preferentially in fast-twitch but not slow-twitch muscle in old mice. Knocking down cTnT in fast skeletal muscle of old mice: (i) increased PKA RI???± and reduced PKA RII???± at the NMJ; (ii) decreased the levels of gene expression of muscle denervation markers; and (iii) enhanced neurotransmission efficiency at NMJ. Conclusions Cardiac troponin T at the NMJ region contributes to NMJ functional decline with ageing mainly in the fast-twitch skeletal muscle through interfering with PKA signalling. This knowledge could inform useful targets for prevention and therapy of age-related decline in muscle function.
机译：背景技术骨骼肌的衰老经历了慢性神经支配，而神经肌肉接头（NMJ）是运动神经元神经与肌肉细胞之间连接的关键结构，随着年龄的增长，缺陷增加。先前对各种物种的研究表明，随着年龄的增长，II型快肌骨骼肌纤维比I型慢肌纤维显示出更多的萎缩和NMJ退化。但是，如何调节此过程在很大程度上尚不清楚。更好地了解NMJ调节骨骼肌纤维型特定神经支配的机制，对于鉴定肌肉减少症的新疗法可能至关重要。心肌肌钙蛋白T（cTnT）是TnT的心肌特异性异构体，是肌肉收缩机制的关键组成部分。它在早期坐骨神经失神经后的早期发育过程中在骨骼肌中表达，在各种神经肌肉疾病中也可能在衰老的肌肉中表达。然而，在骨骼肌中cTnT的亚细胞定位和功能尚不清楚。方法对小鼠，黑长尾猴和人类分离出的骨骼肌进行了研究。使用免疫印迹，免疫沉淀和质谱分析蛋白质表达，使用实时逆转录聚合酶链反应测量基因表达，使用免疫荧光染色进行蛋白质的亚细胞分布测定，并使用肌电图记录分析神经元的神经传递。 NMJ。结果随着年龄的增长，骨骼肌中cTnT表达水平增加。另外，cTnT在NMJ区高度富集，但主要集中在老年小鼠的快肌而不是慢肌。我们进一步发现，蛋白激酶A（PKA）RI 2+亚基被大量去除，而PKA RII 2+和RII 2再次富集于NMJ 3-，优选。在老年小鼠的快速抽搐肌肉而不是慢速抽搐肌肉中。降低老年小鼠快速骨骼肌中的cTnT：（i）在NMJ处PKA RI升高，而PKA RII降低。 （ii）降低了神经去神经标记的基因表达水平; （iii）提高NMJ的神经传递效率。结论NMJ区域的心肌肌钙蛋白T会通过干扰PKA信号传导而导致NMJ功能的衰老，主要是在快肌骨骼肌中。这些知识可以为预防和治疗年龄相关的肌肉功能下降提供有用的靶点。

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