Will you still need me (Ca2+ , TnT, and DHPR), will you still cleave me (calpain), when I'm 64?
Will you still need me (Ca2+ , TnT, and DHPR), will you still cleave me (calpain), when I'm 64?
复制标题
当我 64 岁时，你还会需要我（Ca2、TnT 和 DHPR）吗？你还会切割我（钙蛋白酶）吗？
DOI：
10.1111/acel.12560
复制
发表时间：
2017
期刊：
影响因子：
7.8
通讯作者：
Chase,PBryant
中科院分区：
文献类型：
--
作者：
Pinto,JoséRenato;Muller-Delp,Judy;Chase,PBryant
在许多与衰老过程中生理衰退广泛相关的细胞和分子特征中(ı等人，2013年)，脊椎动物肌肉力量的丧失尤其有问题，因为在人类中，它比肌肉质量的损失更能预测发病率和死亡率(Newman等人，2006年)。人类队列研究表明，随着年龄的增长和疾病的发生，肌肉力量的丧失比肌肉质量的丧失更快(Goodpaster等人，2006年)。然而，与年龄相关的石棺减少的机制相比，与年龄相关的肌肉力量丧失的机制变化更难以识别。年龄导致的肌肉力量丧失一直是一个持续争论的话题。尽管有许多似是而非的假设和巧妙的实验设计，但这些早期的研究无法剖析导致比力(当力被归一化为横截面积时)随年龄增加而减少的主要机制(S)(Phillips等人，1993；Brooks&Faulkner，1994；Faulkner等人，2007)。最近，Delbono研究小组证明，电压传感器钙通道A1亚单位(Cav1)的表达减少。1)--在骨骼肌兴奋-收缩偶联文献中也称为二氢吡啶受体(DHPR)--与骨骼肌力量随年龄增长而丧失有关(Delbono等人，2007年；Taylor等人，2009年)。他们还表明，Cav1。1表达水平可以通过不同的机制来调节，这些机制与基因转录或mRNA表达无关(Delbono等人，2007年；Taylor等人，2009年)。在论文中，Calain抑制挽救了肌钙蛋白T3的碎裂，增加了Cav1。1，并增强衰老久坐小鼠的骨骼肌力。报道了一项新的发现，TnT3调控Cav1。1在骨骼肌纤维中的表达，以及钙蛋白酶介导的TnT3的断裂与Cav1相关。1老年小鼠的下调(Zhang等人，2016)。Delbono和他的同事描述了Cav1是如何随着年龄的增长而减少的。1的水平导致1型ryanodine受体(RyR1)的解偶联，这可能会减少肌浆网在收缩过程中释放的激活钙离子的量(图1)(Delbono，2011；Hernandez-Ochoa等人，2015；Lee等人，2015)。Cav1之间的耦合。1和肌浆网膜上的RyR1最近也被证明受到Stac3蛋白的调节，Stac3是一种新的不涉及Cav1细胞水平变化的兴奋收缩调节机制。1(波斯特等人，2016年)。重要的是，张等人。另有报道称，Calain介导的TnT3断裂和相关的下调
Of the many cellular and molecular hallmarks that are broadly associated with physiological decline during aging (Leopez-Oteın et al., 2013), loss of muscular strength in vertebrates is particularly problematic because in humans it is a better predictor of morbidity and mortality than loss of muscle mass (Newman et al., 2006). Human cohort studies indicate that with both aging and disease, muscular strength is lost more rapidly than muscle mass (Goodpaster et al., 2006). The mechanistic changes that underlie age-related loss of muscular strength, however, have been more elusive to identify than the mechanisms of age-related sarcopenia. Age-induced loss of muscular strength has been a topic of sustained debate. Despite a number of plausible hypotheses and clever experimental designs, these earlier studies were unable to dissect the primary mechanism (s) responsible for the reduction in specific force (when the force is normalized to the cross-sectional area) with aging (Phillips et al., 1993; Brooks & Faulkner, 1994; Faulkner et al., 2007). More recently, the Delbono group demonstrated that decreased expression of the voltage sensor Ca2+ channel a1 subunit (Cav1. 1)—also known as the dihydropyridine receptor (DHPR) in the skeletal muscle excitation–contraction coupling literature—is associated with the loss of skeletal muscle strength with aging (Delbono et al., 2007; Taylor et al., 2009). They also showed that Cav1. 1 expression levels can be regulated by different mechanisms, which are not related to gene transcription or mRNA expression (Delbono et al., 2007; Taylor et al., 2009). In the paper ‘Calpain inhibition rescues troponin T3 fragmentation, increases Cav1. 1, and enhances skeletal muscle force in aging sedentary mice’, Zhang et al. report a novel finding that TnT3 regulates Cav1. 1 expression in skeletal muscle fibers and that calpain-mediated fragmentation of TnT3 is associated with Cav1. 1 downregulation in old mice (Zhang et al., 2016). Delbono and colleagues have described how the age-induced decrease in Cav1. 1 levels leads to uncoupling of the type 1 ryanodine receptor (RyR1), which potentially decreases the amount of activating Ca2+ released by the sarcoplasmic reticulum during contraction (Fig. 1)(Delbono, 2011; Hernandez-Ochoa et al., 2015; Lee et al., 2015). The coupling between Cav1. 1 in the sarcolemma and RyR1 in the sarcoplasmic reticulum membrane has also been recently shown to be modulated by protein Stac3, a novel mechanism for the modulation of excitation–contraction that does not involve changes in the cellular level of Cav1. 1 (Polster et al., 2016). Importantly, Zhang et al. also report that calpain-mediated TnT3 fragmentation and related downregulation of