In the last decades the term Store-operated Ca²⁺ entry (SOCE) has been used in the scientific literature to describe an ubiquitous cellular mechanism that allows recovery of calcium (Ca²⁺) from the extracellular space. SOCE is triggered by a reduction of Ca²⁺ content (i.e. depletion) in intracellular stores, i.e. endoplasmic or sarcoplasmic reticulum (ER and SR). In skeletal muscle the mechanism is primarily mediated by a physical interaction between stromal interaction molecule-1 (STIM1), a Ca²⁺ sensor located in the SR membrane, and ORAI1, a Ca²⁺-permeable channel of external membranes, located in transverse tubules (TTs), the invaginations of the plasma membrane (PM) deputed to propagation of action potentials. It is generally accepted that in skeletal muscle SOCE is important to limit muscle fatigue during repetitive stimulation. We recently discovered that exercise promotes the assembly of new intracellular junctions that contains colocalized STIM1 and ORAI1, and that the presence of these new junctions increases Ca²⁺ entry via ORAI1, while improving fatigue resistance during repetitive stimulation. Based on these findings we named these new junctions Ca²⁺ Entry Units (CEUs). CEUs are dynamic organelles that assemble during muscle activity and disassemble during recovery thanks to the plasticity of the SR (containing STIM1) and the elongation/retraction of TTs (bearing ORAI1). Interestingly, similar structures described as SR stacks were previously reported in different mouse models carrying mutations in proteins involved in Ca²⁺ handling (calsequestrin-null mice; triadin and junctin null mice, etc.) or associated to microtubules (MAP6 knockout mice). Mutations in Stim1 and Orai1 (and calsequestrin-1) genes have been associated to tubular aggregate myopathy (TAM), a muscular disease characterized by: (a) muscle pain, cramping, or weakness that begins in childhood and worsens over time, and (b) the presence of large accumulations of ordered SR tubes (tubular aggregates, TAs) that do not contain myofibrils, mitochondria, nor TTs. Interestingly, TAs are also present in fast twitch muscle fibers of ageing mice. Several important issues remain un-answered: (a) the molecular mechanisms and signals that trigger the remodeling of membranes and the functional activation of SOCE during exercise are unclear; and (b) how dysfunctional SOCE and/or mutations in Stim1, Orai1 and calsequestrin (Casq1) genes lead to the formation of tubular aggregates (TAs) in aging and disease deserve investigation.

在过去的几十年中，科学文献中使用术语储存操作的 Ca ²⁺进入 (SOCE) 来描述一种普遍存在的细胞机制，该机制允许从细胞外空间回收钙 (Ca ^{2+ )。}SOCE 是由细胞内储存（即内质网或肌质网（ER 和 SR））中 Ca ²⁺含量的减少（即消耗）触发的。在骨骼肌中，该机制主要由基质相互作用分子-1 (STIM1)（一种位于 SR 膜中的 Ca ^{2+传感器）和 ORAI1（一种 Ca 2+ ）之间的物理相互作用介导。}- 外膜的可渗透通道，位于横管 (TT) 中，质膜 (PM) 的内陷负责动作电位的传播。人们普遍认为，在骨骼肌中，SOCE 对限制重复刺激期间的肌肉疲劳很重要。我们最近发现，运动促进了包含共定位 STIM1 和 ORAI1 的新细胞内连接的组装，并且这些新连接的存在增加了通过 ORAI1 的 Ca ²⁺进入，同时提高了重复刺激期间的抗疲劳性。基于这些发现，我们将这些新连接点命名为 Ca ²⁺输入单元 (CEU)。由于 SR（包含 STIM1）的可塑性和 TT（承载 ORAI1）的伸长/收缩，CEU 是动态细胞器，在肌肉活动期间组装并在恢复期间分解。有趣的是，之前在不同的小鼠模型中报道了类似的结构被描述为SR 堆栈，这些小鼠模型携带参与 Ca ²⁺处理的蛋白质突变（calsequestrin 缺失小鼠；triadin 和 junctin 缺失小鼠等）或与微管相关（MAP6 敲除小鼠）。Stim1和Orai1的突变(和 calsequestrin-1) 基因与管状聚集性肌病 (TAM) 相关，TAM 是一种肌肉疾病，其特征是：(a) 肌肉疼痛、痉挛或虚弱，始于儿童期并随着时间的推移而恶化，以及 (b)大量有序 SR 管（管状聚集体，TAs）堆积，不含肌原纤维、线粒体或 TT。有趣的是，TAs 也存在于衰老小鼠的快肌纤维中。几个重要问题仍未得到解答：（a）在运动过程中触发膜重塑和 SOCE 功能激活的分子机制和信号尚不清楚；(b) Stim1、Orai1和 calsequestrin ( Casq1)的 SOCE 功能失调和/或突变如何 基因导致衰老和疾病中管状聚集体（TAs）的形成值得研究。