Figure 4.

Schematic representation of membrane contact sites contributed by the SR. In addition to triads, the SR contributes to the formation of additional membrane contact sites in muscle cells. Depletion of intracellular Ca²⁺ stores in the SR induces activation of SOCE, mediated by a physical interaction between STIM1, a Ca²⁺ sensor of the SR and Orai1, a Ca²⁺ channel located in TT, allowing entry of Ca²⁺ from the extracellular space. Repetitive stimulation of muscle contraction was found to promote SR and TT remodeling to form additional sites of interaction between STIM1 and Orai1, called calcium entry units (CEU). These are formed by stacks of flat cisternae of the SR that make contact with elongated tubules extending from TT. In striated muscles, mitochondria are mostly positioned adjacent to triads. Association with the SR is mediated by the voltage-dependent anion channel 1 (VDAC) and RyR. Mitofusin-2 (MFN-2) also contributes to tethering SR and mitochondria. These contact sites are aligned with the inner mitochondrial membrane, where the mitochondrial Ca²⁺ uniporter (MCU) is located. Lysosome–SR nanojunctions mediated by RyR3 channels have been first described in pulmonary arterial myocytes; the RyR3 interactor present on the lysosomal membrane is not known and is therefore indicated with a question mark (?). More recently, these junctions have also been observed in cardiac muscle, while no data are currently available concerning skeletal muscle. The outer nuclear membrane is continuous with the membrane of the SR, allowing the arrangement of a continuous Ca²⁺ storage system between the SR and the nuclear envelope. The inner nuclear membrane forms invaginations that enter the nuclear matrix to support intra-nuclear Ca²⁺ signaling. Created with BioRender.com, accessed on 14 March 2022.