Figure 1.

Schematic drawing of the triad junction, the chief site of the E-C coupling process in skeletal muscles. The predicted localization of the four genes/proteins emphasized in this review article is shown and they are represented in different colors along with the Dihydropyridine Receptor (DHPR), the Ryanodine Receptor type 1 (RyR1) and Calsequestrin (CSQ). In young muscles E-C coupling is effectively maintained through coordinated actions of the E-C coupling machinery and the optimal participation of MG29, MTMR14, SAR, and KLF15. Their concentration and/or effectiveness is reduced with aging, which associates with structural changes of the triad junction itself. Together these biochemical and morphological changes contribute to the reduced coupling between depolarization of the sarcolemma and contraction due to the reduced calcium release capacity of aged muscles. In summary, “E-C coupling quality” is reduced in aged muscles, and becomes a key factor to reduced muscle quality during aging. The steps of the E-C coupling process are described in detail in the text. In skeletal muscles, depolarization of the sarcolemma and its invaginations (t-tubules) represented by the lightning bolt in yellow color alters the configuration of the DHPR, which modifies its interaction with RyR1, leading to the dominant type of calcium release in skeletal muscle (depolarization-induced calcium release, DICR). This initial release phase can be further amplified by a secondary mechanism, calcium-induced calcium release (CICR), the main release mechanism in cardiac muscles. The structural deformation as well as the lack of organized triads is a hallmark of aged muscles and also common in other diseases covered in this article. Not detailed in this figure is the process of calcium entry or re-entry, store-operated calcium entry (SOCE), responsible for continual refilling of the sarcoplasmic reticulum (SR). SOCE is also reduced with aging, which we have postulated contributes to sarcopenia and to the un-matching between muscle mass and muscle contractile force during aging, since force/power decrease significantly more than the observed decrease in muscle mass. We foresee that new generations of drugs could be developed to specifically target the different steps of E-C coupling in disease states to increase efficiency of Ca²⁺ handling.