Figure 5.

Remodeling of excitation–contraction coupling (ECC) in disease. (1) The coupling between Ca²⁺ influx and Ca²⁺ release is compromised because of a loss of tight connections between the transverse and axial tubule system (TATS) and the sarcoplasmic reticulum (SR) with an atrophy and remodeling of the tubular network. (2) RyRs thus become uncoupled and are then activated with a delay by Ca²⁺ diffusion across the cell from coupled RyRs. (3) Consequently, activation of myofilaments is less homogeneous and contraction impaired. (4) SERCA expression is reduced leading to an elevation in diastolic Ca²⁺ and reduced SR Ca²⁺, which in turn leads to a decrease in Ca²⁺ release via RyRs during each ECC cycle, thereby reducing contraction amplitude. (5) RyRs display spontaneous releases of Ca²⁺, (6) generating Ca²⁺ waves. (7) This cytosolic Ca²⁺ overload leads to NCX activation, triggering after-depolarizations and potentially a spontaneous AP.