FIGURE 1.

General scheme of the EC coupling/mitochondrial energetics (ECME) model. The electrophysiological module includes the main ion transport processes involved in EC-coupling, accounting for the transport of Ca²⁺, Na⁺, and K⁺ across the sarcolemma, Ca²⁺ transport inside and across the SR membrane, and Ca²⁺ handling by mitochondria. Five different Ca²⁺ compartments are defined including the mitochondrial matrix, the dyadic subspace, the junctional and network SR, and the myoplasmic compartments. Extracellular Ca²⁺ is considered an adjustable parameter. The mitochondrial module describes the production (F₁, F₀ ATPase) and transport (ANT) of ATP, Ca²⁺ transport, and Ca²⁺ activation of the TCA cycle dehydrogenases. The CK reaction occurs near the mitochondria (but does not include potential limitations imposed by the outer membrane) and the CrP diffuses to the cytoplasmic compartment where there is another pool of CK that catalyzes the regeneration of ATP_ic to fuel constitutive cytoplasmic ATPases (labeled “cyto”). Also the total pool of adenine (C_A) and creatine (C_C) metabolites are indicated by dark shading. The main ATP-consuming processes related to EC coupling are the myofibrillar ATPase (V_AM) and SERCA (J_up), and in the sarcolemma, the Na⁺, K⁺ ATPase (I_NaK), and the Ca²⁺ ATPase (I_pCa).