Figure 2.

Schematic representation of mechanisms causing ${\text{Ca}}_{\text{i}}^{2+}$ overload in a dystrophin-deficient muscle cell. Loss of dystrophin causes destabilization of dystrophin-associated glycoprotein complex (DAGC), membrane tear, and activation of store-operated calcium channels (SOCCs), resulting in abnormal Ca²⁺ entry. High concentrations of extracellular ATP can activate abnormal Ca²⁺ influx via P2X7. RyR dysfunction causes Ca²⁺ leak from the SR and SERCA dysfunction compromises Ca²⁺ resequestration. NOX activation can also increase RyR Ca²⁺ leak. These changes result in abnormal and chronic elevation of the cytoplasmic Ca²⁺ levels. Supraphysiological level Ca²⁺ activates Ca²⁺-dependent proteases and phospholipase and causes muscle necrosis and replacement of muscle by fatty and fibrotic tissues. Sustained elevation of cytoplasmic Ca²⁺ levels also affects mitochondrial function and increases reactive oxygen species (ROS). Collectively, these changes lead to muscle wasting and contractile dysfunction. Bold and broken arrows indicate the enhanced and decreased function of the Ca²⁺ channels, respectively. Cx43, connexin 43; NCX, sodium–calcium exchanger; NHE, sodium–proton exchanger; NOX, NADPH oxidases; PMCA, plasma membrane Ca²⁺ ATPase; P2X7, P2X purinoceptor 7; SAC, stretch-activated channels; SOCC, store-operated Ca²⁺ channel; TRPC1, transient receptor potential channel 1.