Figure 5.

Schematic representation of putative Ca²⁺-mediated pathogenic mechanisms triggered by CAPN3 deficiency. CAPN3 deficiency results in reduced levels of RyR1, SERCA, and CaMKII. In addition, NCX3 activity may also be reduced. The decreased function of major Ca²⁺-handling proteins results in Ca²⁺ dysregulation and increased intracellular [Ca²⁺]. Reduced CaMKII levels together with Ca²⁺ dysregulation compromise CaMK downstream signaling pathways, which may lead to impaired gene transcription, mitochondrial abnormalities, oxidative stress, altered fiber phenotype, and impaired muscle regeneration. Mitochondrial abnormalities aggravate Ca²⁺ dysregulation and oxidative damage. They may also impact energy production and promote apoptosis through Cyt-c release and activation of caspases. Among these mechanisms, multiple feedback loops lead to altered Ca²⁺ levels and may result in myoapoptosis and muscle waste. Black arrows or blunt ends indicate enhancing or inhibitory effects, respectively. Red arrows indicate decreased protein expression. Text in red boxes represent several pathological features of CAPN3, as described in Figure 2.