Fig. 5

A theoretical mechanism of progressive Ca²⁺ dysregulation in IBM and downstream pathological relevance. Stage 1: An initial insult to Ca²⁺ regulation may come from immune-mediated membrane injury (pictured: cytotoxic T-lymphocyte), permeabilization of Ca²⁺ channels by abnormal proteins, and/or reduction in calpain-3. Stage 2: Ca²⁺ elevations in the cytosol are then propagated through ROS production, SR Ca²⁺ leak, and calpain proteolysis of Ca²⁺-regulatory proteins. Stage 3: Prolonged Ca²⁺ dyshomeostasis causes and/or exacerbates the inter-related phenomena of mitochondrial dysfunction, UPR signaling, protein aggregate formation, and contractile dysfunction