Figure 2

Defective membrane repair and muscle inflammation. Plasma membrane damage to dysferlin-deficient muscle fibers with compromised membrane repair causes a prolonged release of "danger" molecules, such as heat shock proteins (HSPs), high mobility group box 1 (HMGB1), ATP and uric acids. These "danger" molecules are recognized by receptors on leukocytes and the muscle fibers, stimulating generation of proinflammatory cytokines such as IL-1β. Other molecules that are exposed or released from the damaged cells activate the complement system, followed by the generation of proinflammation mediators (for example C3a, C5a) and opsonizing C3b. The proinflammatory mediators can trigger the production of proinflammatory cytokines from host cells and make the local vascular endothelium "leaky", thus attracting migration of neutrophils and monocytes. C3b binds to the negatively-charged sarcolemma, stimulating phagocytosis. These molecular and cellular responses cause more severe muscle damage and necrosis, leading to further release of the "danger" molecules and extensive muscle inflammation. The complement system and the inflammatory signaling pathway thus become attractive therapeutic targets for the treatment of dysferlinopathy.