Figure 5.

The network of dysferlin functions. Malfunctioning of one or several aspects contributes to the pathology of dysferlinopathies (red arrows). (1) Impaired sarcolemma repair leads to changes in Ca²⁺ homeostasis and in turn could be affected by intracellular Ca²⁺ compartmentalization and signaling. (2) The T-tubule system is necessary to maintain Ca²⁺ homeostasis and in turn could be affected by abnormalities in Ca²⁺ signaling. (3) Deficits in sarcolemma and T-tubule system repair may cause death of damaged myofibers and promote cycles of the muscle regeneration. Leakage of the muscle fibers contents may change properties of the regenerative niche. (4) Changes in Ca²⁺ compartmentalization and signaling in myofibers can result in dysregulation of, e.g., cytokines secretion and prolonged inflammatory responses. (5) Dysregulation of Ca²⁺ homeostasis may lead to myofibers death, which promotes cycles of muscle regeneration. (6) Sarcolemma repair may depend on the function of T-tubule system as a membrane reservoir and affect T-tubule system function via changes in Ca²⁺ homeostasis. (7) T-tubule system function may be affected by abnormalities in its structure arising during dysferlin-deficient muscle regeneration. (8) Malfunctioning of sarcolemma repair enhances leakage of damage-associated molecules, e.g., annexin A2, promoting inflammation. (9) Prolonged inflammation may result in incomplete cycles of regeneration and pro-inflammatory signaling may inhibit myogenesis.