BPS2026 – STIM1-I115F causing tubular aggregate myopathy and Stormorken syndrome/York platelet syndrome induces defects in skeletal myotubes

A genetic mutation in stromal interaction molecule 1 (STIM1) at I115 (I115F) causes tubular aggregate myopathy (TAM) and Stormorken syndrome/York platelet syndrome (STRMK/YPS), characterized by skeletal muscle weakness, in humans. Excess store-operated Ca 2+ entry (SOCE) caused by the constitutively active I115F is the main cause of this skeletal muscle weakness. This study investigated in detail the mechanisms underlying I115F-induced pathological defects and the possible mechanisms by which these defects can be restored at the cellular level. I115F was expressed in mouse primary skeletal myotubes, which were examined using live single-cell Ca 2+ imaging experiments, transmission electron microscopy, and biochemical approaches. Additionally, the restoration of I115F-induced pathological defects were examined using codifferentiated I115F-expressing myotubes with normal immature myotubes. I115F induced cytosolic Ca 2+ overload by increasing SOCE, resulting in abnormal Ca 2+ release for skeletal muscle contraction. Codifferentiation reversed the I115F-induced defects, restoring cytosolic Ca 2+ to normal levels by increasing myogenin expression and myotube width. Regulating the expression or activity of myogenin could alleviate I115F-induced excess SOCE and the subsequent cytosolic Ca 2+ overload causing skeletal muscle weakness in TAM and STRMK/YPS.