Antioxidants restore store‐operated Ca²⁺ entry in patient‐iPSC‐derived myotubes with tubular aggregate myopathy‐associated Ile484ArgfsX21 STIM1 mutation via upregulation of binding immunoglobulin protein

Abstract

Store‐operated Ca2+ entry (SOCE) is indispensable for intracellular Ca2+ homeostasis in skeletal muscle, and constitutive activation of SOCE causes tubular aggregate myopathy (TAM). To understand the pathogenesis of TAM, we induced pluripotent stem cells (iPSCs) from a TAM patient with a rare mutation (c.1450_1451insGA; p. Ile484ArgfsX21) in the STIM1 gene. This frameshift mutation produces a truncated STIM1 with a disrupted C‐terminal inhibitory domain (CTID) and was reported to diminish SOCE. Myotubes induced from the patient's‐iPSCs (TAM myotubes) showed severely impaired SOCE, but antioxidants greatly restored SOCE partly via upregulation of an endoplasmic reticulum (ER) chaperone, BiP (GRP78), in the TAM myotubes. Our observation suggests that antioxidants are promising tools for treatment of TAM caused by reduced SOCE.

Branched-chain amino acids and L-alanine supplementation ameliorate calcium dyshomeostasis in sarcopenia: New insights for nutritional interventions

“…A part of dissected FDB fibers adhered on coverslips was used for the SOCE measurement, performed according to previous studies ( Conte et al, 2021 ; Sakai-Takemura et al, 2023 ). Particularly, fibers were incubated with a calcium free-solution (mM: 148 NaCl, 4.5 KCl, 10 EGTA, 1 MgCl 2 , 0.44 NaH 2 PO 4 , 12 NaHCO 3 , and 5.5 glucose) and 2 μM thapsigargin (Sigma-Aldrich, United States, cod.…”