Antioxidants restore store-operated Ca 2+ entry in patient-iPSC-derived myotubes with tubular aggregate myopathy-associated Ile484ArgfsX21 STIM1 mutation via upregulation of binding immunoglobulin protein.
Fusako Sakai-TakemuraFumiaki SaitoKen'ichiro NogamiYusuke MaruyamaAhmed ElhussienyKiichiro MatsumuraShin'ichi TakedaYoshitsugu AokiYuko Miyagoe-SuzukiPublished in: FASEB bioAdvances (2023)
Store-operated Ca 2+ entry (SOCE) is indispensable for intracellular Ca 2+ 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.
Keyphrases
- induced pluripotent stem cells
- endoplasmic reticulum
- skeletal muscle
- case report
- high glucose
- poor prognosis
- late onset
- cell proliferation
- signaling pathway
- small molecule
- genome wide
- binding protein
- oxidative stress
- adipose tissue
- reactive oxygen species
- endoplasmic reticulum stress
- amino acid
- duchenne muscular dystrophy
- diabetic rats
- protein protein
- heat stress