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

Fusako Sakai-Takemura; Fumiaki Saito; Ken'ichiro Nogami; Yusuke Maruyama; Ahmed Elhussieny; Kiichiro Matsumura; Shin'ichi Takeda; Yoshitsugu Aoki; Yuko Miyagoe-Suzuki

doi:10.1096/fba.2023-00069

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

FASEB Bioadv. 2023 Oct 26;5(11):453-469. doi: 10.1096/fba.2023-00069. eCollection 2023 Nov.

Authors

Affiliations

¹ Department of Molecular Therapy National Institute of Neuroscience, National Center of Neurology and Psychiatry Tokyo Japan.
² Department of Neurology, School of Medicine Teikyo University Tokyo Japan.
³ Department of Neurology, Neurological Institute, Graduate School of Medical Science Kyushu University Fukuoka Japan.
⁴ Department of Gene Regulation, Faculty of Pharmaceutical Science Tokyo University of Science Chiba Japan.
⁵ Department of Neurology, Faculty of Medicine Minia University Minia Egypt.

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.

Keywords: Stromal interaction molecule 1; antioxidants; binding immunoglobulin protein; calcium; calcium release‐activated calcium channel protein 1 (ORAI1); induced pluripotent stem cells; skeletal muscle; store‐operated Ca2+ entry; tubular aggregate myopathy.