悪性高熱症(MH)は, 全身麻酔時の重篤な合併症のひとつで全身麻酔に伴い発熱・筋硬直・不整脈・代謝性アシドーシスが生じる。原因は骨格筋小胞体からのCa2+放出亢進と考えられている。本研究ではMH既往患者のうち特にI型リアノジン受容体遺伝子(RYR1)に変異を有する患者からiPS細胞を作出し, 骨格筋への選択的な分化誘導を行った。その結果, 一部の疾患株で筋収縮様の変態が確認できた。さらに培養上清の乳酸値も高く細胞の異常代謝が示唆された。また, 抗RYR1抗体を用いて免疫染色したところ, 顆粒状のシグナルが細胞内に散見された。本研究により, MHの新規細胞モデルを提唱できる可能性を示した。
Malignant hyperthermia (MH), is a type of severe reaction that occurs to particular medications used during anesthesia. Symptoms include muscle rigidity, high fever, a fast heart rate, and mixed acidosis. In a large proportion of cases, the propensity for MH is due to a mutation of the type I ryanodine receptor (RYR1), located on the sarcoplasmic reticulum. RYR1 opens in response to increases in intracellular Ca2+ level mediated by L-type calcium channels, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. Here, we generated MH iPS cells from blood cells of the patients who have RYR1 gene mutation. MH iPS cells were successfully differentiated into skeletal muscle cells. Several patient cells exhibited muscle rigidity-like alteration and high concentration of lactate in the culture supernatant. Also accumulated RYR1 puncta were detected in the patient muscle cells. These findings can propose a new cellular model of MH.

研究種目 : 挑戦的萌芽研究
研究期間 : 2015～2017
課題番号 : 15K15574
研究分野 : 医歯薬学