Modeling statin-induced myopathy with hiPSC-derived myocytes reveals that impaired proteostasis underlies the myotoxicity and is targetable for the prevention.

IF 5 2区 生物学 Q2 CELL BIOLOGY
Xiaolin Zhao, Liyang Ni, Miharu Kubo, Mariko Matsuto, Hidetoshi Sakurai, Makoto Shimizu, Yu Takahashi, Ryuichiro Sato, Yoshio Yamauchi
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引用次数: 0

Abstract

Statins, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, have been widely prescribed to lower circulating low-density lipoprotein cholesterol levels and reduce the risk of cardiovascular disease. Although statins are well tolerated, statin-associated muscle symptoms (SAMS) are the major adverse effect and cause statin intolerance. Therefore, understanding the molecular mechanisms of SAMS and developing effective strategies for its prevention are of significant clinical importance; however, both remain unclear. Here, we establish a model of statin-induced myopathy (SIM) with human induced pluripotent stem cell (hiPSC)-derived myocytes (iPSC-MCs) and investigate the effect of statins on protein homeostasis (proteostasis) that affects skeletal muscle wasting and myotoxicity. We show that treating hiPSC-MCs with statins induces atrophic phenotype and myotoxicity, establishing an hiPSC-based SIM model. We then examine whether statins impair the balance between protein synthesis and degradation. The results show that statins not only suppress protein synthesis but also promote protein degradation by upregulating the expression of the muscle-specific E3 ubiquitin ligase Atrogin-1 in a mevalonate pathway-dependent manner. Mechanistically, blocking the mevalonate pathway inactivates the protein kinase Akt, leading to the inhibition of mTOR complex 1 (mTORC1) but the activation of GSK3β and FOXO1. These changes explain the statin-induced impairment in proteostasis. Finally, we show that pharmacological blockage of FOXO1 prevents SIM in hiPSC-MCs, implicating FOXO1 as a key mediator of SIM. Taken together, this study suggests that the mevalonate pathway is critical for maintaining skeletal muscle proteostasis and identifies FOXO1 as a potential target for preventing SIM.NEW & NOTEWORTHY This work established a human induced pluripotent stem (iPS) cell-based model for statin-induced myopathy (SIM) and demonstrated that blocking the mevalonate pathway disrupts the balance between protein synthesis and degradation, leading to myopathy. Furthermore, the present study showed that pharmacological inhibition of the transcription factor FOXO1 prevents SIM in human iPS cell-derived myocytes, suggesting that FOXO1 is a key mediator of SIM and a potential target for its prevention.

他汀类药物是一种 HMG-CoA 还原酶抑制剂,被广泛用于降低循环中的低密度脂蛋白胆固醇水平和减少心血管疾病风险。虽然他汀类药物的耐受性良好,但他汀类药物相关肌肉症状(SAMS)是主要的不良反应,也是他汀类药物不耐受的原因。因此,了解他汀类药物相关肌肉症状的分子机制并制定有效的预防策略具有重要的临床意义;然而,这两点仍不明确。在此,我们利用人体诱导多能干细胞(hiPSC)衍生的肌细胞(iPSC-MCs)建立了他汀类药物诱导的肌病(SIM)模型,并研究了他汀类药物对影响骨骼肌萎缩和肌毒性的蛋白质稳态(proteostasis)的影响。我们发现,用他汀类药物处理 hiPSC-MCs 会诱导萎缩表型和肌毒性,从而建立了基于 hiPSC 的 SIM 模型。然后,我们研究了他汀类药物是否会损害蛋白质合成和降解之间的平衡。结果表明,他汀类药物不仅抑制蛋白质合成,还通过上调肌肉特异性E3泛素连接酶Atrogin-1的表达,以甲羟戊酸通路依赖的方式促进蛋白质降解。从机制上讲,阻断甲羟戊酸途径会使蛋白激酶 Akt 失活,导致 mTORC1 受抑制,但 GSK3β 和 FOXO1 被激活。这些变化解释了他汀类药物诱导的蛋白稳态损伤。最后,我们发现药理阻断 FOXO1 可防止 hiPSC-MCs 中的 SIM,这表明 FOXO1 是 SIM 的关键介质。综上所述,本研究表明甲羟戊酸通路对维持骨骼肌蛋白稳态至关重要,并确定 FOXO1 为预防 SIM 的潜在靶点。
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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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