Zaripova Ksenia A, Belova Svetlana P, Kostrominova Tatiana Y, Shenkman Boris S, Nemirovskaya Tatiana L
Myology Laboratory, Institute of Biomedical Problems (IBP), RAS, 123007 Moscow, Russia.
Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine-Northwest, Gary, IN 46202, USA.
Int J Mol Sci. 2025 Jan 6;26(1):414. doi: 10.3390/ijms26010414.
During skeletal muscle unloading, phosphoinositide 3-kinase (PI3K), and especially PI3K gamma (PI3Kγ), can be activated by changes in membrane potential. Activated IP3 can increase the ability of Ca to enter the nucleus through IP3 receptors. This may contribute to the activation of transcription factors that initiate muscle atrophy processes. LY294002 inhibitor was used to study the role of PI3K in the ATP-dependent regulation of skeletal muscle signaling during three days of unloading. Inhibition of PI3K during soleus muscle unloading slows down the atrophic processes and prevents the accumulation of ATP and the expression of the E3 ubiquitin ligase MuRF1 and ubiquitin. It also prevents the increase in the expression of IP3 receptors and regulates the activity of Ca-dependent signaling pathways by reducing the mRNA expression of the Ca-dependent marker calcineurin (CaN) and decreasing the phosphorylation of CaMKII. It also affects the regulation of markers of anabolic signaling in unloaded muscles: IRS1 and 4E-BP. PI3K is an important mediator of skeletal muscle atrophy during unloading. Developing strategies for the localized skeletal muscle release of PI3K inhibitors might be one of the future treatments for inactivity and disease-induced muscle atrophy.
在骨骼肌卸载过程中，磷酸肌醇3激酶（PI3K），尤其是PI3Kγ，可被膜电位变化激活。激活的肌醇三磷酸（IP3）可增强钙离子通过IP3受体进入细胞核的能力。这可能有助于启动肌肉萎缩过程的转录因子的激活。使用LY294002抑制剂研究PI3K在卸载三天期间对骨骼肌信号转导的ATP依赖性调节中的作用。比目鱼肌卸载期间抑制PI3K可减缓萎缩过程，并防止ATP积累以及E3泛素连接酶肌肉萎缩相关蛋白1（MuRF1）和泛素的表达。它还可防止IP3受体表达增加，并通过降低钙依赖性标志物钙调神经磷酸酶（CaN）的mRNA表达以及减少钙/钙调蛋白依赖蛋白激酶II（CaMKII）的磷酸化来调节钙依赖性信号通路的活性。它还影响卸载肌肉中合成代谢信号标志物的调节：胰岛素受体底物1（IRS1）和真核细胞起始因子4E结合蛋白（4E-BP）。PI3K是卸载期间骨骼肌萎缩的重要介质。开发局部释放PI3K抑制剂的策略可能是未来治疗因不活动和疾病引起的肌肉萎缩的方法之一。
