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骨骼肌萎缩相关分子机制及信号通路研究进展

柯义兵¹, 阿布都克热木·达吾提¹, 郭浩然¹, 王勇平^2,*

¹兰州大学第一临床医学院，兰州 730000；²兰州大学第一医院骨科，兰州 730000

摘要

双孔钾离子通道(two-pore-domain potassium channels, K2P)家族在多种器官和细胞类型中广泛表达，并发挥重要的生理调节作用。K2P家族对多种化学和物理刺激非常敏感，与神经信号传递、离子稳态、细胞发育和死亡、突触可塑性等密切相关，其异常表达和功能障碍与一系列疾病相关，包括自身免疫性疾病、中枢神经系统疾病、心血管疾病等。本文就K2P家族中的TREK-1钾通道的结构、功能、调节剂，以及TREK-1与相关疾病作一综述。骨骼肌质量维持的分子机制涉及多种信号通路之间的相互作用。在正常生理条件下，相互交叉的信号通路用于控制和协调骨骼肌肥大和萎缩，最终使肌肉蛋白质合成和降解之间达到平衡。当蛋白质合成的总速率超过蛋白质降解的速率时，肌肉逐渐肥大，而当蛋白质合成的总速率低于蛋白质降解的速率时，肌肉则发生萎缩。肌细胞萎缩中主要涉及两种蛋白质降解途径，即泛素(ubiquitin, Ub)-蛋白酶体途径和自噬-溶酶体途径(autophagy-lysosomal pathway, ALP)。蛋白质降解途径在肌肉萎缩期间被激活，导致肌肉质量的损失。肌肉萎缩可在营养不良、衰老以及恶病质等多种条件下出现，骨科疾病引发的骨骼肌萎缩主要包括骨折导致的失用性肌萎缩以及去神经性肌萎缩。控制和协调骨骼肌蛋白质合成及降解的信号通路包括胰岛素样生长因子1 (insulin-like growth factor 1, IGF1)-Akt-哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)、肌生长抑制素(myostatin)-激活素A (activin A)-Smad、G蛋白α 抑制活性多肽2 (G protein α inhibitory peptide 2, Gαi2)-PKC、核因子κB (nuclear factor κB, NF-κB)、外胚层发育不良A2 受体(ectodysplasin A2 receptor, EDA2R)-NF-κB 诱导激酶(NF-κBinducing kinase, NIK)、丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信号通路。本文综述了骨骼肌发生萎缩时蛋白质的降解途径及调节肌萎缩蛋白质降解的相关信号通路。

关键词： 肌萎缩; IGF1-Akt-mTOR; myostatin-activin A-Smad; Gαi2-PKC; NF-κB; EDA2R-NIK; 信号通路

Research progress on molecular mechanism related to skeletal muscle atrophy

KE Yi-Bing¹, ABUDOUKEREMU Dawuti¹, GUO Hao-Ran¹, WANG Yong-Ping^2,*

¹The 1st School of Clinical Medicine of Lanzhou University, Lanzhou 730000, China；²Department of Orthopaedics, the First Hospital of Lanzhou University, Lanzhou 730000, China

Abstract

The maintenance of skeletal muscle quality involves various signal pathways that interact with each other. Under normal physiological conditions, these intersecting signal pathways regulate and coordinate the hypertrophy and atrophy of skeletal muscles, balancing the protein synthesis and degradation of muscle. When the total rate of protein synthesis exceeds that of protein degradation, the muscle gradually becomes enlarged, while when the total rate of protein synthesis is lower than that of protein degradation, the muscle shrinks. Myocyte atrophy mainly involves two protein degradation pathways, namely ubiquitin-proteasome and autophagy-lysosome. Protein degradation pathway is activated during muscle atrophy, resulting in the loss of muscle mass. Muscle atrophy can occur under various conditions such as malnutrition, aging and cachexia. Skeletal muscle atrophy caused by orthopedic diseases mainly includes disuse muscular atrophy caused by fracture and denervation muscular atrophy. The signal pathways that control and coordinate protein synthesis and degradation in skeletal muscle include insulin-like growth factor 1 (IGF1)-Akt-mammalian target of rapamycin (mTOR), myostatin-activin A-Smad, G protein α inhibitory peptide 2 (Gαi2)-PKC, nuclear factor κB (NF-κB), ectodysplasin A2 receptor (EDA2R)-NF-κB inducing kinase (NIK) and mitogen-activated protein kinase (MAPK) pathways. This paper provides a comprehensive review of the protein degradation pathways in skeletal muscle atrophy and the associated signal pathways regulating protein degradation in muscular atrophy.

Key words: amyotrophy; IGF1-Akt-mTOR; myostatin-activin A-Smad; Gαi2-PKC; NF-κB; EDA2R-NIK; signal pathway

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通讯作者：王勇平　　E-mail:

引用本文：

柯义兵, 阿布都克热木·达吾提, 郭浩然, 王勇平. 骨骼肌萎缩相关分子机制及信号通路研究进展[J]. 生理学报 2024; 76 (6): 1056-1068.

KE Yi-Bing, ABUDOUKEREMU Dawuti, GUO Hao-Ran, WANG Yong-Ping. Research progress on molecular mechanism related to skeletal muscle atrophy. Acta Physiol Sin 2024; 76 (6): 1056-1068 (in Chinese with English abstract).