Freshage Research Group, Department of Physiology, Faculty of Medicine, University of Valencia and CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, 46010 Valencia, Spain.
Centro de Salud San Isidro, Consorcio Hospital General Universitario de Valencia, 46014 Valencia, Spain.
Cells. 2022 Sep 28;11(19):3041. doi: 10.3390/cells11193041.
Hypomorphic Glucose 6-P dehydrogenase (G6PD) alleles, which cause G6PD deficiency, affect around one in twenty people worldwide. The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.
低功能葡萄糖 6-磷酸脱氢酶 (G6PD) 等位基因导致 G6PD 缺乏症，影响全球约五分之一的人口。G6PD 缺乏症的高发率可能反映了一种对疟疾广泛流行的进化适应，因为缺乏 G6PD 的红细胞 (RBC) 对感染人类的疟原虫具有敌意。尽管医学对这种酶缺乏症的兴趣主要集中在 RBC 上，但最近的证据表明，G6PD 缺乏症对健康有更广泛的影响，包括在骨骼肌疾病中。G6PD 催化戊糖磷酸途径 (PPP) 的限速步骤，该途径为 DNA 复制提供核苷酸合成的前体以及还原型烟酰胺腺嘌呤二核苷酸磷酸 (NADPH)。NADPH 参与细胞活性氧 (ROS) 的解毒和从头脂质合成。PPP 活性增加与不同组织（包括骨骼肌、肝脏和肾脏）中的细胞生长刺激之间的关联已有报道。PPP 活性在胚胎发生、去神经支配、缺血、机械过载、肌坏死剂注射和体育锻炼期间增加骨骼肌。事实上，在一次剧烈运动后，骨骼肌酶活性的相对增加幅度最大的是 G6PD，这表明 PPP 的激活发生在骨骼肌中，以为肌肉修复提供底物。年龄相关的肌肉质量和力量损失导致骨骼肌中 G6PD 活性和蛋白含量降低。在 和小鼠中过表达 G6PD 可防止代谢应激、氧化损伤和与年龄相关的功能下降，并延长中位寿命。这篇综述讨论了骨骼肌中运动训练的众所周知的积极作用是否通过增加 G6PD 来介导。
