Swain J L, Hines J J, Sabina R L, Harbury O L, Holmes E W
J Clin Invest. 1984 Oct;74(4):1422-7. doi: 10.1172/JCI111553.
Controversy exists as to whether the purine nucleotide cycle is important in normal skeletal muscle function. Patients with disruption of the cycle from a deficiency of AMP deaminase exhibit variable degrees of muscle dysfunction. An animal model was used to examine the effect of inhibition of the purine nucleotide cycle on muscle function. When the compound 5-amino-4-imidazolecarboxamide riboside (AICAriboside) is phosphorylated to the riboside monophosphate in the myocyte it is an inhibitor of adenylosuccinate lyase, one of the enzymes of the purine nucleotide cycle. AICAriboside was infused in 28 mice, and 22 mice received saline. Gastrocnemius muscle function was assessed in situ by recording isometric tension developed during stimulation. The purine nucleotide content of the muscle was measured before and after stimulation. Disruption of the purine nucleotide cycle during muscle stimulation was evidenced by a greater accumulation of adenylosuccinate, the substrate for adenylosuccinate lyase, in the animals receiving AICAriboside (0.60 +/- 0.10 vs. 0.05 +/- 0.01 nmol/mumol total creatine, P less than 0.0001). There was also a larger accumulation of inosine monophosphate in the AICAriboside vs. saline-treated animals at end stimulation (73 +/- 6 vs. 56 +/- 5 nmol/mumol total creatine, P less than 0.03). Inhibition of flux through the cycle was accompanied by muscle dysfunction during stimulation. Total developed tension in the AICAriboside group was 40% less than in the saline group (3,023 +/- 1,170 vs. 5,090 +/- 450 g . s, P less than 0.002). An index of energy production can be obtained by comparing the change in total phosphagen content per unit of developed tension in the two groups. This index indicates that less high energy phosphate compounds were generated in the AICAriboside group, suggesting that interruption of the purine nucleotide cycle interfered with energy production in the muscle. We conclude from these studies that defective energy generation is one mechanism whereby disruption of the purine nucleotide cycle produces muscle dysfunction.
关于嘌呤核苷酸循环在正常骨骼肌功能中是否重要存在争议。因AMP脱氨酶缺乏而导致该循环中断的患者表现出不同程度的肌肉功能障碍。使用动物模型来研究抑制嘌呤核苷酸循环对肌肉功能的影响。当化合物5-氨基-4-咪唑甲酰胺核苷（AICA核苷）在肌细胞中磷酸化为核苷单磷酸时，它是嘌呤核苷酸循环中的一种酶——腺苷酸琥珀酸裂解酶的抑制剂。将AICA核苷注入28只小鼠体内，22只小鼠注射生理盐水。通过记录刺激过程中产生的等长张力在原位评估腓肠肌功能。在刺激前后测量肌肉的嘌呤核苷酸含量。在接受AICA核苷的动物中，腺苷酸琥珀酸（腺苷酸琥珀酸裂解酶的底物）积累更多，这证明了肌肉刺激过程中嘌呤核苷酸循环的中断（0.60±0.10对0.05±0.01 nmol/μmol总肌酸，P<0.0001）。在刺激结束时，AICA核苷处理组与生理盐水处理组相比，肌苷单磷酸的积累也更多（73±6对56±5 nmol/μmol总肌酸，P<0.03）。循环通量的抑制伴随着刺激过程中的肌肉功能障碍。AICA核苷组产生的总张力比生理盐水组低40%（3,023±1,170对5,090±450 g·s，P<0.002）。通过比较两组中每单位产生张力的总磷酸肌酸含量变化可以获得能量产生指数。该指数表明AICA核苷组产生的高能磷酸化合物较少，这表明嘌呤核苷酸循环的中断会干扰肌肉中的能量产生。我们从这些研究中得出结论，能量生成缺陷是嘌呤核苷酸循环中断导致肌肉功能障碍的一种机制。
