Krag Thomas O, Pinós Tomàs, Nielsen Tue L, Duran Jordi, García-Rocha Mar, Andreu Antoni L, Vissing John
Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;
Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Mitochondrial Pathology and Neuromuscular Disorders Laboratory, Vall d'Hebron Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain;
Am J Physiol Regul Integr Comp Physiol. 2016 Aug 1;311(2):R307-14. doi: 10.1152/ajpregu.00489.2015. Epub 2016 Jun 8.
McArdle disease (muscle glycogenosis type V) is a disease caused by myophosphorylase deficiency leading to "blocked" glycogen breakdown. A significant but varying glycogen accumulation in especially distal hind limb muscles of mice affected by McArdle disease has recently been demonstrated. In this study, we investigated how myophosphorylase deficiency affects glucose metabolism in hind limb muscle of 20-wk-old McArdle mice and vastus lateralis muscles from patients with McArdle disease. Western blot analysis and activity assay demonstrated that glycogen synthase was inhibited in glycolytic muscle from McArdle mice. The level and activation of proteins involved in contraction-induced glucose transport (AMPK, GLUT4) and glycogen synthase inhibition were increased in quadriceps muscle of McArdle mice. In addition, pCaMKII in quadriceps was reduced, suggesting lower insulin-induced glucose uptake, which could lead to lower glycogen accumulation. In comparison, tibialis anterior, extensor digitorum longus, and soleus had massive glycogen accumulation, but few, if any, changes or adaptations in glucose metabolism compared with wild-type mice. The findings suggest plasticity in glycogen metabolism in the McArdle mouse that is related to myosin heavy chain type IIB content in muscles. In patients, the level of GLUT4 was vastly increased, as were hexokinase II and phosphofructokinase, and glycogen synthase was more inhibited, suggesting that patients adapt by increasing capture of glucose for direct metabolism, thereby significantly reducing glycogen buildup compared with the mouse model. Hence, the McArdle mouse may be a useful tool for further comparative studies of disease mechanism caused by myophosphorylase deficiency and basic studies of metabolic adaptation in muscle.
麦克尔迪氏病（Ⅴ型肌肉糖原贮积症）是一种由肌磷酸化酶缺乏导致糖原分解“受阻”引起的疾病。最近已证实，受麦克尔迪氏病影响的小鼠，尤其是后肢远端肌肉中存在大量且不同程度的糖原积累。在本研究中，我们调查了肌磷酸化酶缺乏如何影响20周龄麦克尔迪氏病小鼠后肢肌肉以及麦克尔迪氏病患者股外侧肌的葡萄糖代谢。蛋白质免疫印迹分析和活性测定表明，麦克尔迪氏病小鼠糖酵解肌肉中的糖原合酶受到抑制。麦克尔迪氏病小鼠股四头肌中参与收缩诱导性葡萄糖转运（AMPK、GLUT4）和糖原合酶抑制相关蛋白的水平及活性增加。此外，股四头肌中的pCaMKII减少，提示胰岛素诱导的葡萄糖摄取降低，这可能导致糖原积累减少。相比之下，与野生型小鼠相比，胫骨前肌、趾长伸肌和比目鱼肌有大量糖原积累，但葡萄糖代谢几乎没有变化或适应性改变。这些发现表明，麦克尔迪氏病小鼠的糖原代谢具有可塑性，这与肌肉中肌球蛋白重链IIB的含量有关。在患者中，GLUT4水平大幅升高，己糖激酶II和磷酸果糖激酶也是如此，糖原合酶受到的抑制更强，这表明患者通过增加对葡萄糖的摄取以进行直接代谢来进行适应，从而与小鼠模型相比显著减少了糖原积累。因此，麦克尔迪氏病小鼠可能是进一步比较研究肌磷酸化酶缺乏引起的疾病机制以及肌肉代谢适应性基础研究的有用工具。
