Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation
Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation
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DOI：
10.1152/ajpregu.00212.2014
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发表时间：
2014-11-15
影响因子：
2.8
通讯作者：
Zong, Haihong
中科院分区：
文献类型：
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作者：
Shemesh, Adi;Wang, Yichen;Zong, Haihong
Pompe病是由于缺乏酸性-α-葡萄糖苷酶(GAA)，导致衰弱的骨骼肌萎缩，特征是糖原和自噬小泡的积累。鉴于溶酶体作为mTORC1激活平台的作用，我们在庞贝病模型中检测了mTORC1的活性。GAA基因敲除的C2C12成肌细胞和GAA缺陷的人皮肤成纤维细胞在婴儿Pompe患者中发现mTORC1活性降低。用细胞通透性的亮氨酸类似物L-亮氨酰-L-亮氨酸甲酯处理后，mTORC1的激活恢复。在活体中，庞贝小鼠的骨骼肌基础和亮氨酸刺激的mTORC1活性也降低，而胰岛素和亮氨酸的联合治疗使mTORC1的激活正常化。长期喂养亮氨酸恢复了基础和亮氨酸刺激的mTORC1激活，同时部分保护了庞贝小鼠免受脊柱后凸和肌肉质量下降的影响。经亮氨酸处理的庞贝小鼠表现出自发活动和跑步能力的增加，肌肉蛋白质分解和糖原积累减少。综上所述，这些数据表明，GAA缺乏导致mTORC1激活减少，这是骨骼肌萎缩表型的部分原因。此外，饮食中补充亮氨酸对mTORC1的刺激可以预防庞贝病小鼠模型中发生的一些有害的骨骼肌功能障碍。
Pompe disease is due to a deficiency in acid-alpha-glucosidase (GAA) and results in debilitating skeletal muscle wasting, characterized by the accumulation of glycogen and autophagic vesicles. Given the role of lysosomes as a platform for mTORC1 activation, we examined mTORC1 activity in models of Pompe disease. GAA-knockdown C2C12 myoblasts and GAA-deficient human skin fibroblasts of infantile Pompe patients were found to have decreased mTORC1 activation. Treatment with the cell-permeable leucine analog L-leucyl-L-leucine methyl ester restored mTORC1 activation. In vivo, Pompe mice also displayed reduced basal and leucine-stimulated mTORC1 activation in skeletal muscle, whereas treatment with a combination of insulin and leucine normalized mTORC1 activation. Chronic leucine feeding restored basal and leucine-stimulated mTORC1 activation, while partially protecting Pompe mice from developing kyphosis and the decline in muscle mass. Leucine-treated Pompe mice showed increased spontaneous activity and running capacity, with reduced muscle protein breakdown and glycogen accumulation. Together, these data demonstrate that GAA deficiency results in reduced mTORC1 activation that is partly responsible for the skeletal muscle wasting phenotype. Moreover, mTORC1 stimulation by dietary leucine supplementation prevented some of the detrimental skeletal muscle dysfunction that occurs in the Pompe disease mouse model.