Muscle weakness correlates with muscle atrophy and precedes the development of inclusion body or rimmed vacuoles in the mouse model of DMRV/hIBM
Muscle weakness correlates with muscle atrophy and precedes the development of inclusion body or rimmed vacuoles in the mouse model of DMRV/hIBM
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DOI：
10.1152/physiolgenomics.90219.2008
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发表时间：
2008-09-01
影响因子：
4.6
通讯作者：
Nishino, Ichizo
中科院分区：
文献类型：
--
作者：
Malicdan, May Christine V.;Noguchi, Satoru;Nishino, Ichizo
Malicdan MC, Noguchi S, Hayashi YK, Nishino I.肌肉无力与肌肉萎缩相关，并先于DMRV/hIBM小鼠模型的包涵体或边缘空泡的发展。中国生物医学工程学报（英文版），2008。首次发表于2008年7月15日；doi: 10.1152 / physiolgenomics.90219.2008。远端肌病伴边缘液泡（DMRV），也称为遗传性包涵体肌病（hIBM），临床表现为虚弱和萎缩，最初累及远端肌肉，病理表现为肌纤维中存在边缘液泡（rv）或细胞内蛋白沉积。它是由在唾液酸合成中起重要作用的udp - n -乙酰氨基葡萄糖胺2- epimase / n -乙酰氨基甘露胺激酶（N-acetylmannosamine kinase， GNE）基因突变引起的。最近，我们建立了一个小鼠模型（基因（-/-）hGNED176VTg），它表现出与DMRV患者相似的肌肉无力和病理变化。为了更好地了解DMRV的发病机制，我们确定了DMRV模型小鼠整体运动性能的时间变化与分离骨骼肌的结构和功能以及肌肉病理的关系。这些DMRV小鼠表现出肌肉无力，全肌质量和横截面积（CSA）减少，收缩力降低，与年龄相关。单纤维CSA进一步支持了涉及I型和II型纤维的肌肉萎缩的发现。这些结果表明，在体内和体外，萎缩与年轻时的力产生减少高度相关，从而暗示萎缩在DMRV的病理机制中起重要作用。在老年，特别是在腓肠肌中，在IIA型纤维中可见RVs和细胞内包涵体，进一步加重了力的降低和特定的抽搐-破伤风比的增加。
Malicdan MC, Noguchi S, Hayashi YK, Nishino I. Muscle weakness correlates with muscle atrophy and precedes the development of inclusion body or rimmed vacuoles in the mouse model of DMRV/hIBM. Physiol Genomics 35: 106-115, 2008. First published July 15, 2008; doi: 10.1152/physiolgenomics.90219.2008.-Distal myopathy with rimmed vacuoles (DMRV), also called hereditary inclusion body myopathy (hIBM), is characterized clinically by weakness and atrophy that initially involves the distal muscles and pathologically by the presence of rimmed vacuoles (RVs) or intracellular protein deposits in myofibers. It is caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene that is important in sialic acid synthesis. Recently, we generated a mouse model (Gne(-/-)hGNED176VTg) that exhibits muscle weakness and pathological changes similar to DMRV patients. To gain better understanding of the pathomechanism of DMRV, we determined temporal changes in the overall motor performance of this model mouse for DMRV in correlation with the structure and function of isolated skeletal muscles and muscle pathology. These DMRV mice exhibited muscle weakness, decreased whole muscle mass and cross-sectional area (CSA), and reduced contractile power in an age-related manner. Single-fiber CSA further supported the finding of muscle atrophy that involved both type I and type II fibers. These results suggest that atrophy is highly correlated with reduced production of force at young age, both in vivo and ex vivo, thereby implicating the important role of atrophy in the pathomechanism of DMRV. In older age, and particularly in gastrocnemius muscles, RVs and intracellular inclusions were seen in type IIA fibers, further aggravating reduction of force and specific increase in twitch-tetanus ratio.