Desmin in muscle formation and maintenance: Knockouts and consequences
Desmin in muscle formation and maintenance: Knockouts and consequences
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DOI：
10.1247/csf.22.103
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发表时间：
1997-02-01
影响因子：
1.5
通讯作者：
Weitzer, G
中科院分区：
文献类型：
--
作者：
Capetanaki, Y;Milner, DJ;Weitzer, G
结蛋白是中间丝 (IF) 家族的肌肉特异性成员，是骨骼肌和心脏中最早已知的生肌标记物之一。它的表达先于所有已知的肌肉蛋白，包括肌源性螺旋-环-螺旋 (mHLH) 调节因子的 MyoD 家族成员（myf5 除外）。在成熟的横纹肌中，结蛋白 Ifs 围绕 Z 盘，将它们连接在一起，并将收缩装置与肌膜和细胞核整合在一起。在胚胎干 (ES) 细胞中使用反义 RNA 和同源重组技术进行的体外研究表明，结蛋白在肌生成过程中发挥着至关重要的作用，因为抑制结蛋白表达会阻止成肌细胞融合和肌管形成。在 C2C12 细胞和分化的胚状体中，结蛋白的缺失会干扰正常的生肌程序，这通过 mHLH 转录调节因子的抑制来证明。为了研究结蛋白在体内所有肌肉类型中的功能，我们通过同源重组产生了结蛋白缺失小鼠。令人惊讶的是，这些小鼠中相当多的小鼠能够存活并具有生育能力，这可能是由于波形蛋白、巢蛋白或丝线蛋白的补偿。然而，结蛋白缺失小鼠在出生后早期就表现出涉及心脏、骨骼和平滑肌的多系统疾病。心脏和骨骼肌组织的组织学和电子显微镜分析揭示了肌肉结构的严重破坏和退化。结构异常包括肌原纤维横向排列的丧失、肌原纤维锚定于肌膜的扰动、线粒体数量和组织异常以及核形状和定位的丧失。细胞粘附松散和细胞间隙增大是突出的缺陷。这些异常的后果在心脏中最为严重，其表现出心肌进行性变性和坏死，并伴有广泛的钙化。平滑肌异常包括发育不全和变性。损伤的严重程度和肌肉使用之间存在直接相关性，可能是由于在缺乏结蛋白的情况下对正常机械损伤和/或修复缺陷的敏感性增加。总之，迄今为止的研究表明，尽管结蛋白对于体外肌肉分化是绝对必要的，但在没有这种中间丝蛋白的情况下，肌肉发育也可以在体内发生。然而，结蛋白似乎在维持肌原纤维、肌纤维和整个肌肉组织结构和功能完整性方面发挥着重要作用。
Desmin, the muscle-specific member of the intermediate filament (IF) family, is one of the earliest known myogenic markers in both skeletal muscle and heart. Its expression precedes that of all known muscle proteins including the members of the MyoD family of myogenic helix-loop-helix (mHLH) regulators with the exception of myf5. In mature striated muscle, desmin Ifs surround the Z-discs, interlink them together and integrate the contractile apparatus with the sarcolemma and the nucleus. In vitro studies using both antisense RNA and homologous recombination techniques in embryonic stem (ES) cells demonstrated that desmin plays a crucial role during myogenesis, as inhibition of desmin expression blocked myoblast fusion and myotube formation. Both in C2C12 cells and differentiating embryoid bodies, the absence of desmin interferes with the normal myogenic program, as manifested by the inhibition of the mHLH transcription regulators, To investigate the function of desmin in all muscle types in vivo, we generated desmin null mice through homologous recombination. Surprisingly, a considerable number of these mice are viable and fertile, potentially due to compensation by vimentin, nestin or synemin. However, desmin null mice demonstrate a multisystem disorder involving cardiac, skeletal and smooth muscle, beginning early in their postnatal life. Histological and electron microscopic analysis in both heart and skeletal muscle tissues reveals severe disruption of muscle architecture and degeneration. Structural abnormalities include loss of lateral alignment of myofibrils, perturbation of myofibril anchorage to the sarcolemma, abnormal mitochondrial number and organization, and loss of nuclear shape and positioning. Loose cell adhesion and increased intercellular space are prominent defects. The consequences of these abnormalities are most severe in the heart, which exhibits progressive degeneration and necrosis of the myocardium accompanied by extensive calcification. Abnormalities of smooth muscle included hypoplasia and degeneration. There is a direct correlation between severity of damage and muscle usage, possibly due to increased susceptibility to normal mechanical damage and/or to repair deficiency in the absence of desmin. In conclusion, the studies so far have demonstrated that though desmin is absolutely necessary for muscle differentiation in vitro, muscle development can take place in vivo in the absence of this intermediate filament protein. However, desmin seems to play an essential role in the maintenance of myofibril, myofiber and whole muscle tissue structural and functional integrity.