Capetanaki Y, Milner D J, Weitzer G
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Cell Struct Funct. 1997 Feb;22(1):103-16. doi: 10.1247/csf.22.103.
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.
结蛋白是中间丝（IF）家族中肌肉特异性成员，是骨骼肌和心脏中最早已知的成肌标志物之一。其表达先于所有已知的肌肉蛋白，包括成肌螺旋-环-螺旋（mHLH）调节因子MyoD家族的成员，但myf5除外。在成熟的横纹肌中，结蛋白中间丝围绕Z盘，将它们相互连接，并将收缩装置与肌膜和细胞核整合在一起。利用反义RNA和同源重组技术在胚胎干细胞（ES）中进行的体外研究表明，结蛋白在肌生成过程中起关键作用，因为抑制结蛋白表达会阻断成肌细胞融合和肌管形成。在C2C12细胞和分化的胚状体中，结蛋白的缺失都会干扰正常的成肌程序，表现为mHLH转录调节因子受到抑制。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基因敲除小鼠。令人惊讶的是，相当数量的这些小鼠能够存活并繁殖，这可能是由于波形蛋白、巢蛋白或伴肌动蛋白的补偿作用。然而，结蛋白基因敲除小鼠表现出多系统紊乱，涉及心脏、骨骼和平滑肌，在出生后早期就开始出现。对心脏和骨骼肌组织进行的组织学和电子显微镜分析显示，肌肉结构严重破坏并发生退化。结构异常包括肌原纤维横向排列丧失、肌原纤维与肌膜的锚定紊乱、线粒体数量和组织异常以及细胞核形状和定位丧失。细胞黏附松散和细胞间空间增加是突出的缺陷。这些异常的后果在心脏中最为严重，心脏表现出心肌进行性退化和坏死，并伴有广泛钙化。平滑肌异常包括发育不全和退化。损伤严重程度与肌肉使用之间存在直接相关性，这可能是由于对正常机械损伤的易感性增加和/或在没有结蛋白的情况下修复缺陷所致。总之，迄今为止的研究表明，尽管结蛋白在体外对肌肉分化绝对必要，但在体内没有这种中间丝蛋白时肌肉仍可发育。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及功能完整性方面起重要作用。
