Shavlakadze Thea, Winn Nadine, Rosenthal Nadia, Grounds Miranda D
School of Anatomy and Human Biology, the University of Western Australia, Crawley, Perth, Western Australia 6009, Australia.
Growth Horm IGF Res. 2005 Feb;15(1):4-18. doi: 10.1016/j.ghir.2004.11.001. Epub 2005 Jan 21.
Transgenic mice that overexpress insulin-like growth factor-1 (IGF-I) specifically in skeletal muscle have generated much information about the role of this factor for muscle growth and remodelling and provide insight for therapeutic applications of IGF-I for different pathological states and ageing. However, difficulties arise when attempting to critically compare the significance of data obtained in vivo by using different genetically engineered mouse lines and various experimental models. Complications arise due to complexity of the IGF-I system, since multiple transcripts of the IGF-I gene encode different isoforms generated by alternate promoter usage, differential splicing and post-translational modification, and how IGF-I gene expression relates to its diverse autocrine, paracrine and endocrine modes of action in vivo has still to be elucidated. In addition, there are problems related to specification of the exact IGF-I isoform used, expression patterns of the promoters, and availability of the transgene product under different experimental conditions. This review discusses the factors that must be considered when reconciling data from cumulative studies on IGF-I in striated muscle growth and differentiation using genetically modified mice. Critical evaluation of the literature focuses specifically on: (1) the importance of detailed information about the IGF-I isoforms and their mode of action (local, systemic or both); (2) expression pattern and strength of the promoters used to drive transgenic IGF-I in skeletal muscle cells (mono and multi-nucleated); (3) local compared with systemic action of the transgene product and possible indirect effects of transgenic IGF-I due to upregulation of other genes within skeletal muscle; (4) re-interpretation of these results in light of the most recent approaches to the dissection of IGF-I function. Full understanding of these complex in vivo issues is essential, not only for skeletal muscle but for many other tissues, in order to effectively extend observations derived from transgenic studies into potential clinical situations.
在骨骼肌中特异性过表达胰岛素样生长因子-1（IGF-I）的转基因小鼠，已经产生了许多关于该因子在肌肉生长和重塑中作用的信息，并为IGF-I在不同病理状态和衰老中的治疗应用提供了见解。然而，当试图严格比较使用不同基因工程小鼠品系和各种实验模型在体内获得的数据的重要性时，就会出现困难。由于IGF-I系统的复杂性，会出现并发症，因为IGF-I基因的多个转录本编码由交替启动子使用、差异剪接和翻译后修饰产生的不同异构体，并且IGF-I基因表达与其在体内不同的自分泌、旁分泌和内分泌作用模式之间的关系仍有待阐明。此外，还存在与所用确切IGF-I异构体的规格、启动子的表达模式以及不同实验条件下转基因产物的可用性相关的问题。本综述讨论了在整合使用转基因小鼠对IGF-I在横纹肌生长和分化方面的累积研究数据时必须考虑的因素。对文献的批判性评估特别关注：（1）关于IGF-I异构体及其作用模式（局部、全身或两者兼有）的详细信息的重要性；（2）用于驱动骨骼肌细胞（单核和多核）中转基因IGF-I的启动子的表达模式和强度；（3）转基因产物的局部作用与全身作用以及由于骨骼肌内其他基因上调导致的转基因IGF-I的可能间接影响；（4）根据剖析IGF-I功能的最新方法对这些结果进行重新解释。全面理解这些复杂的体内问题不仅对于骨骼肌而且对于许多其他组织都是至关重要的，以便有效地将转基因研究得出的观察结果扩展到潜在的临床情况中。
