Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function
Viral mediated expression of insulin-like growth factor I blocks the aging-related loss of skeletal muscle function
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DOI：
10.1073/pnas.95.26.15603
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发表时间：
1998-12-22
影响因子：
11.1
通讯作者：
Sweeney, HL
中科院分区：
文献类型：
--
作者：
Barton-Davis, ER;Shoturma, DI;Sweeney, HL
在衰老过程中，哺乳动物损失了三分之一的骨骼肌质量和力量。尽管这种损失的机制尚不完全清楚，但我们尝试通过增加肌肉的再生能力来减轻损失。这涉及到注射重组腺相关病毒，指导胰岛素样生长因子 I (IGF-I) 在分化的肌纤维中过度表达。我们证明，IGF-I 表达促进年轻成年小鼠的肌肉质量平均增加 15%，力量增加 14%，并且显着地防止老年小鼠的衰老相关肌肉变化，导致与成年小鼠相比，力量增加 27% 未注射的旧肌肉。肌肉质量和纤维类型分布保持在与年轻人相似的水平。我们认为这些效应主要是由于 IGF-I 激活卫星细胞刺激肌肉再生，这支持了这样的假设：与衰老相关的肌肉功能损伤的主要原因是肌肉使用过程中持续损伤的累积失败修复。我们的研究结果表明，将 IGF-I 基因转移到肌肉中可以构成人类基因疗法的基础，以预防与衰老相关的肌肉功能丧失，并且可能对骨骼肌损伤速度加快的疾病有益。
During the aging process, mammals lose up to a third of their skeletal muscle mass and strength. Although the mechanisms underlying this loss are not entirely understood, we attempted to moderate the loss by increasing the regenerative capacity of muscle. This involved the injection of a recombinant adeno-associated virus directing overexpression of insulin-like growth factor I (IGF-I) in differentiated muscle fibers, We demonstrate that the IGF-I expression promotes an average increase of 15% in muscle mass and a 14% increase in strength in young adult mice, and remarkably, prevents aging-related muscle changes in old adult mice, resulting in a 27% increase in strength as compared with uninjected old muscles. Muscle mass and fiber type distributions were maintained at levels similar to those in young adults. We propose that these effects are primarily due to stimulation of muscle regeneration via the activation of satellite cells by IGF-I, This supports the hypothesis that the primary cause of aging-related impairment of muscle function is a cumulative failure to repair damage sustained during muscle utilization. Our results suggest that gene transfer of IGF-I into muscle could form the basis of a human gene therapy for preventing the loss of muscle function associated with aging and may be of benefit in diseases where the rate of damage to skeletal muscle is accelerated.