Motor neurone targeting of IGF-1 prevents specific force decline in ageing mouse muscle
Motor neurone targeting of IGF-1 prevents specific force decline in ageing mouse muscle
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DOI：
10.1113/jphysiol.2005.100032
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发表时间：
2006-01-15
影响因子：
5.5
通讯作者：
Delbono, O
中科院分区：
文献类型：
--
作者：
Payne, AM;Zheng, ZL;Delbono, O
IGF-1是运动神经元和骨骼肌的有效生长因子。已知肌肉IGF-1对运动神经元提供靶源性营养作用。因此，肌肉中IGF-1的过度表达可以有效地延缓或预防两种组织中衰老的有害影响。由于与年龄相关的肌肉功能下降部分源于运动神经元损失，因此产生了破伤风毒素片段-C（TTC）融合蛋白以将IGF-1靶向运动神经元。IGF-1-TTC保留IGF-1活性，如通过[H-3]胸苷掺入L 6成肌细胞所示。脊髓运动神经元在体外有效地结合和内化IGF-1-TTC。类似地，IGF-1-TTC注射到骨骼肌中被摄取并在体内逆行转运到脊髓，这一过程被注射肌肉的去神经支配所阻止。三个月的IGF-1-TTC注射到衰老小鼠的肌肉中并没有增加肌肉重量或肌纤维大小，但与注射生理盐水，IGF-1或TTC的老年对照组相比，单纤维比力显着增加。没有注射改变肌纤维类型组成，但神经肌肉接头后终端更大，更复杂的肌肉纤维注射IGF-1-TTC相比，其他组，这表明保存肌纤维神经支配。这项工作表明，在衰老小鼠的脊髓运动神经元中诱导IGF-1的过表达可以防止肌纤维比力下降，这是骨骼肌衰老的标志。
IGF-1 is a potent growth factor for both motor neurones and skeletal muscle. Muscle IGF-1 is known to provide target-derived trophic effects on motor neurones. Therefore, IGF-1 overexpression in muscle is effective in delaying or preventing deleterious effects of ageing in both tissues. Since age-related decline in muscle function stems partly from motor neurone loss, a tetanus toxin fragment-C (TTC) fusion protein was created to target IGF-1 to motor neurones. IGF-1-TTC retains IGF-1 activity as indicated by [H-3]thymidine incorporation into L6 myoblasts. Spinal cord motor neurones effectively bound and internalized the IGF-1-TTC in vitro. Similarly, IGF-1-TTC injected into skeletal muscles was taken up and retrogradely transported to the spinal cord in vivo, a process prevented by denervation of injected muscles. Three monthly IGF-1-TTC injections into muscles of ageing mice did not increase muscle weight or muscle fibre size, but significantly increased single fibre specific force over aged controls injected with saline, IGF-1, or TTC. None of the injections changed muscle fibre type composition, but neuromuscular junction post-terminals were larger and more complex in muscle fibres injected with IGF-1-TTC, compared to the other groups, suggesting preservation of muscle fibre innervation. This work demonstrates that induced overexpression of IGF-1 in spinal cord motor neurones of ageing mice prevents muscle fibre specific force decline, a hallmark of ageing skeletal muscle.