Overexpression of IGF-1 exclusively in skeletal muscle prevents age-related decline in the number of dihydropyridine receptors
Overexpression of IGF-1 exclusively in skeletal muscle prevents age-related decline in the number of dihydropyridine receptors
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DOI：
10.1074/jbc.273.44.28845
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发表时间：
1998-10-30
影响因子：
4.8
通讯作者：
Delbono, O
中科院分区：
文献类型：
--
作者：
Renganathan, M;Messi, ML;Delbono, O
兴奋-收缩解偶联已被确定为衰老哺乳动物骨骼肌无力（肌肉减少症）的潜在机制。兴奋-收缩解偶联的基本机制是大量的兰尼碱受体（RyR 1）与二氢吡啶受体（DHPR）解偶联（Delbono，O.，O'Rourke，K，S，and Ettinger，W. H，（1995）J，J. 148，211-222）。在本研究中，我们使用仅在骨骼肌中过表达人胰岛素样生长因子-1的转基因小鼠来检验高浓度IGF-1防止DHPR数量和肌肉力量的年龄相关性降低的假设。在所有年龄（1-24个月），转基因小鼠表达的IGF-1浓度比非转基因小鼠高10-20倍。转基因比目鱼肌（主要是I型纤维肌）、趾长伸肌（主要是II型纤维肌）以及I型和II型纤维肌池中的DHPR数量比非转基因年轻（6个月）、成年（12个月）和老年（24个月）小鼠高50-100%，DHPR/RyR 1比率高40%。此外，在转基因肌肉中未观察到DHPR和DHPR/RyR 1比率的年龄相关变化。老年转基因比目鱼肌和趾长伸肌的特异性单颤和强直肌力比老年非转基因肌肉高50%。总之，这些结果支持了IGF-1依赖性预防与年龄相关的DHPR表达下降与老年转基因小鼠更强的肌肉收缩相关的概念。
Excitation-contraction uncoupling has been identified as a mechanism underlying skeletal muscle weakness in aging mammals (sarcopenia). The basic mechanism for excitation-contraction uncoupling is a larger number of ryanodine receptors (RyR1) uncoupled to dihydropyridine receptors (DHPRs) (Delbono, O., O'Rourke, K, S,, and Ettinger, W. H, (1995) J, Membr. Biol. 148, 211-222), In the present study, we used transgenic mice overexpressing human insulin-like growth factor-1 exclusively in skeletal muscle to test the hypothesis that a high concentration of IGF-1 prevents age-related decreases in DHPR number and in muscle force. Transgenic mice express 10-20-fold higher IGF-1 concentrations than nontransgenic mice at all ages (1-24 months). The number of DHPRs is 50-100% higher, and the DHPR/RyR1 ratio is 40% higher in transgenic soleus (predominantly type I fiber muscles), extensor digitorum longus (predominantly type II fiber muscles), and the pool of type I and type II fiber muscles than in nontransgenic young (6 months), adult (12 months), and old (24 months) mice. Furthermore, no age-related changes in DHPRs and the DHPR/RyR1 ratio were observed in transgenic muscles. The specific single twitch and tetanic muscle force in old transgenic soleus and extensor digitorum longus muscles are 50% higher than in old nontransgenic muscles, Taken together, these results support the concept that IGF-1- dependent prevention of age-related decline in DHPR expression is associated with stronger muscle contraction in older transgenic mice.