Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle
Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle
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DOI：
10.1093/hmg/ddn264
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Schiaffino, Stefano
中科院分区：
文献类型：
--
作者：
Blaauw, Bert;Mammucari, Cristina;Schiaffino, Stefano
杜氏肌营养不良模型mdx小鼠的骨骼肌在偏心收缩后最大强直力过度降低。这种肌营养不良蛋白缺乏的肌肉对机械应力易感性的具体迹象可以作为定量测试来衡量治疗干预的效果。通过小鼠诱导转基因，我们发现当Akt活性增加时，mdx小鼠偏心收缩引起的力下降与野生型小鼠相似。这种作用与肌肉肥大无关，也不会被雷帕霉素治疗阻断。直接拉伸时，mdx和Akt-mdx小鼠皮肤肌纤维偏心收缩引起的力下降相似。然而，从mdx肌肉中分离出来的皮肤纤维在体内暴露于偏心收缩时产生的等距力比野生型纤维小，这种力的抑制被Akt激活完全阻止。这些实验表明，肌营养不良蛋白缺陷肌的肌纤维-细胞骨架系统在体内拉伸时极易受到偏心收缩引起的损伤，而这种损伤可以通过激活Akt来预防。微阵列和PCR分析表明，Akt激活可诱导z -disk和costameres相关蛋白以及具有抗氧化或伴侣蛋白功能的蛋白编码基因上调。Akt激活后，肌营养蛋白和异ferlin蛋白水平也升高。
Skeletal muscles of the mdx mouse, a model of Duchenne Muscular Dystrophy, show an excessive reduction in the maximal tetanic force following eccentric contractions. This specific sign of the susceptibility of dystrophin-deficient muscles to mechanical stress can be used as a quantitative test to measure the efficacy of therapeutic interventions. Using inducible transgenesis in mice, we show that when Akt activity is increased the force drop induced by eccentric contractions in mdx mice becomes similar to that of wild-type mice. This effect is not correlated with muscle hypertrophy and is not blocked by rapamycin treatment. The force drop induced by eccentric contractions is similar in skinned muscle fibers from mdx and Akt-mdx mice when stretch is applied directly to skinned fibers. However, skinned fibers isolated from mdx muscles exposed to eccentric contractions in vivo develop less isometric force than wild-type fibers and this force depression is completely prevented by Akt activation. These experiments indicate that the myofibrillar-cytoskeletal system of dystrophin-deficient muscle is highly susceptible to a damage caused by eccentric contraction when elongation is applied in vivo, and this damage can be prevented by Akt activation. Microarray and PCR analyses indicate that Akt activation induces up-regulation of genes coding for proteins associated with Z-disks and costameres, and for proteins with anti-oxidant or chaperone function. The protein levels of utrophin and dysferlin are also increased by Akt activation.