Apoptosis-Inducing Factor Regulates Skeletal Muscle Progenitor Cell Number and Muscle Phenotype
Apoptosis-Inducing Factor Regulates Skeletal Muscle Progenitor Cell Number and Muscle Phenotype
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DOI：
10.1371/journal.pone.0027283
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发表时间：
2011-11-04
期刊：
影响因子：
3.7
通讯作者：
Chanoine, Christophe
中科院分区：
文献类型：
--
作者：
Armand, Anne-Sophie;Laziz, Iman;Chanoine, Christophe
凋亡诱导因子（Apoptosis Inducing Factor， AIF）是一种高度保守、普遍存在于线粒体膜间隙的黄蛋白。在体内，AIF对氧化应激诱导的神经元和心肌细胞凋亡具有保护作用。相反，在体外，AIF已被证明在诱导线粒体死亡途径时具有促凋亡作用，一旦AIF易位到细胞核，它就会促进染色质凝聚和大规模的DNA片段化。鉴于aif亚型丑角（Hq）突变小鼠模型表现出严重的肌肉减少症，我们对aif亚型小鼠的骨骼肌进行了更详细的检查。成人缺乏aif的骨骼肌纤维表现出氧化应激和严重的萎缩形式，与肌核的丢失和快到慢的纤维类型转换有关，无论是在“慢”肌肉如比目鱼肌，还是在“快”肌肉如指长伸肌，很可能是由于MEF2活性的增加。这种纤维型开关在注射心脏毒素的Hq小鼠的再生比目鱼肌和EDL肌中保留。此外，Hq小鼠比目鱼肌和EDL肌的肌肉再生严重延迟。新鲜培养的Hq小鼠的肌纤维、比目鱼肌和EDL肌切片显示卫星细胞池减少，用锰-salen自由基清除剂EUK-8预处理aif拟形小鼠可以恢复卫星细胞池。与对照组相比，在Hq原代培养中，卫星细胞的激活时间似乎异常长。然而，AIF缺乏不影响成肌细胞的增殖和分化。因此，AIF保护骨骼肌免受氧化应激诱导的损伤可能是通过保护卫星细胞免受氧化应激和维持骨骼肌干细胞的数量和激活。
Apoptosis Inducing Factor (AIF) is a highly conserved, ubiquitous flavoprotein localized in the mitochondrial intermembrane space. In vivo, AIF provides protection against neuronal and cardiomyocyte apoptosis induced by oxidative stress. Conversely in vitro, AIF has been demonstrated to have a pro-apoptotic role upon induction of the mitochondrial death pathway, once AIF translocates to the nucleus where it facilitates chromatin condensation and large scale DNA fragmentation. Given that the aif hypomorphic harlequin (Hq) mutant mouse model displays severe sarcopenia, we examined skeletal muscle from the aif hypomorphic mice in more detail. Adult AIF-deficient skeletal myofibers display oxidative stress and a severe form of atrophy, associated with a loss of myonuclei and a fast to slow fiber type switch, both in "slow" muscles such as soleus, as well as in "fast" muscles such as extensor digitorum longus, most likely resulting from an increase of MEF2 activity. This fiber type switch was conserved in regenerated soleus and EDL muscles of Hq mice subjected to cardiotoxin injection. In addition, muscle regeneration in soleus and EDL muscles of Hq mice was severely delayed. Freshly cultured myofibers, soleus and EDL muscle sections from Hq mice displayed a decreased satellite cell pool, which could be rescued by pretreating aif hypomorphic mice with the manganese-salen free radical scavenger EUK-8. Satellite cell activation seems to be abnormally long in Hq primary culture compared to controls. However, AIF deficiency did not affect myoblast cell proliferation and differentiation. Thus, AIF protects skeletal muscles against oxidative stress-induced damage probably by protecting satellite cells against oxidative stress and maintaining skeletal muscle stem cell number and activation.