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首页> 外文期刊>Epigenetics & Chromatin >Myoblast expansion defects leads to muscle growth delay and subsequent compensatory adaptation in adult Atrx cKO skeletal muscle
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Myoblast expansion defects leads to muscle growth delay and subsequent compensatory adaptation in adult Atrx cKO skeletal muscle

机译：成肌细胞扩张缺陷导致成年Atrx cKO骨骼肌的肌肉生长延迟和随后的代偿适应

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BackgroundThe growth of muscle tissue and its regeneration frominjury is crucially dependent on a self-renewing populationof muscle progenitor cells called satellite cells. Activatedsatellite cells give rise to a rapidly expandingpopulation of myoblasts that increase muscle mass bydifferentiating into new or adding into pre-existing musclefibers. Patients with mutations in the chromatinremodeling gene ATRX are clinically characterised bysevere cognitive disabilities and muscular hypotonia,thus dramatically compromising their independent locomotoryability.Materials and methodsWe generated a skeletal muscle specific knockout mousemodel by interbreeding Myf5-Cre mice with mice harbouringthe Atrx floxed conditional knockout allele (hereinreferred to as Atrx cKO). Body mass of Atrx cKO andcontrol littermates were measured along with generalmorphometric analysis of select hindlimb muscles at 3-weeks, 5-weeks, and greater than 8-weeks of age. Methodsof analysis included single muscle fiber preparations fromthe extensor digitorum longus (EDL) and soleus musclesas well as RNA expression analysis from the EDL andsoleus muscles. Primary myoblasts were also culturedfrom dissociated muscle tissue from the hindlimbs andanalyzed via immuno-fluorescent microscopy. Neuromuscularacuity and endurance was assessed in Atrx cKO andcontrol littermates by the roto-rod apparatus. Musclestrength was assessed by utilizing a digital grip strengthmeasuring apparatus.ResultsAtrx cKO mice presented with telltale characteristics ofweaker musculature, exemplified by spinal kyphosis andreduced body mass at 3-weeks of age. Satellite cell derivedmyoblasts from Atrx cKO mice were incapable of rapidexpansion in culture but were fully capable of terminallydifferentiating. Atrx cKO myoblasts displayed delayed cellcycle progression through mid-late S-phase and rampantsigns of genomic instability characterised by fragmentednuclei, g-H2AX foci, and telomeric aberrations. Despiteinefficient myoblast proliferative capacity, Atrx cKO animalswere able to re-establish normal body mass by adulthood.Muscular fitness and function in Atrx cKO micewas also age dependent, as younger 3-week old Atrx cKOmice had a reduced capacity to stay on the roto-rod andpoorer gripping strength. However, differences in gripstrength of adult Atrx cKO mice were almost indistinguishablefrom their control littermates. Data regardingpathways mediating the hypertrophic compensatory adaptationin Atrx cKO mice will also be presented.ConclusionsInefficient expansion of activated satellite cells in AtrxcKO mice results in delayed muscle development up to3-weeks of age, when myonuclear accretion reaches itsplateau. Reduced muscle mass at 3-weeks of age also correlatedwith poorer performance in physical tasks thatrequire muscular force, endurance, and coordination.Compensatory mechanisms are triggered after 3-weeks ofage in Atrx cKO mice that allow for the eventual recoveryof body mass and muscle functionality in adults.
机译：背景技术肌肉组织的生长及其从损伤中的再生至关重要地依赖于称为卫星细胞的肌肉祖细胞的自我更新种群。活化的卫星细胞会引起成肌细胞的迅速膨胀，通过分化成新的或添加到先前存在的肌纤维来增加肌肉质量。染色质重塑基因ATRX突变的患者在临床上表现为严重的认知障碍和肌肉张力低下，从而极大地损害了其独立的运动能力。材料和方法我们通过将Myf5-Cre小鼠与具有Atrx斑点条件性基因敲除等位基因的小鼠进行杂交，建立了骨骼肌特异性基因敲除小鼠模型。此处称为Atrx cKO）。在3周，5周和大于8周龄时，对Atrx cKO和对照同窝仔的体重进行了测量，并对选定的后肢肌肉进行了一般形态分析。分析方法包括用长指伸肌（EDL）和比目鱼肌制备单条肌纤维，以及用EDL和比目鱼肌进行RNA表达分析。还从后肢分离的肌肉组织中培养原代成肌细胞，并通过免疫荧光显微镜进行分析。通过旋转棒设备在Atrx cKO和对照同窝动物中评估神经肌肉敏锐度和耐力。结果通过使用数字握力测量仪评估肌肉强度。结果Atrx cKO小鼠表现出较弱的肌肉组织的明显特征，例如在3周龄时脊柱驼背和体重减轻。来自Atrx cKO小鼠的卫星细胞衍生的成肌细胞不能在培养中快速扩增，但是完全能够终末分化。 Atrx cKO成肌细胞在中晚期S期表现出延迟的细胞周期进程，并出现了以核碎裂，g-H2AX灶和端粒畸变为特征的基因组不稳定现象。尽管成肌细胞增殖能力低下，但Atrx cKO动物能够在成年后恢复正常体重.Atrx cKO小鼠的肌肉适应性和功能也与年龄有关，因为3周龄的年轻Atrx cKO小鼠保持在杆上的能力降低。抓地力较差。但是，成年的Atrx cKO小鼠在握力上的差异与对照组相比几乎没有区别。结论还介绍了介导Atrx cKO小鼠肥厚性代偿性适应性途径的数据。结论当肌核积聚到达其平台时，AtrxcKO小鼠中活化的卫星细胞的低效扩增导致肌肉发育延迟到3周龄。 3周龄时肌肉质量下降也与需要肌肉力量，耐力和协调性的体力活动表现不佳有关。AtrxcKO小鼠经3周龄训练后触发了补偿机制，最终使体内体重和肌肉功能恢复。大人。

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