CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function
CLOCK and BMAL1 regulate MyoD and are necessary for maintenance of skeletal muscle phenotype and function
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DOI：
10.1073/pnas.1014523107
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发表时间：
2010-11-02
影响因子：
11.1
通讯作者：
Esser, Karyn A.
中科院分区：
文献类型：
--
作者：
Andrews, Jessica L.;Zhang, Xiping;Esser, Karyn A.
MyoD是肌生成的主要调节因子，在其mRNA和蛋白质水平上表现出昼夜节律，这表明在肌肉表型和功能的日常维持中可能起作用。我们报告说，MyoD是昼夜节律的转录激活因子时钟和BMAL 1，以节奏的方式结合到MyoD启动子的核心增强子的直接目标。Clock（Delta 19）和Bmal 1（-/-）突变小鼠的骨骼肌在标准化最大力方面表现出相似的30%降低。在单纤维水平上观察到类似的力降低。电子显微镜（EM）显示Clock（Delta 19）、Bmal 1（-/-）和MyoD（-/-）小鼠骨骼肌中的肌丝结构被破坏。肌丝组织的改变与肌动蛋白、肌球蛋白、肌联蛋白和几种MyoD靶基因的表达减少有关。EM分析还表明，来自Clock（Delta 19）和Bmal 1（-/-）小鼠的肌肉的线粒体体积减少了40%。这些突变小鼠中剩余的线粒体显示异常形态和呼吸解偶联增加。在MyoD（-/-）小鼠的肌肉中未观察到这种线粒体病理学。我们认为Clock（Delta 19）和Bmal 1（-/-）小鼠中Pgc-1 alpha和Pgc-1 beta的表达改变可能是这种病理学的基础。总之，我们的结果表明，CLOCK或BMAL 1的破坏导致骨骼肌细胞水平的结构和功能改变。MyoD作为时钟控制基因的鉴定提供了一种机制，通过该机制，昼夜节律钟可以产生肌肉特异性昼夜节律转录组，对成人骨骼肌的日常维护起适应性作用。
MyoD, a master regulator of myogenesis, exhibits a circadian rhythm in its mRNA and protein levels, suggesting a possible role in the daily maintenance of muscle phenotype and function. We report that MyoD is a direct target of the circadian transcriptional activators CLOCK and BMAL1, which bind in a rhythmic manner to the core enhancer of the MyoD promoter. Skeletal muscle of Clock(Delta 19) and Bmal1(-/-) mutant mice exhibited similar to 30% reductions in normalized maximal force. A similar reduction in force was observed at the single-fiber level. Electron microscopy (EM) showed that the myofilament architecture was disrupted in skeletal muscle of Clock(Delta 19), Bmal1(-/-), and MyoD(-/-) mice. The alteration in myofilament organization was associated with decreased expression of actin, myosins, titin, and several MyoD target genes. EM analysis also demonstrated that muscle from both Clock(Delta 19) and Bmal1(-/-) mice had a 40% reduction in mitochondrial volume. The remaining mitochondria in these mutant mice displayed aberrant morphology and increased uncoupling of respiration. This mitochondrial pathology was not seen in muscle of MyoD(-/-) mice. We suggest that altered expression of both Pgc-1 alpha and Pgc-1 beta in Clock(Delta 19) and Bmal1(-/-) mice may underlie this pathology. Taken together, our results demonstrate that disruption of CLOCK or BMAL1 leads to structural and functional alterations at the cellular level in skeletal muscle. The identification of MyoD as a clock-controlled gene provides a mechanism by which the circadian clock may generate a muscle-specific circadian transcriptome in an adaptive role for the daily maintenance of adult skeletal muscle.