Genomic and Proteomic Profiling Reveals Reduced Mitochondrial Function and Disruption of the Neuromuscular Junction Driving Rat Sarcopenia
Genomic and Proteomic Profiling Reveals Reduced Mitochondrial Function and Disruption of the Neuromuscular Junction Driving Rat Sarcopenia
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DOI：
10.1128/mcb.01036-12
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发表时间：
2013-01-01
影响因子：
5.3
通讯作者：
Glassa, David J.
中科院分区：
文献类型：
--
作者：
Ibebunjo, Chikwendu;Chick, Joel M.;Glassa, David J.
骨骼肌减少症（年龄相关的骨骼肌质量和功能丧失）的分子机制尚不清楚。为了确定与肌肉减少症相关性最好的分子变化，并可能有助于其发病机制，我们确定了6，12，18，21，24和27个月大的大鼠肌肉中的全局基因表达谱。这些大鼠在21个月时开始表现出肌肉减少症。基因表达与肌肉质量或年龄变化的相关性，以及功能注释分析确定了与衰老基因特征不同的肌肉减少症基因特征。具体而言，线粒体能量代谢（例如，三羧酸循环和氧化磷酸化）途径基因下调最多，并且与肌肉减少症最显著相关。此外，与神经肌肉接头通畅性相关的基因/通路（提供了肌肉减少症相关的功能性去神经支配和神经肌肉接头重塑的分子证据）、蛋白质降解和炎症也受到干扰。6、18和27个月时样本的蛋白质组学分析证实了线粒体能量代谢蛋白和神经肌肉接头蛋白的耗竭。总之，这些发现表明，同时刺激有丝分裂软骨形成和减少肌肉蛋白水解和炎症的治疗方法具有治疗肌肉减少症的潜力。
Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months. These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes, and functional annotation analysis identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/path ways associated with neuromuscular junction patency (providing molecular evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation. Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins. Together, these findings suggest that therapeutic approaches that simultaneously stimulate mitochondrogenesis and reduce muscle proteolysis and inflammation have potential for treating sarcopenia.