Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia

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/pathways 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.肌少症（sarcopenia）是与年龄相关的骨骼肌质量与功能丧失，其潜在分子机制仍未明确。为筛选与肌少症关联最为紧密、且可能参与其发病过程的分子变化，我们对6、12、18、21、24及27月龄大鼠的肌肉组织开展了全基因表达谱分析。该大鼠模型在21月龄时开始出现肌少症表型。通过分析基因表达与肌肉质量或年龄变化的相关性，并结合功能注释分析，我们成功区分出了肌少症特有的基因特征与单纯衰老相关的基因特征。具体而言，线粒体能量代谢（如三羧酸循环与氧化磷酸化）通路基因是下调幅度最大、且与肌少症关联最为显著的基因集。此外，与神经肌肉接头完整性相关的基因/通路（为肌少症相关的功能性去神经支配及神经肌肉接头重塑提供了分子证据）、蛋白质降解通路及炎症相关通路均出现异常调控。对6、18、27月龄样本的蛋白质组学分析，进一步验证了线粒体能量代谢相关蛋白及神经肌肉接头相关蛋白的耗竭现象。综上，本研究结果提示，同时激活线粒体生物发生、抑制肌肉蛋白降解并减轻炎症的治疗策略，有望用于肌少症的临床干预。