Cell atlas of the ageing human skeletal muscle - Asian ATAC
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Muscle atrophy and frailty are common manifestations of sarcopenia and are critical contributors to morbidity and mortality in the elderly. Deciphering the underlying molecular mechanisms of sarcopenia has major implications for understanding human ageing, yet progress has been slow, in part due to the complexity of characterizing skeletal muscle niche heterogeneity (with myofibres being more abundant) and the difficulty of accessing well-characterized human samples. Here, we have generated a single-cell/single-nucleus transcriptomic and chromatin accessibility map of human limb skeletal muscles encompassing over 387,000 cells/nuclei from individuals ranging from 15 to 99 years of age with distinct fitness and frailty levels. We describe i) the changes in cell populations during distinct ages, including the emergence of new ones in the elderly, and ii) the cell-specific and multicellular network features (at the transcriptomic and epigenetic levels) that are associated with these changes. Based on cross-comparison with genetic data, we also identify key elements of chromatin architecture marking susceptibility to sarcopenia. Our study provides the basis for the identification of novel targets in the skeletal muscle amenable to medical, pharmacological and lifestyle interventions in late life.
肌肉萎缩与衰弱是肌少症（sarcopenia）的常见临床表现，亦是老年人群发病与死亡的关键诱因。解析肌少症潜在的分子机制，对理解人类衰老进程具有重要意义，但相关研究进展缓慢，部分原因在于骨骼肌微环境（skeletal muscle niche）异质性的表征复杂度较高（其中肌纤维占比最高），且难以获取经过充分表征的人类样本。本研究针对人类肢体骨骼肌构建了单细胞/单细胞核转录组（single-cell/single-nucleus transcriptomic）与染色质可及性（chromatin accessibility）图谱，样本覆盖15至99岁、健康水平与衰弱程度各不相同的个体，总计包含超过387000个细胞/细胞核。本研究阐明了两项核心内容：其一，不同年龄阶段细胞群体的动态变化，包括老年群体中新出现的细胞类群；其二，与上述变化相关的细胞特异性及多细胞网络特征（涵盖转录组与表观遗传层面）。通过与遗传数据的交叉比对，本研究还鉴定出标记肌少症易感风险的染色质架构关键元件。本研究为鉴定晚年阶段可通过医学、药物及生活方式干预的骨骼肌新型靶点提供了重要基础。
