COMPREHENSIVE TRANSCRIPTOMIC PROFILING REVEALS IMPAIRED POLYAMINE METABOLISM AS A CONTRIBUTOR TO AGE-RELATED MUSCLE DECLINE

Sarcopenia, the age-related decline in skeletal muscle mass and function, remains poorly understood, particularly at the spatial and fiber type-specific levels. We present a spatial transcriptomic atlas of skeletal muscle from young and aged mice, resolving transcriptional reprogramming across fiber types and tissue compartments. Our analyses reveal alterations in sarcomeric organization, excitation-contraction coupling, oxidative stress responses, and fiber type-specific metabolic rewiring. Conserved molecular signatures across muscles and species highlight Car3 as a potential biomarker of sarcopenia. We also uncover a selective downregulation of polyamine biosynthetic enzymes, leading to reduced spermidine levels in aged muscle. This decline affects muscle-resident populations, as limiting polyamine metabolic flux in both murine and human fibro-adipogenic progenitors (FAPs) induces aging-like features, including myofibroblast differentiation, extracellular matrix dysregulation, and impaired myogenesis. Together, our findings reveal spatially organized, fiber type-specific, and polyamine-linked mechanisms of muscle aging and position the polyamine pathway as a promising therapeutic target.肌肉减少症（Sarcopenia）是一类与年龄相关的骨骼肌质量与功能衰退性疾病，目前其病理机制仍未得到充分阐释，尤其在空间维度及肌纤维类型特异性层面的研究尚存诸多空白。本研究构建了年轻与老年小鼠骨骼肌的空间转录组图谱（spatial transcriptomic atlas），解析了不同肌纤维类型及组织分区中的转录重编程过程。 分析结果显示，老年小鼠骨骼肌的肌节结构、兴奋-收缩耦联、氧化应激应答及肌纤维类型特异性代谢重编程均出现显著异常。跨肌肉组织与物种的保守分子特征筛选表明，Car3可作为肌肉减少症潜在的生物标志物。本研究同时发现，多胺生物合成酶存在选择性下调，进而导致老年骨骼肌内亚精胺（spermidine）水平降低。 该亚精胺水平下降会影响肌肉驻留细胞群的功能：在小鼠与人类成纤维脂肪祖细胞（fibro-adipogenic progenitors, FAPs）中限制多胺代谢通量，均可诱导出衰老相关表型，包括肌成纤维细胞分化、细胞外基质失调及成肌功能障碍。 综上，本研究揭示了肌肉衰老中具有空间组织特异性、肌纤维类型特异性且与多胺通路（polyamine pathway）相关的调控机制，并将多胺通路确立为极具潜力的治疗靶点。