Age-related muscle wasting and dysfunction render the elderly population vulnerable and incapacitated, while underlying mechanisms are poorly understood. Here, we implicate the CERS1 enzyme of the de novo sphingolipid synthesis pathway in the pathogenesis of age-related skeletal muscle impairment. In humans, CERS1 abundance declines with aging in skeletal muscle cells and, correlates with biological pathways involved in muscle function and myogenesis. Furthermore, CERS1 is upregulated during myogenic differentiation. Pharmacological or genetic inhibition of CERS1 in aged mice blunts myogenesis and deteriorates aged skeletal muscle mass and function, which is associated with the occurrence of morphological features typical of inflammation and fibrosis. Ablation of the CERS1 orthologue lagr-1 in Caenorhabditis elegans similarly exacerbates the age-associated decline in muscle function and integrity. We discover genetic variants reducing CERS1 expression in human skeletal muscle and Mendelian randomization analysis in the UK biobank cohort shows that these variants reduce muscle grip strength and overall health. In summary, our findings link age-related impairments in muscle function to a reduction in CERS1, thereby underlining the importance of the sphingolipid biosynthesis pathway in age-related muscle homeostasis.

中文翻译：

---

骨骼肌中 CERS1 的抑制会加剧与年龄相关的肌肉功能障碍

与年龄相关的肌肉萎缩和功能障碍使老年人群变得脆弱和丧失能力，而其潜在机制却知之甚少。在这里，我们将鞘脂从头合成途径的 CERS1 酶与年龄相关骨骼肌损伤的发病机制联系起来。在人类中，CERS1丰度随着骨骼肌细胞的衰老而下降，并且与肌肉功能和肌生成相关的生物途径相关。此外，CERS1在肌原性分化过程中上调。在老年小鼠中对CERS1进行药理学或遗传抑制会削弱肌肉生成并恶化老年骨骼肌质量和功能，这与炎症和纤维化典型形态特征的发生有关。秀丽隐杆线虫中CERS1直系同源物lagr-1的消融同样会加剧与年龄相关的肌肉功能和完整性下降。我们发现基因变异减少了人类骨骼肌中CERS1的表达，英国生物库队列中的孟德尔随机化分析表明这些变异会降低肌肉握力和整体健康状况。总之，我们的研究结果将年龄相关的肌肉功能损伤与CERS1的减少联系起来，从而强调了鞘脂生物合成途径在年龄相关的肌肉稳态中的重要性。