Laboratory of Integrative Systems Physiology, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Metabolomics Platform, Faculty of Biology and Medicine, University of Lausanne (UNIL), Lausanne, Switzerland.
Elife. 2024 Mar 20;12:RP90522. doi: 10.7554/eLife.90522.
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, abundance declines with aging in skeletal muscle cells and, correlates with biological pathways involved in muscle function and myogenesis. Furthermore, is upregulated during myogenic differentiation. Pharmacological or genetic inhibition of 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 orthologue in similarly exacerbates the age-associated decline in muscle function and integrity. We discover genetic variants reducing 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 , thereby underlining the importance of the sphingolipid biosynthesis pathway in age-related muscle homeostasis.
年龄相关性肌肉减少和功能障碍使老年人群易受伤害和丧失能力，而其潜在机制尚不清楚。在这里，我们将从头合成鞘脂代谢途径中的 CERS1 酶牵连到与年龄相关的骨骼肌损伤的发病机制中。在人类中，CERS1 丰度随年龄的增长在骨骼肌细胞中下降，并与涉及肌肉功能和肌发生的生物学途径相关。此外，CERS1 在成肌分化过程中上调。在老年小鼠中，用药物抑制 CERS1 或基因敲除会使成肌作用减弱，并使衰老的骨骼肌质量和功能恶化，这与炎症和纤维化的典型形态特征的发生有关。CERS1 的同源物 在 中的缺失同样会加剧与年龄相关的肌肉功能和完整性下降。我们发现了降低人类骨骼肌中 CERS1 表达的遗传变异，英国生物库队列的孟德尔随机分析表明，这些变异会降低肌肉握力和整体健康水平。总之，我们的研究结果将肌肉功能的年龄相关性损伤与 CERS1 的减少联系起来，从而强调了鞘脂生物合成途径在与年龄相关的肌肉动态平衡中的重要性。
