Inhibition ofCERS1in skeletal muscle exacerbates age-related muscle dysfunction

Age-related muscle wasting and dysfunction render the elderly population vulnerable and incapacitated, while underlying mechanisms are poorly understood. Here, we implicate theCERS1enzyme of the de novo sphingolipid synthesis pathway in the pathogenesis of age-related skeletal muscle impairment. In humans,CERS1abundance declines with aging in skeletal muscle cells and, correlates with biological pathways involved in muscle function and myogenesis. Furthermore,CERS1is upregulated during myogenic differentiation. Pharmacological or genetic inhibition ofCERS1in 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 theCERS1orthologuelagr-1inC. eleganssimilarly exacerbates the age-associated decline in muscle function and integrity. We discover genetic variants reducingCERS1expression 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 inCERS1, thereby underlining the importance of the sphingolipid biosynthesis pathway in age-related muscle homeostasis.