| Title: | Inhibition of CERS1 in skeletal muscle exacerbates age-related muscle dysfunction |
| Journal: | eLife |
| Published: | 20 Mar 2024 |
| DOI: | https://doi.org/10.7554/elife.90522.3 |
Publication 10086
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Abstract
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. </p>
16 Authors
- Martin Wohlwend
- Pirkka-Pekka Laurila
- Ludger JE Goeminne
- Tanes Lima
- Ioanna Daskalaki
- Xiaoxu Li
- Giacomo von Alvensleben
- Barbara Crisol
- Renata Mangione
- Hector Gallart-Ayala
- Olivier Burri
- Stephen Butler
- Jonathan Morris
- Nigel Turner
- Julijana Ivanisevic
- Johan Auwerx
1 Application
| Application ID | Title |
|---|---|
| 48020 | Exploring Diet/Lifestyle/Health factors as causes and modifiers of genetic determinants of healthspan, ageing and longevity |
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