Laurila Pirkka-Pekka, Wohlwend Martin, Imamura de Lima Tanes, Luan Peiling, Herzig Sébastien, Zanou Nadège, Crisol Barbara, Bou-Sleiman Maroun, Porcu Eleonora, Gallart-Ayala Hector, Handzlik Michal K, Wang Qi, Jain Suresh, D'Amico Davide, Salonen Minna, Metallo Christian M, Kutalik Zoltan, Eichmann Thomas O, Place Nicolas, Ivanisevic Julijana, Lahti Jari, Eriksson Johan G, Auwerx Johan
Laboratory of Integrative Systems Physiology, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Institute of Sport Sciences and Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
Nat Aging. 2022 Dec;2(12):1159-1175. doi: 10.1038/s43587-022-00309-6. Epub 2022 Dec 16.
Age-related muscle dysfunction and sarcopenia are major causes of physical incapacitation in older adults and currently lack viable treatment strategies. Here we find that sphingolipids accumulate in mouse skeletal muscle upon aging and that both genetic and pharmacological inhibition of sphingolipid synthesis prevent age-related decline in muscle mass while enhancing strength and exercise capacity. Inhibition of sphingolipid synthesis confers increased myogenic potential and promotes protein synthesis. Within the sphingolipid pathway, we show that accumulation of dihydroceramides is the culprit disturbing myofibrillar homeostasis. The relevance of sphingolipid pathways in human aging is demonstrated in two cohorts, the UK Biobank and Helsinki Birth Cohort Study in which gene expression-reducing variants of SPTLC1 and DEGS1 are associated with improved and reduced fitness of older individuals, respectively. These findings identify sphingolipid synthesis inhibition as an attractive therapeutic strategy for age-related sarcopenia and co-occurring pathologies.
与年龄相关的肌肉功能障碍和肌肉减少症是老年人身体机能丧失的主要原因，目前缺乏可行的治疗策略。我们发现，衰老过程中鞘脂在小鼠骨骼肌中积累，对鞘脂合成的基因抑制和药物抑制均可防止与年龄相关的肌肉质量下降，同时增强力量和运动能力。抑制鞘脂合成可增加成肌潜能并促进蛋白质合成。在鞘脂途径中，我们表明二氢神经酰胺的积累是扰乱肌原纤维稳态的罪魁祸首。在英国生物银行和赫尔辛基出生队列研究这两个队列中证实了鞘脂途径在人类衰老中的相关性，其中SPTLC1和DEGS1基因表达降低的变体分别与老年人更好和更差的身体适应性相关。这些发现表明，抑制鞘脂合成是治疗与年龄相关的肌肉减少症及并发疾病的一种有吸引力的治疗策略。
