The Metabolomic Pathways of the Senescence‐Associated Secretory Phenotype in C2C12 Myoblasts
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abstract
Cellular senescence is considered a hallmark of aging that often occurs in tissues and cells in response to DNA damage. Most healthy cells become senescent after a fixed number of divisions or irreparable genomic damage, often because of external conditions such as circulating factors that are released by adjacent senescent cells. These secreted factors, known as the senescence‐associated secretory phenotype (SASP), are capable of in vivo reprogramming of otherwise healthy cells, ultimately inducing senescence. The involvement of cellular senescence in a variety of aging‐related diseases has been thoroughly examined, however the role of cellular senescence and the SASP in aging muscle remains understudied. Therefore, the objective of this study was to examine the role of metabolites as potential components of the SASP through an easily reproducible model of senescence in skeletal muscle myoblasts. C2C12 myoblasts were treated with an antitumour antibiotic, bleomycin, to cause DNA damage‐induced senescence, or with a vehicle control. Cells and associated media were collected 24 hours after treatment for metabolomic profiling using capillary‐electrophoresis – mass spectrometry (CE‐MS). Samples were compared to untreated myoblasts or fresh growth media and normalized to total cell count and protein content prior to analysis. Pathway analysis using the KEGG database revealed a substantial impact on amino acid metabolism within senescent cells, specifically phenylalanine and histidine metabolism. The media associated with senescent cells had a similar impact on amino acid metabolism, but also showed a significant impact on several polyunsaturated fatty acids, including arachidonic acid and docosahexaenoic acid. Notably, trimethylamine N‐oxide (TMAO), a metabolite previously shown to promote endothelial senescence/dysfunction and neuroinflammation, was detected at significantly higher levels in the media surrounding senescent myoblasts relative to vehicle‐treated controls (fold change = 2.878, p < 0.05). These data suggest that DNA damage‐induced senescence significantly impacts the metabolome of skeletal muscle cells. Future work will aim to evaluate the targeted impact of candidate metabolites as potential senescence inducers.
