Abstract
Tumour suppressor p53 is known to be associated with the maintenance of mitochondrial functional properties in the skeletal muscles. As deactivation or mutation of p53 can affect the synthesis of lipids, investigating the relationship between p53-related energy generation metabolism and perturbation of lipid profile is critical. In this study, 329 lipid species (among 412 identified species) in two different skeletal muscle tissues (the gastrocnemius and soleus) from p53 knockout (KO) mice were quantitatively analysed using nanoflow ultrahigh performance liquid chromatography tandem mass spectrometry (nUPLC-MS/MS). Overall, lipids from the soleus tissues were more affected by p53 KO than those from the gastrocnemius in most lipid profiles. In p53 KO, lysophosphatidylcholine (LPC), lysophosphatidylserine (LPS), phosphatidic acid (PA), sphingomyelin (SM), and triacylglycerol (TAG), including 6 TAG (44:2, 46:0, 58:5, 58:8, 58:9, and 50:0), were significantly increased (p < 0.05) by 1.4–2-fold only in the soleus tissue. Overall monohexosylceramide (MHC) levels, including those of 3 MHC species (d18:0/24:0, d18:1/22:0, and d18:1/24:0), were significantly increased (p < 0.05) by 2–4 fold, only in the gastrocnemius tissue. The results suggest that lipid profiles are significantly altered by the lack of p53 in muscle tissues.
Highlights
The p53 tumour suppressor protein orchestrates cellular transcription programs in response to diverse stress signals, including DNA damage and oxidative stress, that lead to cell cycle arrest, apoptosis, and senescence[1, 2]
Because p53 serves as an important mediator for mitochondrial functional properties[15, 16] and a critical mitochondrial enzyme such as cytochrome c oxidase present a 20-fold higher expression in the Sol than in the Gas[27], lipid profiles in mitochondria-rich Sol tissue can be more influenced by p53 KO than those in the Gas, which consists of mixed fibres that rely both on mitochondrial respiration and glycolysis to generate energy[28]
As the change in the Sol was more significant than that in Gas, it can be deduced that change in lipids of the Sol is associated with the alteration of mitochondrial function in the skeletal muscle tissue, as Sol is mitochondria-rich while Gas is not
Summary
The p53 tumour suppressor protein orchestrates cellular transcription programs in response to diverse stress signals, including DNA damage and oxidative stress, that lead to cell cycle arrest, apoptosis, and senescence[1, 2]. We quantify lipids from two skeletal muscle tissues of p53 KO mice using nUPLC-ESI-MS/MS to detect changes in aerobic metabolism by lipidomic perturbations in a p53-null setting: the gastrocnemius (Gas), which is involved in running by obtaining energy from both mitochondrial respiration and glycolysis, and the soleus (Sol), which is recruited in standing still by the supply of energy mainly from mitochondrial respiration For this purpose, a non-targeted analysis of lipids, including phospholipids (PLs), glycerolipids (GLs), and sphingolipids (SLs), was performed on pooled tissue sample from wild type (WT) and p53 KO mice by nUPLC-ESI-MS/MS using an ion trap MS. Alterations in anaerobic metabolism through the change in lipid profiles of the two skeletal muscle tissues of mice lacking p53 were statistically assessed in comparison to those of WT mice
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