Sirtuin 1 activator alleviated lethal inflammatory injury via promotion of autophagic degradation of pyruvate kinase M2

by Selleckchem | Jun 29 2023

Upregulation of pyruvate kinase M2 (PKM2) is critical for the orchestration of metabolism and inflammation in critical illness, while autophagic degradation is a recently revealed mechanism that counter-regulates PKM2. Accumulating evidence suggests that sirtuin 1 (SIRT1) function as a crucial regulator in autophagy. The present study investigated whether SIRT1 activator would downregulate PKM2 in lethal endotoxemia via promotion of its autophagic degradation. The results indicated that lethal dose of lipopolysaccharide (LPS) exposure decreased the level of SIRT1. Treatment with SRT2104, a SIRT1 activator, reversed LPS-induced downregulation of LC3B-II and upregulation of p62, which was associated with reduced level of PKM2. Activation of autophagy by rapamycin also resulted in reduction of PKM2. The decline of PKM2 in SRT2104-treated mice was accompanied with compromised inflammatory response, alleviated lung injury, suppressed elevation of blood urea nitrogen (BUN) and brain natriuretic peptide (BNP), and improved survival of the experimental animals. In addition, co-administration of 3-methyladenine, an autophagy inhibitor, or Bafilomycin A1, a lysosome inhibitor, abolished the suppressive effects of SRT2104 on PKM2 abundance, inflammatory response and multiple organ injury. Therefore, promotion of autophagic degradation of PKM2 might be a novel mechanism underlying the anti-inflammatory benefits of SIRT1 activator.

Comments:

The study you mentioned investigated the effects of a SIRT1 activator, SRT2104, on the regulation of pyruvate kinase M2 (PKM2) in lethal endotoxemia, a condition characterized by severe inflammation. The researchers aimed to determine whether SRT2104 could downregulate PKM2 through the promotion of autophagic degradation, and whether this downregulation would have beneficial effects on inflammation and organ injury.

The results of the study showed that exposure to a lethal dose of lipopolysaccharide (LPS), an endotoxin that triggers an inflammatory response, decreased the level of SIRT1. However, treatment with SRT2104 reversed this LPS-induced downregulation of SIRT1. Activation of SIRT1 by SRT2104 led to an increase in the levels of LC3B-II, a marker of autophagy, and a decrease in the levels of p62, a protein associated with autophagic degradation.

Furthermore, the downregulation of PKM2 was observed in SRT2104-treated mice, as well as in mice treated with rapamycin, a drug known to activate autophagy. The decrease in PKM2 abundance in SRT2104-treated mice was accompanied by a reduction in inflammatory response, alleviation of lung injury, decreased levels of blood urea nitrogen (BUN) and brain natriuretic peptide (BNP), and improved survival of the experimental animals.

To further investigate the role of autophagy in the effects of SRT2104, the researchers co-administered 3-methyladenine (an autophagy inhibitor) or Bafilomycin A1 (a lysosome inhibitor) along with SRT2104. They found that the suppressive effects of SRT2104 on PKM2 abundance, inflammatory response, and organ injury were abolished in the presence of these inhibitors. This suggests that autophagic degradation of PKM2 is a crucial mechanism underlying the anti-inflammatory benefits of SIRT1 activation.

In conclusion, this study provides evidence that SIRT1 activation by SRT2104 promotes autophagic degradation of PKM2, resulting in reduced inflammation, improved organ function, and increased survival in lethal endotoxemia. These findings suggest that targeting the autophagic degradation of PKM2 through SIRT1 activation may have therapeutic potential for treating critical illnesses associated with excessive inflammation.