FGF21 attenuates sepsis-induced myocardial injury via AMPK-mediated mitochondrial biogenesis.
FGF21 may protect against sepsis-induced myocardial injury by enhancing mitochondrial function, but human studies are needed to confirm these findings.
Where it sits
this study against the rest of the aicar (acadesine) corpusSummary and findings
The study investigated the role of FGF21 in sepsis-induced myocardial injury using a mouse model. Cardiac-specific overexpression of FGF21 improved survival rates and reduced myocardial damage. The effects were mediated through the AMPK/PGC-1α pathway, with AICAR mimicking these protective effects.
Abstract
Sepsis is a life-threatening infection that often leads to myocardial injury. Here we explored the role of fibroblast growth factor 21 (FGF21) in sepsis-induced myocardial injury and its underlying mechanism. A mouse model of sepsis-associated myocardial injury was established by cecal ligation and puncture (CLP). Serum FGF21 levels were upregulated in CLP mice (sham: ∼300 pg/mL; CLP: ∼420 pg/mL). CLP led to myocardial injury, inflammation, and apoptosis. Cardiac-specific overexpression of FGF21 via AAV9-cTnT improved 5-day survival rate from ∼20% (CLP) to ∼60% (CLP + OE-FGF21), reduced histological damage, suppressed apoptosis, and upregulated p-AMPK/AMPK and PGC-1α. In LPS-treated H9C2 cells, FGF21 overexpression reversed the LPS-induced decline in mitochondrial function. The AMPK agonist AICAR mimicked, while the AMPK antagonist Compound C partially reversed, the protective effects of FGF21. In conclusion, FGF21 overexpression alleviates sepsis-associated myocardial injury by restoring mitochondrial function via AMPK/PGC-1α pathway.
Background
Sepsis is a severe condition that can lead to myocardial injury, significantly impacting patient outcomes. Previous research has suggested that mitochondrial dysfunction plays a role in this process. This study explores the potential of FGF21 to mitigate myocardial injury in sepsis by promoting mitochondrial biogenesis through the AMPK/PGC-1α pathway.
Methods
The study used a mouse model of sepsis-induced myocardial injury created by cecal ligation and puncture (CLP). Cardiac-specific overexpression of FGF21 was achieved using AAV9-cTnT. The primary outcomes measured included survival rate, histological damage, apoptosis, and expression of p-AMPK/AMPK and PGC-1α. Additionally, LPS-treated H9C2 cells were used to assess mitochondrial function.
Results
FGF21 overexpression increased the 5-day survival rate from ∼20% in CLP mice to ∼60% in CLP + OE-FGF21 mice. It also reduced myocardial histological damage and apoptosis. The study found increased levels of p-AMPK/AMPK and PGC-1α, indicating enhanced mitochondrial biogenesis. AICAR, an AMPK agonist, mimicked the protective effects of FGF21, while Compound C, an AMPK antagonist, partially reversed them.
Interpretation
The findings suggest that FGF21 has a protective role in sepsis-induced myocardial injury, likely through the AMPK/PGC-1α pathway. While the results are promising, they are based on a mouse model, which may not fully translate to human physiology. The study adds to the growing body of literature on the role of mitochondrial biogenesis in cardiac protection but requires further validation in human studies.
Key findings
- Serum FGF21 levels increased from ∼300 pg/mL in sham to ∼420 pg/mL in CLP mice.
- 5-day survival rate improved from ∼20% in CLP to ∼60% in CLP + OE-FGF21.
- FGF21 overexpression reduced histological damage and apoptosis.
- FGF21 upregulated p-AMPK/AMPK and PGC-1α.
- AICAR mimicked the protective effects of FGF21.
Limitations
- mouse model, not human
- single pathway focus
- short-term 5-day survival endpoint
- potential species-specific effects