Sepsis frequently results in multi-organ dysfunction, including sepsis-associated myocardial injury, which contributes to mortality. This study investigated whether fibroblast growth factor 21 (FGF21) modulates cardiac injury in sepsis and explored underlying mechanisms focused on mitochondrial biogenesis and the AMPK/PGC-1α signaling axis.
The investigators established a mouse model of sepsis-associated myocardial injury using cecal ligation and puncture (CLP). Cardiac-specific overexpression of FGF21 was delivered by an AAV9 vector under the cTnT promoter (AAV9-cTnT) to target the heart. Complementary in vitro experiments used H9C2 cardiomyoblasts treated with lipopolysaccharide (LPS) to model sepsis-like cellular stress.
Serum FGF21 concentrations were reported to increase in CLP mice compared with sham controls. Reported values in the abstract were approximately 300 pg/mL in sham animals versus approximately 420 pg/mL in CLP animals, indicating an endogenous upregulation of FGF21 during the septic insult.
Cardiac-targeted overexpression of FGF21 (AAV9-cTnT OE-FGF21) improved short-term survival in the CLP model. The 5-day survival rate increased from about 20% in untreated CLP animals to about 60% in CLP animals with cardiac FGF21 overexpression, demonstrating a substantial survival benefit associated with myocardial FGF21 augmentation in this experimental setting.
CLP induced myocardial injury with histological damage, increased inflammatory changes, and enhanced cardiomyocyte apoptosis as summarized in the abstract. Overexpression of FGF21 in the heart reduced histological damage and suppressed apoptosis, consistent with a cardioprotective effect during sepsis.
At the molecular level, cardiac overexpression of FGF21 was associated with increases in the phosphorylated AMP-activated protein kinase to total AMPK ratio (p-AMPK/AMPK) and upregulation of PGC-1α, a master regulator of mitochondrial biogenesis. These changes indicate activation of the AMPK/PGC-1α pathway, providing a plausible mechanism by which FGF21 supports mitochondrial function and cellular energy homeostasis in septic myocardium.
In H9C2 cells exposed to LPS, which models sepsis-associated cellular stress, FGF21 overexpression reversed LPS-induced declines in mitochondrial function. The abstract reports that mitochondrial dysfunction induced by LPS was ameliorated by FGF21, supporting the in vivo findings that FGF21 helps restore mitochondrial integrity in sepsis-related cardiac injury.
To probe pathway dependency, the study used pharmacologic AMPK modulators in the cellular model. The AMPK agonist AICAR reproduced protective effects similar to FGF21 overexpression, while the AMPK antagonist Compound C partially reversed FGF21’s protective impact on mitochondrial function. These pharmacologic interventions corroborate that AMPK activation contributes to the cardioprotective mechanism of FGF21.
Summary of findings: Cardiac-targeted overexpression of FGF21 improved survival, reduced histological cardiac damage, suppressed apoptosis, and restored mitochondrial function in a murine CLP model of sepsis. Mechanistically, protection correlated with activation of AMPK and upregulation of PGC-1α, consistent with enhanced mitochondrial biogenesis. In vitro LPS-treated H9C2 experiments and pharmacologic modulation (AICAR and Compound C) supported the role of the AMPK/PGC-1α pathway in mediating FGF21’s effects.
Clinical and translational implications: The data suggest that enhancing cardiac FGF21 signaling or targeting the AMPK/PGC-1α axis to restore mitochondrial biogenesis may represent a therapeutic strategy to mitigate sepsis-associated myocardial injury. However, the abstract reports preclinical results only.
Limitations reported in source: The abstract provides core results but does not report detailed experimental protocols, group sizes, comprehensive statistical analyses, long-term outcomes, or potential off-target effects. These details were not reported in the abstract and would require consultation of the full text for a complete assessment and determination of translational readiness.
In this preclinical study, FGF21 attenuated sepsis-induced myocardial injury through activation of the AMPK/PGC-1α pathway and restoration of mitochondrial function, with supporting evidence from both CLP mice and LPS-treated cardiomyoblasts. Pharmacologic AMPK modulation aligned with FGF21’s effects, indicating AMPK-dependent mitochondrial biogenesis as a central mechanism of cardioprotection in sepsis-associated myocardial injury.