AMP-activated protein kinase (AMPK) is a key sensor of cellular energy. The 
activation of AMPK by metformin prevents cardiac remodeling after myocardial 
infarction (MI). Besides, the innate immune response through TLRs is activated 
during MI. In the present study, the effects of short-term treatment with 
metformin on TLRs activity and its relation with AMPK in isoproterenol-induced 
MI were assessed in rats. To induce MI, a subcutaneous injection of 
isoproterenol was given to Wistar rats for two consecutive days. Metformin (25, 
50, and 100mg/kg) was orally administered to rats twice daily for two days. 
Interstitial fibrosis was dose-dependently attenuated in the treated groups in 
comparison to the MI group (score: 1.25 ± 0.28 with 100 mg/kg metformin versus 
3.5 ± 0.28; P<0.001). Further, metformin reduced TLR-dependent inflammatory 
cytokines as indexed by reduced myocardial levels of TNFα (maximum 68%; P<0.001) 
and IL6 (maximum 84%; P<0.001) as well as by reduced myocardial MPO activity 
(25%; P<0.01). It was found that the level of phosphorylated AMPK was 
significantly upregulated by 165% (P<0.001) when treated with 100 mg/kg of 
metformin, but not with 25 and 50mg/kg. This was associated with a remarkable 
suppression of TLR4 expression and reduction of protein level of TLRs adapter 
protein, MyD88 (P<0.01) in the infarcted myocardium. These results suggest that 
AMPK activation by metformin and the subsequent suppression of TLRs activity 
could be considered as a target in protecting the infarcted heart, which may 
indicate a link between AMPK and TLRs.