Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms

Abstract

The metabolic actions of the antidiabetic agent metformin reportedly occur via the activation of the AMP-activated protein kinase (AMPK) in the heart and other tissues in the presence or absence of changes in cellular energy status. In this study, we tested the hypothesis that metformin has AMPK-independent effects on metabolism in heart muscle. Fatty acid oxidation and glucose utilization (glycolysis and glucose uptake) were measured in isolated working hearts from halothane-anesthetized male Sprague-Dawley rats and in cultured heart-derived H9c2 cells in the absence or in the presence of metformin (2 mM). Fatty acid oxidation and glucose utilization were significantly altered by metformin in hearts and H9c2 cells. AMPK activity was not measurably altered by metformin in either model system, and no impairment of energetic state was observed in the intact hearts. Furthermore, the inhibition of AMPK by 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine (Compound C), a well-recognized pharmacological inhibitor of AMPK, or the overexpression of a dominant-negative form of AMPK failed to prevent the metabolic actions of metformin in H9c2 cells. The exposure of H9c2 cells to inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) or protein kinase C (PKC) partially or completely abrogated metformin-induced alterations in metabolism in these cells, respectively. Thus the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms.

Metformin Inhibits Isoproterenol-induced Cardiac Hypertrophy in Mice

“…However, chronic subcutaneous infusion of 150 mg/kg/24 h metformin did not activate AMPK phosphorylation in heart. In agreement with our study, an AMPK-independent effect of metformin was recently reported, in which the administration of 2 mM metformin did not alter AMPK activity in the heart of Sprague-Dawley rats and H9C2 cells although metformin altered fatty acid oxidation and glucose utilization [40]. Metformin also does not increase AMPK activity in mice liver, while it reduces alcohol-induced hepatic lipid accumulation [41].…”

Diminished Autophagy Limits Cardiac Injury in Mouse Models of Type 1 Diabetes

“…These autophagy-independent effects of AMPK may account for the ability of metformin to protect the diabetic heart. It is also possible that metformin can use AMPK-independent mechanisms to confer cardioprotection in diabetes (55).…”

Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling

“…HER2 suppression, however, can sufficiently be blocked by knockdown of the PP2A and mTOR target p70S6kinase, pointing at a PP2A/mTOR-dependent mechanism underlying metformin function. Also, some of the metabolic effects seen in isolated working rat hearts and cultures of heart-derived cells after metformin treatment clearly seem AMPK independent (32). In accordance with these data, we show here that metformin has an immediate effect on the phosphorylation of the PP2A/mTOR targets p70S6 kinase, S6, and tau, but does not show a significant influence on the phosphorylation of the AMPK target ACC, and only a comparably small effect on AMPK itself in primary cortical neurons at the concentrations used here.…”