Paradoxical Effects of Metformin on the Cell Cycle in L6 Myoblasts

Abstract

Metformin, the most commonly prescribed treatment for type II diabetes, is also known as an anti‐cancer agent. While most metabolic actions of metformin appear to act through AMP kinase (AMPK) there is currently a controversy about whether AMPK is involved in the long‐term actions of metformin. Recent reports have shown that cancer stem cells are preferentially inhibited by metformin, and shifted into a stationary growth cell phase. We found that L6 cell myoblasts also showed attenuation of growth during chronic treatment with 1 mM metformin. However, flow cytometry demonstrated that the surviving cells were paradoxically shifted into the S‐phase. These effects were reversed by the simultaneous presence of the AMPK inhibitor Compound C. By contrast, mouse embryonic stem cells exposed to 10 mM metformin for 24 h showed no shift in their cell cycle. These unexpected findings in comparison to the cancer cells may shed light on the mechanisms of normal development, embryonic development, and cancer in response to metformin.