Improved resistance to exercise in mice treated with metformin

Poorly-controlled diabetes induces structural changes leading to muscle weakness, muscle hypotrophy and muscle fibers changes. Skeletal muscle differentiation is a process in which proliferative myoblasts break free from the cell cycle and fuse to form multinucleated myotubes. These events are orchestrated by early myogenic regulator factors (MyoD, Myf-5, myogenin and Myf-6) and late myogenic protein MHC (myosin heavy chain), through p38 MAP kinase/ERK pathway modulation. Metformin (Met) is a first-line anti diabetic therapy. Our previous data suggested that Met induces ERK pathway activation and MHC synthesis in vitro muscle model (C2C12). (Nutr. Metab. Cardiovasc Dis. In press). Aim of this work is to confirm in vitro and to study in vivo in the rodent model the action of Met during myogenesis. In particular we studied muscle proteosynthesis and morphologic characteristics in the late phase of muscle differentiation. Cells were incubated after 72h of differentiation, with 400 μM Met for 4, 8 and 24 hours. We used a positive control with 0.1 nM insulin added to medium and a negative control in which Met and insulin were not added. MRFs protein contents, evaluated by Western Blot and Immunofluorescence studies, were higher in cells treated with Met. Furthermore, Met treatment is able to increase cell mass and fusion competence indicating that Met may regulate myogenesis and fibers hypertrophy. To test those results in vivo, we investigated the action of Met on exercise performance in adult C57BL6 mice. Mice were injected intra abdominally with Met (250 mg/kg) and the control mice with 0.9% saline for 30 days. An endurance performance treadmill running test made at the beginning and at the end of this study revealed that Met treated mice exhibit an enhanced performance respect to the control mice (VO2max ml/kg0.75per min: Met 14.41 ± 1.5 respect to control 12.6 ± 2.8). Our findings show a novel therapeutic indication of metformin for muscle hypotrophy in diabetes mellitus and in other chronic wasting diseases.