Metformin Action Prevents Sedentariness-induced Damages in Mice

Metformin (Metf), a widely prescribed drug to treat type 2 diabetes, is being increasingly considered for treatment and prevention of sedentariness damages, insulin resistance and obesity, as well as for the extension of healthy lifespan. Recent data demonstrate that long-term treatment with Metf in middle-aged male mice extends healthy lifespan in male mice. In order to determine if Metf action was limited to middle age condition, our group studied Metf effects on sedentary adult young mice. To achieve this aim, C57BL/6 mice male at 12 weeks of age was treated with Metf (250 mg/kg per day, in drinking water) for 3 months. Control mice group drank water only. A muscular performance, evaluated by a submaximal running test prior and upon completion of the study, revealed that Metf treated mice exhibit an enhanced performance respect to the control mice. To assess how Metf enhanced physical performance and healthy lifespan of the sedentary animals, we analyzed the principal target tissues of insulin resistance: skeletal muscle, liver and visceral adipose tissues. Western Blot results revealed that Metf activated AMPK in these tissues, suggesting how this drug could prevent dysregulation of glucose and lipid metabolism. In liver, Metf decreased the levels of the principal kinases involved in hepatic stress conditions, ERKs. In skeletal muscle, Metf increased the activation of AKT, a central kinase involved not only in insulin signaling but also in cellular mechanisms of skeletal muscle function maintenance. Moreover, we would clarified this Metf molecular role on skeletal muscle using an immortalized model of satellite cells, C2C12 cells line. Immunofluorescence and Western Blot analysis revealed that Metf did not modify the C2C12 proliferation capacity, while positively influenced the differentiation process and the myotube maturation. Together, our novel results suggest that Metf may have a positive action not only on the promotion of healthy aging but also on the prevention of sedentariness damages.