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Metformin increases the PGC-1 protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo

¹Institute of Health Science, and ²Graduate School of Human Environment Studies, Kyushu University, Kasuga, Fukuoka; ³Department of Human Development, Nakamura Gakuen University, Jonan-ku, Fukuoka; and ⁴Second Division of Internal Medicine, Chikushi Hospital, Fukuoka University, Chikushino, Fukuoka, Japan

Submitted 28 February 2006 ; accepted in final form 7 August 2006

AMP-activated protein kinase (AMPK), which was activated by an antihyperglycemic drug metformin, has been hypothesized to mediate metabolic adaptations. The purposes of the present study were 1) to confirm whether acute metformin administration induced AMPK phosphorylation and 2) to determine whether chronic metformin treatment increased the peroxisome proliferator-activated receptor- coactivator-1 (PGC-1) protein expression, glycolytic and oxidative enzyme activities, and cytochrome c and glucose transporter-4 (GLUT4) protein expressions in the rat soleus and red and white gastrocnemius muscles. The single oral administration of metformin (300 mg/kg body wt) enhanced the AMPK phosphorylation at 5 and/or 6 h after treatment. In the chronic study, rats were fed either normal chow or chow containing 1% metformin for 14 days. Metformin treatment resulted in a mean daily metformin intake of 631 mg·kg body wt^–1·day^–1. Metformin increased the PGC-1 content in all three muscles. Metformin increased the hexokinase activity in the white gastrocnemius, the citrate synthase activity in all three muscles, and the -hydroxyacyl-CoA dehydrogenase activity in the soleus. The cytochrome c protein content in the soleus muscle also increased. The GLUT4 content was unchanged by metformin. These results suggest that metformin enhances the PGC-1 expression and mitochondrial biogenesis possibly at least in part via AMPK phosphorylation in the skeletal muscle. Metformin has thus been proposed to possibly ameliorate insulin resistance, at least partially, by means of such metabolic effects.

biguanide; glucose transporter-4; mitochondrial enzymes; Type 2 diabetes; peroxisome proliferator-activated receptor- coactivator-1

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