Metformin increases the PGC-1alpha protein and oxidative enzyme activities possibly via AMPK phosphorylation in skeletal muscle in vivo.
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-gamma coactivator-1alpha (PGC-1alpha) 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-1alpha content in all three muscles. Metformin increased the hexokinase activity in the white gastrocnemius, the citrate synthase activity in all three muscles, and the beta-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-1alpha 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.
Suwa
Masataka
M
Institute of Health Science, Kyushu University, Kasuga, Fukuoka 816-8580, Japan. suwa-m@students.ihs.kyushu-u.ac.jp
Egashira
Toru
T
Nakano
Hiroshi
H
Sasaki
Haruka
H
Kumagai
Shuzo
S
D055372:AMP-Activated Protein Kinases; D000284:Administration, Oral; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008687:Metformin / Q000008:administration & dosage*; D009097:Multienzyme Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000378:metabolism*
D051275:Glucose Transporter Type 4; D009097:Multienzyme Complexes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; C495694:Slc2a4 protein, rat; D014157:Transcription Factors; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases