Role of AMP-activated protein kinase in exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle -insight from analysis of a transgenic mouse model-.
To examine the role of muscle AMP-activated protein kinase (AMPK) in maximal exercise capacity, whole body glucose homeostasis, and glucose transport in skeletal muscle, we generated muscle-specific transgenic mice carrying cDNAs of inactive AMPK alpha2 (alpha2i TG). Fed blood glucose was slightly higher in alpha2i TG mice compared to wild type littermates, however, the difference was not statistically significant. In alpha2i TG mice, glucose tolerance was slightly impaired in male, but not in female mice, compared to wild type littermates. Maximal exercise capacity was dramatically reduced in alpha2i TG mice, suggesting that AMPK alpha2 has a critical role in skeletal muscle during exercise. We confirmed that known insulin-independent stimuli of glucose transport including mitochondrial respiration inhibition, hyperosmolarity, and muscle contraction increased both AMPK alpha1 and alpha2 activities in isolated EDL muscle in wild type mice. While, alpha2 activation was severely blunted and alpha1 activation was only slightly reduced in alpha2i TG mice by these insulin independent stimuli compared to wild type mice. Mitochondrial respiration inhibition-induced glucose transport was fully inhibited in isolated EDL muscles in alpha2i TG mice. However, contraction- or hyperosmolarity-induced glucose transport was nearly normal. These results suggest that AMPK alpha2 activation is essential for some, but not all insulin-independent glucose transport.
Fujii
Nobuharu
N
Research Division, Joslin Diabetes Center, and the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, One Joslin Place, Boston, MA 02215, USA. nobuharu.fujii@joslin.harvard.edu
Seifert
Matthew M
MM
Kane
Erin M
EM
Peter
Lauren E
LE
Ho
Richard C
RC
Winstead
Schuyler
S
Hirshman
Michael F
MF
Goodyear
Laurie J
LJ
D000091162:AMP-Activated Protein Kinase Kinases; D019943:Amino Acid Substitution; D000818:Animals; D001692:Biological Transport; D005260:Female; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000502:physiology; D010805:Physical Conditioning, Animal; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D013012:Sorbitol / Q000494:pharmacology
D007328:Insulin; D012402:Rotenone; D013012:Sorbitol; D006003:Glycogen; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D005947:Glucose