Genetic and metabolic effects on skeletal muscle AMPK in young and older twins.
The protein complex AMP-activated protein kinase (AMPK) is believed to play an important role in the regulation of skeletal muscle glucose and lipid metabolism. Defects in the AMPK system might therefore be an important factor in the pathogenesis of type 2 diabetes. We aimed to identify genetic and environmental mechanisms involved in the regulation of AMPK expression and activity and to examine the association between AMPK protein levels and activity on the one hand, and glucose and fat metabolism on the other. We investigated skeletal muscle biopsies from 100 young and 82 older mono- and dizygotic nondiabetic twins excised during the basal and insulin-stimulated states of a physiological hyperinsulinemic-euglycemic clamp. AMPKalpha1, -alpha2, and -gamma3 mRNA expression was investigated using real-time PCR, and Western blotting was employed to measure protein levels. Multiple regression analyses indicated that skeletal muscle AMPK mRNA and protein expression as well as activity were regulated by sex, age, obesity, and aerobic capacity. Comparison of intraclass correlations on AMPK measurements from mono- and dizygotic twins suggested that skeletal muscle AMPK expression was under minor genetic influence. AMPKgamma3 protein expression and activity were negatively related to whole body glucose uptake through the nonoxidative metabolic pathway and positively related to phosphorylation of glycogen synthase. Our results suggest that skeletal muscle AMPK expression is under minor genetic control but regulated by age and sex and associated with obesity and aerobic capacity. Furthermore, our results indicate a role for gamma3-containing AMPK complexes in downregulation of insulin-stimulated nonoxidative glucose metabolism possibly through inhibition of glycogen synthase activity.
Mortensen
Brynjulf
B
Department of Exercise and Sport Sciences, University of Copenhagen, Denmark. Brym@steno.dk
Poulsen
Pernille
P
Wegner
Lise
L
Stender-Petersen
Kirstine L
KL
Ribel-Madsen
Rasmus
R
Friedrichsen
Martin
M
Birk
Jesper B
JB
Vaag
Allan
A
Wojtaszewski
Jørgen F P
JF
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000375:Aging / Q000378:metabolism*; D015308:Anaerobic Threshold / Q000235:genetics / Q000502:physiology; D003718:Denmark; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology*; D018995:Myosin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D009765:Obesity / Q000378:metabolism; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012042:Registries; D012727:Sex Characteristics; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic
D007527:Isoenzymes; D009124:Muscle Proteins; D012333:RNA, Messenger; D055372:AMP-Activated Protein Kinases; D018995:Myosin Heavy Chains; D005947:Glucose