TY - JOUR

T1 - Genetic and metabolic effects on skeletal muscle AMPK in young and older twins

AU - Mortensen, Brynjulf

AU - Poulsen, Pernille

AU - Wegner, Lise

AU - Stender-Petersen, Kirstine Lynge

AU - Ribel-Madsen, Rasmus

AU - Friedrichsen, Martin

AU - Birk, Jesper Bratz

AU - Vaag, Allan

AU - Wojtaszewski, Jørgen

N1 - CURIS 2009 5200 105

PY - 2009

Y1 - 2009

N2 - 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 one hand, and glucose and fat metabolism on the other hand. We investigated skeletal muscle biopsies from 100 young and 82 older mono- and dizygotic non-diabetic twins excised during the basal and insulin-stimulated states of a physiological hyperinsulinemic-euglycemic clamp. AMPK subunit alpha1, 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 measures from mono- and dizygotic twins suggested that skeletal muscle AMPK expression was under minor genetic influence. AMPK gamma3 protein expression and activity were negatively related to whole-body glucose uptake through the non-oxidative metabolic pathway, and positively related to phosphorylation of glycogen synthase. In conclusion, 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 down-regulation of insulin-stimulated non-oxidative glucose metabolism possibly through inhibition of glycogen synthase activity. Key words: AMP-activated protein kinase, heritability, glucose metabolism.

AB - 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 one hand, and glucose and fat metabolism on the other hand. We investigated skeletal muscle biopsies from 100 young and 82 older mono- and dizygotic non-diabetic twins excised during the basal and insulin-stimulated states of a physiological hyperinsulinemic-euglycemic clamp. AMPK subunit alpha1, 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 measures from mono- and dizygotic twins suggested that skeletal muscle AMPK expression was under minor genetic influence. AMPK gamma3 protein expression and activity were negatively related to whole-body glucose uptake through the non-oxidative metabolic pathway, and positively related to phosphorylation of glycogen synthase. In conclusion, 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 down-regulation of insulin-stimulated non-oxidative glucose metabolism possibly through inhibition of glycogen synthase activity. Key words: AMP-activated protein kinase, heritability, glucose metabolism.

U2 - 10.1152/ajpendo.00058.2009

DO - 10.1152/ajpendo.00058.2009

M3 - Journal article

C2 - 19671840

VL - 297

SP - E956-E964

JO - American Journal of Physiology - Endocrinology and Metabolism

JF - American Journal of Physiology - Endocrinology and Metabolism

SN - 0193-1849

IS - 4

ER -