Changes in exercise-induced gene expression in 5′-AMP-activated protein kinase γ3-null and γ3 R225Q transgenic mice

5'-AMP-activated protein kinase (AMPK) is important for metabolic sensing. We used AMPK gamma 3 mutant-overexpressing Tg-Prkag3(225Q) and AMPK gamma 3-knockout Prkag3(-/-) mice to determine the role of the AMPK gamma 3 isoform in exercise-induced metabolic and gene regulatory responses in skeletal muscle. Mice were studied after 2 h swimming or 2.5 h recovery. Exercise increased basal and insulin-stimulated glucose transport, with similar responses among genotypes. In Tg-Prkag3(225Q) mice, acetyl-CoA carboxylase (ACC) phosphorylation was increased and triglyceride content was reduced after exercise, suggesting that this mutation promotes greater reliance on lipid oxidation. In contrast, ACC phosphorylation and triglyceride content was similar between wild-type and Prkag3(-/-) mice. Expression of genes involved in lipid and glucose metabolism was altered by genetic modification of AMPK gamma 3. Expression of lipoprotein lipase 1, carnitine palmitoyl transferase 1b, and 3-hydroxyacyl-CoA dehydrogenase was increased in Tg-Prkag3(225Q) mice, with opposing effects in Prkag3(-/-) mice after exercise. GLUT4, hexokinase 11 (HKII), and glycogen synthase mRNA expression was increased in Tg-Prkag3(225Q) mice after exercise. GLUT4 and HKII mRNA expression was increased in wild-type mice and blunted in Prkag3(-/-) mice after recovery. In conclusion, the Prkag3(225Q) mutation, rather than presence of a functional AMPK gamma 3 isoform, directly promotes metabolic and gene regulatory responses along lipid oxidative pathways in skeletal muscle after endurance exercise.