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5'-AMP-activated protein kinase (AMPK) is important for metabolic sensing. We used AMPKγ3 mutant-overexpressing Tg-Prkag3^sup 225Q^ and AMPKγ3-knockout Prkag3^sup -/-^ mice to determine the role of the AMPKγ3 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^sup 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^sup -/-^ mice. Expression of genes involved in lipid and glucose metabolism was altered by genetic modification of AMPKγ3. Expression of lipoprotein lipase 1, carnitine palmitoyl transferase 1b, and 3-hydroxyacyl-CoA dehydrogenase was increased in Tg-Prkag3^sup 225Q^ mice, with opposing effects in Prkag3^sup -/-^ mice after exercise. GLUT4, hexokinase II (HKII), and glycogen synthase mRNA expression was increased in Tg-Prkag3^sup 225Q^ mice after exercise. GLUT4 and HKII mRNA expression was increased in wild-type mice and blunted in Prkag3^sup -/-^ mice after recovery. In conclusion, the Prkag3^sup 225Q^ mutation, rather than presence of a functional AMPKγ3 isoform, directly promotes metabolic and gene regulatory responses along lipid oxidative pathways in skeletal muscle after endurance exercise. Diabetes 54: 3484-3489, 2005
ACC, acetyl-CoA carboxylase; AMPK, 5'-AMP-activated protein kinase; CPT1b, carnitine palmitoyl transferase 1b; EDL, extensor digitorum longus; HAD, 3-hydroxyacyl-CoA dehydrogenase; HKII, hexokinase II; IMTG, intramuscular triglyceride; KHBB, Krebs-Henseleit bicarbonate buffer; LPL1, lipoprotein lipase 1.
5'-AMP-activated protein kinase (AMPK) is a cellular energy sensor that responds to alterations in the AMP-to-ATP ratio. Activation of AMPK in response to metabolic stress initiates several signaling cascades aimed at restoring energy balance, including stimulation of catabolic (ATP-generating) pathways, such as fatty acid oxidation (1), glucose uptake (2,3) and glycolysis, as well as inhibition of anabolic (ATP consuming) pathways, such as synthesis of fatty acids (4) and protein (5). Several physiological consequences of exercise, including muscle contraction, hypoxia, ischemia, heat shock, glycogen catabolism, and decreased pH, are associated with AMPK activation (6). However, multiple signal transduction cascades, including mitogen-activated protein kinases (7,8), calcineurin (9), hypoxia-inducible factor-1α (10), and calmodulin-dependent protein kinase (11) are engaged in response to exercise, thus the role of AMPK in...