Normal hypertrophy accompanied by phosphoryation and activation of AMP-activated protein kinase {alpha}1 following overload in LKB1 knockout mice

doi:10.1113/jphysiol.2007.143685

SKELETAL MUSCLE AND EXCERCISE

Normal hypertrophy accompanied by phosphoryation and activation of AMP-activated protein kinase ${alpha}$ 1 following overload in LKB1 knockout mice

Sean L. McGee¹^,2, Kirsty J. Mustard¹, D. Grahame Hardie¹ and Keith Baar¹

¹ Division of Molecular Physiology, University of Dundee, Dundee, UK
² The Department of Physiology, The University of Melbourne, Parkville, Australia

The activation of the AMP-activated protein kinase (AMPK) andinhibition of the mammalian target of rapamycin complex 1 (mTORC1)is hypothesized to underlie the fact that muscle growth followingresistance exercise is decreased by concurrent endurance exercise.To directly test this hypothesis, the capacity for muscle growthwas determined in mice lacking the primary upstream kinase forAMPK in skeletal muscle, LKB1. Following either 1 or 4 weeksof overload, there was no difference in muscle growth betweenthe wild type (wt) and LKB1^–/– mice (1 week: wt,38.8 ± 7.75%; LKB1^–/–, 27.8 ± 12.98%;4 week: wt, 75.8 ± 15.2%; LKB1^–/–, 85.0 ±22.6%). In spite of the fact that the LKB1 had been knockedout in skeletal muscle, the phosphorylation and activity ofthe ${alpha}$ 1 isoform of AMPK were markedly increased in both the wtand the LKB1^–/– mice. To identify the upstream kinase(s)responsible, we studied potential upstream kinases other thanLKB1. The activity of both Ca²⁺–calmodulin-dependent proteinkinase kinase ${alpha}$ (CaMKK ${alpha}$ ) (5.05 ± 0.86-fold) and CaMKKβ(10.1 ± 2.59-fold) increased in the overloaded muscles,and this correlated with their increased expression. Phosphorylationof TAK-1 also increased 10-fold following overload in both thewt and LKB1 mice. Even though the ${alpha}$ 1 isoform of AMPK was activatedby overload, there were no increases in expression of mitochondrialproteins or GLUT4, indicating that the ${alpha}$ 1 isoform is not involvedin these metabolic adaptations. The phosphorylation of TSC2,an upstream regulator of the TORC1 pathway, at the AMPK site(Ser1345) was increased in response to overload, and this wasnot affected by LKB1 deficiency. Taken together, these datasuggest that the ${alpha}$ 1 isoform of AMPK is preferentially activatedin skeletal muscle following overload in the absence of metabolicadaptations, suggesting that this isoform might be importantin the regulation of growth but not metabolism.