The activation of the AMP-activated protein kinase (AMPK) and inhibition of the mammalian target of rapamycin complex 1 (mTORC1) is hypothesized to underlie the fact that muscle growth following resistance exercise is decreased by concurrent endurance exercise. To directly test this hypothesis, the capacity for muscle growth was determined in mice lacking the primary upstream kinase for AMPK in skeletal muscle, LKB1. Following either 1 or 4 weeks of overload, there was no difference in muscle growth between the 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 knocked out in skeletal muscle, the phosphorylation and activity of the alpha 1 isoform of AMPK were markedly increased in both the wt and the LKB1(-/-) mice. To identify the upstream kinase(s) responsible, we studied potential upstream kinases other than LKB1. The activity of both Ca2+-calmodulin-dependent protein kinase kinase alpha (CaMKK alpha) (5.05 +/- 0.86-fold) and CaMKK beta (10.1 +/- 2.59-fold) increased in the overloaded muscles, and this correlated with their increased expression. Phosphorylation of TAK-1 also increased 10-fold following overload in both the wt and LKB1 mice. Even though the alpha 1 isoform of AMPK was activated by overload, there were no increases in expression of mitochondrial proteins or GLUT4, indicating that the alpha 1 isoform is not involved in 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 was not affected by LKB1 deficiency. Taken together, these data suggest that the alpha 1 isoform of AMPK is preferentially activated in skeletal muscle following overload in the absence of metabolic adaptations, suggesting that this isoform might be important in the regulation of growth but not metabolism.
- 5'-AMP-ACTIVATED PROTEIN-KINASE
- HUMAN SKELETAL-MUSCLE
- UPSTREAM KINASE