Thomson DM, Porter BB, Tall JH, Kim H-J, Barrow JR, Winder WW. Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice. Am J Physiol Endocrinol Metab 292: E196 -E202, 2007. First published August 22, 2006; doi:10.1152/ajpendo.00366.2006.-LKB1 has been identified as a component of the major upstream kinase of AMP-activated protein kinase (AMPK) in skeletal muscle. To investigate the roles of LKB1 in skeletal muscle, we used muscle-specific LKB1 knockout (MLKB1KO) mice that exhibit low expression of LKB1 in heart and skeletal muscle, but not in other tissues. The importance of LKB1 in muscle physiology was demonstrated by the observation that electrical stimulation of the muscle in situ increased AMPK phosphorylation and activity in the wild-type (WT) but not in the muscle-specific LKB1KO mice. Likewise, phosphorylation of acetyl-CoA carboxylase (ACC) was markedly attenuated in the KO mice. The LKB1KO mice had difficulty running on the treadmill and exhibited marked reduction in distance run in voluntary running wheels over a 3-wk period (5.9 Ϯ 0.9 km/day for WT vs. 1.7 Ϯ 0.7 km/day for MLKB1KO mice). The MLKB1KO mice anesthetized at rest exhibited significantly decreased phospho-AMPK and phospho-ACC compared with WT mice. KO mice exhibited lower levels of mitochondrial protein expression in the red and white regions of the quadriceps. These observations, along with previous observations from other laboratories, clearly demonstrate that LKB1 is the major upstream kinase in skeletal muscle and that it is essential for maintaining mitochondrial marker proteins in skeletal muscle. These data provide evidence for a critical role of LKB1 in muscle physiology, one of which is maintaining basal levels of mitochondrial oxidative enzymes. Capacity for voluntary running is compromised with muscle and heart LKB1 deficiency. adenosine 3Ј-cyclic monophosphate-activated protein kinase; muscle specific LKB1 knockout mouse; muscle mitochondria; citrate synthase AMP-ACTIVATED PROTEIN KINASE (AMPK) is a major regulator of skeletal muscle energy metabolism (3,5,27,29). It is activated in response to exercise and muscle contraction and other conditions of metabolic stress when AMP concentration increases (12,19,26,30). When active, AMPK works to restore cellular energy balance by promoting ATP-generating processes such as fatty acid oxidation and glucose uptake, while inhibiting anabolic processes, such as protein synthesis, that consume ATP (3-5, 14, 27-29). In addition to its role in maintaining energy homeostasis during exercise, AMPK is also thought to play an important role in many adaptations to chronic exercise such as elevations in protein levels of GLUT4, hexokinase II, and mitochondrial proteins (2,7,9,25,31,34). AMPK is a heterotrimer composed of a catalytic ␣-subunit and regulatory ␤-and ␥-subunits. Binding of AMP to the ␥-subunit of AMPK promotes phosphorylation at Thr 172 on its ␣-subunit, which is requisite for its activity. Several...