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1 Physiology and Developmental Biology, Brigham Young University, Provo, Utah, United States
2 Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah, United States
* To whom correspondence should be addressed. E-mail: william_winder{at}byu.edu.
LKB1 has been identified as a component of the major upstream kinase of AMP-activated protein kinase in skeletal muscle. To investigate the roles of LKB1 in skeletal muscle we utilized muscle specific LKB1 knockout (MLKB1KO) mice which 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 LKB1 knockout mice. Likewise, phosphorylation of acetyl-CoA carboxylase was markedly attenuated in the knockout mice. The LKB1 knockout mice had difficulty running on the treadmill and exhibited marked reduction in distance run in voluntary running wheels over a three week period (5.9 ± 0.9 Km/d for WT vs 1.7 ± 0.7 Km/d for MLKB1KO mice). The MLKB1KO mice anesthetized at rest exhibited significantly decreased phospho-AMPK and phospho-ACC compared to WT mice. Knockout 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.
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