LKB1 was reported in September 2003 to be a component of the AMP-activated protein kinase (AMPKK) activity in extracts of liver and of cells in culture. AMPKK phosphorylates and activates AMPK which then phosphorylates proteins involved in stimulation of fatty acid oxidation, stimulation of glucose uptake, increasing insulin sensitivity and in controlling content of hexokinase, GLUT4, and mitochondria! oxidative enzymes in skeletal muscle. AMPKK and AMPK are activated in muscle in response to muscle contraction. Because of the well-demonstrated effects of AMPK activation on glucose uptake, fatty acid oxidation, GLUT4 expression, and insulin sensitivity, this signaling system has been targeted for development of Pharmaceuticals for prevention and treatment of type 2 diabetes. We have recently developed a muscle specific LKB1 knockout mouse in our laboratory that will enable elucidation of roles and mechanisms of activation and actions of the tumor suppressor protein, LKB1, in skeletal muscle. More specifically, these experiments will verify that LKB1 is a component of the AMPKK complex in skeletal muscle and provide new information regarding its regulation. The specific proteins associating with LKB1 in resting and contracting muscle to produce AMPKK activity will be determined. Using recombinant proteins expressed in mammalian cells we will determine which components of the LKB1 complex (postulated to be LKB1, STRAD, MO25 and HSP90) are essential for AMPKK activity. The mechanisms of activation of LKB1 in muscle will be investigated. Finally, the mechanisms of enhancement of GLUT4 transcription by LKB1 and AMPK in skeletal muscle will be studied. This information will be crucial for design of Pharmaceuticals targeting this pathway for treatment of type 2 diabetes. The proposed studies will provide additional rationale for convincing a predominantly sedentary population of the importance of regular exercise in combating inactivity-related diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Boyce, Amanda T
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Brigham Young University
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Chen, Ting; Moore, Timothy M; Ebbert, Mark T W et al. (2016) Liver kinase B1 inhibits the expression of inflammation-related genes postcontraction in skeletal muscle. J Appl Physiol (1985) 120:876-88
Hardman, Shalene E; Hall, Derrick E; Cabrera, Alyssa J et al. (2014) The effects of age and muscle contraction on AMPK activity and heterotrimer composition. Exp Gerontol 55:120-8
Tanner, Colby B; Madsen, Steven R; Hallowell, David M et al. (2013) Mitochondrial and performance adaptations to exercise training in mice lacking skeletal muscle LKB1. Am J Physiol Endocrinol Metab 305:E1018-29
Brown, J D; Hancock, C R; Mongillo, A D et al. (2011) Effect of LKB1 deficiency on mitochondrial content, fibre type and muscle performance in the mouse diaphragm. Acta Physiol (Oxf) 201:457-66
Smith, Cody D; Compton, Richard A; Bowler, Joshua S et al. (2011) Characterization of the liver kinase B1-mouse protein-25 -Ste-20-related adaptor protein complex in adult mouse skeletal muscle. J Appl Physiol (1985) 111:1622-8
Nakken, G Nathan; Jacobs, Daniel L; Thomson, David M et al. (2010) Effects of excess corticosterone on LKB1 and AMPK signaling in rat skeletal muscle. J Appl Physiol 108:298-305
Thomson, David M; Hancock, Chad R; Evanson, Bradley G et al. (2010) Skeletal muscle dysfunction in muscle-specific LKB1 knockout mice. J Appl Physiol 108:1775-85
Fillmore, Natasha; Jacobs, Daniel L; Mills, David B et al. (2010) Chronic AMP-activated protein kinase activation and a high-fat diet have an additive effect on mitochondria in rat skeletal muscle. J Appl Physiol (1985) 109:511-20
Thomson, D M; Winder, W W (2009) AMP-activated protein kinase control of fat metabolism in skeletal muscle. Acta Physiol (Oxf) 196:147-54
Thomson, D M; Brown, J D; Fillmore, N et al. (2009) AMP-activated protein kinase response to contractions and treatment with the AMPK activator AICAR in young adult and old skeletal muscle. J Physiol 587:2077-86

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