Maintenance of tissue adenine nucleotide (And=ATP+ADP+AMP) concentration is essential to support a broad range of cellular process. This is essentially true in skeletal muscle where ATP-dependent reactions can abruptly increase many fold during contractions. Processes that directly impact And metabolism involve the rate of energy expenditure (e.g., exercise intensity) and the activity of AMP deaminase (AMPD1), a tightly regulated enzyme. We have recently shown that a novel AMP- activated protein kinase (AMPK) phosphorylates purified AMPD1 in vitro; this induces a kinetic activation of AMPD1 that would be most significant at low physiological [AMP/f). This proposal evaluates the control of AMPD1 by enzyme phosphorylation/dephosphorylation, the involvement of AMPK, the role of AMP deaminase as 'gatekeeper' for And degradation, and the functional and metabolic consequences of absent or excessive AMP deamination in fast-twitch skeletal muscle in vivo. In vitro, in situ perfused, and in vivo preparations will be used to evaluate whether AMPD1 enzyme phosphorylation: contributes to AMP deaminase kinetic activation in vivo; occurs by activation of AMPK during contractions and via treatment with 5-aminoimadazone-4- carboxyamide ribonucleoside (AICAR) in vivo; and, is dephosphorylated by protein phosphatase 2A, leading to kinetic inactivation. We will evaluate the 'gatekeeper' role on AMPD1 on And degradation and recovery processes, by AMPD1 induced by AMPK. Further, we will assess whether absence of AMP deamination during contractions in vivo, established with a specific high-affinity inhibitor; AMPD1 gene deletion or adenylate kinase (AK1) gene deletion, impairs muscle function, and accelerates And degradation. These novel studies will contribute fundamental information to understand the control of AMP deamination in muscle, ' its impact on muscle function, and its role as a 'gatekeeper' for And metabolism in muscle.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-RAP (03))
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Lymn, Richard W
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University of Missouri-Columbia
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Hancock, Chad R; Janssen, Edwin; Terjung, Ronald L (2006) Contraction-mediated phosphorylation of AMPK is lower in skeletal muscle of adenylate kinase-deficient mice. J Appl Physiol 100:406-13
Hancock, C R; Brault, J J; Terjung, R L (2006) Protecting the cellular energy state during contractions: role of AMP deaminase. J Physiol Pharmacol 57 Suppl 10:17-29
Hancock, Chad R; Brault, Jeffrey J; Wiseman, Robert W et al. (2005) 31P-NMR observation of free ADP during fatiguing, repetitive contractions of murine skeletal muscle lacking AK1. Am J Physiol Cell Physiol 288:C1298-304
Hancock, Chad R; Janssen, Edwin; Terjung, Ronald L (2005) Skeletal muscle contractile performance and ADP accumulation in adenylate kinase-deficient mice. Am J Physiol Cell Physiol 288:C1287-97
Abraham, Kirk A; Terjung, Ronald L (2004) Phosphate uptake in rat skeletal muscle is reduced during isometric contractions. J Appl Physiol 97:57-62
Abraham, Kirk A; Brault, Jeffrey J; Terjung, Ronald L (2004) Phosphate uptake and PiT-1 protein expression in rat skeletal muscle. Am J Physiol Cell Physiol 287:C73-8
Brault, Jeffrey J; Terjung, Ronald L (2003) Creatine uptake and creatine transporter expression among rat skeletal muscle fiber types. Am J Physiol Cell Physiol 284:C1481-9
Brault, Jeffrey J; Abraham, Kirk A; Terjung, Ronald L (2003) Phosphocreatine content of freeze-clamped muscle: influence of creatine kinase inhibition. J Appl Physiol 94:1751-6
Brault, Jeffrey J; Abraham, Kirk A; Terjung, Ronald L (2003) Muscle creatine uptake and creatine transporter expression in response to creatine supplementation and depletion. J Appl Physiol 94:2173-80
Terjung, Ronald L; Zarzeczny, Ryszard; Yang, H T (2002) Muscle blood flow and mitochondrial function: influence of aging. Int J Sport Nutr Exerc Metab 12:368-78

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