Physiology of Malonyl-CoA in Muscle during Exercise

Summary

Principal Investigator: WILLIAM WINDER
Abstract: The principal purpose of the proposed experiments is to elucidate the mechanisms of regulation of malonyl-CoA (inhibitor of fatty acid oxidation) content in skeletal muscle. This will be accomplished by studying the short-term mechanisms of regulation of acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-CoA. Upstream signaling proteins, AMP-activated protein kinase (AMPK) and AMP-activated protein kinase kinase (AMPKK) will be investigated. AMPK and AMPKK are also likely involved in contraction-induced stimulation of glucose uptake and control of expression of genes for GLUT4, hexokinase, and mitochondrial oxidative enzymes. Results will be applicable to these other important processes that appear to be regulated by the AMPKK/AMPK signaling system. Phosphorylation states of the AMPK phosphorylation site of muscle ACC and of the threonine 172 (AMPKK site) site in AMPK will be correlated with activity of purified ACC preparations, activity of ACC from electrically stimulated muscle, and activity of ACC in muscle from rats run on the treadmill. Roles of creatine phosphate (AMPK inhibitor) and 5'-AMP (AMPKK and AMPK activator) will be investigated using in vitro and in situ models. The effect of insulin on the rate of dephosphorylation of the AMPK phosphorylation site of ACC and the AMPKK site of AMPK will characterized. If effects of insulin are noted, the downstream signaling steps will be investigated, using wortmannin and phosphatase inhibitors. A putative AMPK kinase will be isolated from skeletal muscle and characterized with respect to molecular weight and regulation by creatine phosphate, 5'-AMP, and calcium/calmodulin. The question of whether AMPKK can be activated by phosphorylation during muscle contraction similarly to AMPK will be investigated. Adaptations of the AMPK/AMPKK signaling system to endurance training will be further characterized. Type 2 diabetes mellitus and obesity are two interrelated metabolic diseases that are increasing in incidence in the United States at alarming rates. These experiments will provide new information on regulation of AMPK and AMPKK, key enzymes that have now become targets for development of new pharmaceuticals for treatment of Type 2 diabetes and possibly obesity. This information will also provide essential basic information for investigation of the hypothesis that some forms of type 2 diabetes are due to defects in the AMPK/AMPKK signaling pathway. The results will provide additional rationale for the use of regular exercise in preventing and treating type 2 diabetes and obesity.
Funding Period: 1992-05-01 - 2008-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase
    D S Rubink
    Dept of Physiology and Developmental Biology, 545 WIDB, Brigham Young Univ, Provo, UT 84602, USA
    J Appl Physiol (1985) 98:1221-7. 2005
  2. ncbi AMP-activated protein kinase kinase activity and phosphorylation of AMP-activated protein kinase in contracting muscle of sedentary and endurance-trained rats
    Denise Hurst
    Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA
    Am J Physiol Endocrinol Metab 289:E710-5. 2005
  3. ncbi Endurance training increases skeletal muscle LKB1 and PGC-1alpha protein abundance: effects of time and intensity
    Eric B Taylor
    Department of Physiology and Developmental Biology, 545 WIDB, Brigham Young University, Provo, UT 84602, USA
    Am J Physiol Endocrinol Metab 289:E960-8. 2005
  4. ncbi Evidence against regulation of AMP-activated protein kinase and LKB1/STRAD/MO25 activity by creatine phosphate
    Eric B Taylor
    Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah 84602, USA
    Am J Physiol Endocrinol Metab 290:E661-9. 2006
  5. ncbi Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice
    D M Thomson
    Dept of Physiology and Developmental Biology, Brigham Young Univ, Provo, UT 84602, USA
    Am J Physiol Endocrinol Metab 292:E196-202. 2007
  6. ncbi LKB1 and the regulation of malonyl-CoA and fatty acid oxidation in muscle
    D M Thomson
    Dept of Physiology and Developmental Biology, Brigham Young Univ, Provo, UT 84602, USA
    Am J Physiol Endocrinol Metab 293:E1572-9. 2007
  7. ncbi AMP-activated protein kinase phosphorylates transcription factors of the CREB family
    D M Thomson
    Dept of Physiology and Developmental Biology, 545 WIDB, Brigham Young Univ, Provo, UT 84602, USA
    J Appl Physiol (1985) 104:429-38. 2008
  8. pmc AMP-activated protein kinase control of fat metabolism in skeletal muscle
    D M Thomson
    Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA
    Acta Physiol (Oxf) 196:147-54. 2009

Scientific Experts

  • D M Thomson
  • Eric B Taylor
  • Jeremy D Lamb
  • William W Winder
  • Cori L Compton
  • David G Chesser
  • William J Ellingson
  • Denise Hurst
  • Lyle J Greenwood
  • D S Rubink
  • W W Winder
  • Richard W Hurst
  • Seth T Herway
  • Troy D Cline
  • Brian B Porter

Detail Information

Publications8

  1. ncbi Effect of phosphorylation by AMP-activated protein kinase on palmitoyl-CoA inhibition of skeletal muscle acetyl-CoA carboxylase
    D S Rubink
    Dept of Physiology and Developmental Biology, 545 WIDB, Brigham Young Univ, Provo, UT 84602, USA
    J Appl Physiol (1985) 98:1221-7. 2005
    ..This may contribute to low-muscle malonyl-CoA values and increasing fatty acid oxidation rates during long-term exercise when plasma fatty acid concentrations are elevated...
  2. ncbi AMP-activated protein kinase kinase activity and phosphorylation of AMP-activated protein kinase in contracting muscle of sedentary and endurance-trained rats
    Denise Hurst
    Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA
    Am J Physiol Endocrinol Metab 289:E710-5. 2005
    ..These results suggest that AMPKK is activated during electrical stimulation of both trained and nontrained muscle by mechanisms other than covalent modification...
  3. ncbi Endurance training increases skeletal muscle LKB1 and PGC-1alpha protein abundance: effects of time and intensity
    Eric B Taylor
    Department of Physiology and Developmental Biology, 545 WIDB, Brigham Young University, Provo, UT 84602, USA
    Am J Physiol Endocrinol Metab 289:E960-8. 2005
    ..The increase in LKB1 and PGC-1alpha with endurance and interval training may function to maintain the training-induced increases in mitochondrial mass...
  4. ncbi Evidence against regulation of AMP-activated protein kinase and LKB1/STRAD/MO25 activity by creatine phosphate
    Eric B Taylor
    Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah 84602, USA
    Am J Physiol Endocrinol Metab 290:E661-9. 2006
    ..In conclusion, these results suggest that creatine phosphate is not a direct regulator of LKB1 or AMPK activity. Creatine phosphate may indirectly modulate AMPK activity by replenishing ATP at the onset of muscle contraction...
  5. ncbi Skeletal muscle and heart LKB1 deficiency causes decreased voluntary running and reduced muscle mitochondrial marker enzyme expression in mice
    D M Thomson
    Dept of Physiology and Developmental Biology, Brigham Young Univ, Provo, UT 84602, USA
    Am J Physiol Endocrinol Metab 292:E196-202. 2007
    ..Capacity for voluntary running is compromised with muscle and heart LKB1 deficiency...
  6. ncbi LKB1 and the regulation of malonyl-CoA and fatty acid oxidation in muscle
    D M Thomson
    Dept of Physiology and Developmental Biology, Brigham Young Univ, Provo, UT 84602, USA
    Am J Physiol Endocrinol Metab 293:E1572-9. 2007
    ..Regardless, our results suggest that LKB1 is an important regulator of malonyl-CoA levels and fatty acid oxidation in skeletal muscle...
  7. ncbi AMP-activated protein kinase phosphorylates transcription factors of the CREB family
    D M Thomson
    Dept of Physiology and Developmental Biology, 545 WIDB, Brigham Young Univ, Provo, UT 84602, USA
    J Appl Physiol (1985) 104:429-38. 2008
    ..We conclude that CREB and related proteins are direct downstream targets for AMPK and are therefore likely involved in mediating some effects of AMPK on expression of genes having a CRE in their promoters...
  8. pmc AMP-activated protein kinase control of fat metabolism in skeletal muscle
    D M Thomson
    Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA
    Acta Physiol (Oxf) 196:147-54. 2009
    ..Likewise, AMPK may regulate transport of FAs into the cell through FAT/CD36. AMPK may also regulate capacity for FA oxidation by phosphorylation of transcription factors such as CREB or coactivators such as PGC-1alpha...