Exercise has beneficial effects on the treatment as well as prevention of type 2 diabetes. Physical activity activates diverse metabolic signaling pathways in skeletal muscle, and over time induces modification of metabolic gene expression. A novel protein, sucrose-non-fermenting protein kinase 1 /AMPK-related kinase (SNARK), has been identified as a putative signaling protein in skeletal muscle and has been hypothesized to regulate multiple metabolic functions. Studies have shown that SNARK is expressed in skeletal muscle and it was found that exercise and contraction increase SNARK activity in both rodent and human skeletal muscle. The overall goal of the proposed research project is to elucidate the regulation and function of SNARK in mediating the effects of exercise in skeletal muscle. For this purpose, four specific aims were identified: 1) To elucidate the mechanism of SNARK activation in skeletal muscle;2) To determine whether SNARK mediates fatty acid metabolism in skeletal muscle;3) To determine the role of SNARK signaling in exercise training- induced adaptations in skeletal muscle;and 4) To determine the function of skeletal muscle SNARK in whole body metabolism. Elucidating the function of SNARK will be important in understanding exercise-stimulated metabolic adaptations and has the potential to define new pharmacological targets for both treatment and prevention of type 2 diabetes.

Public Health Relevance

Diabetes is a major public health concern and exercise has an undisputed role in the treatment and prevention of this disease. The goal of this research proposal is to determine the role of the novel AMPK-related kinase SNARK in regulating metabolic responses to exercise in skeletal muscle. This will lead to a better understanding of the beneficial effects of exercise in diabetes and could help to identify novel therapies for diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068626-09
Application #
8309342
Study Section
Special Emphasis Panel (ZRG1-MOSS-H (04))
Program Officer
Laughlin, Maren R
Project Start
2004-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$383,844
Indirect Cost
$146,170
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Stanford, Kristin I; Middelbeek, Roeland J W; Townsend, Kristy L et al. (2013) Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 123:215-23
Lessard, Sarah J; Rivas, Donato A; Alves-Wagner, Ana B et al. (2013) Resistance to aerobic exercise training causes metabolic dysfunction and reveals novel exercise-regulated signaling networks. Diabetes 62:2717-27
Lauritzen, Hans P M M; Galbo, Henrik; Toyoda, Taro et al. (2010) Kinetics of contraction-induced GLUT4 translocation in skeletal muscle fibers from living mice. Diabetes 59:2134-44
Jessen, Niels; Koh, Ho-Jin; Folmes, Clifford D et al. (2010) Ablation of LKB1 in the heart leads to energy deprivation and impaired cardiac function. Biochim Biophys Acta 1802:593-600
Sharoff, Carrie G; Hagobian, Todd A; Malin, Steven K et al. (2010) Combining short-term metformin treatment and one bout of exercise does not increase insulin action in insulin-resistant individuals. Am J Physiol Endocrinol Metab 298:E815-23
Koh, Ho-Jin; Toyoda, Taro; Fujii, Nobuharu et al. (2010) Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle. Proc Natl Acad Sci U S A 107:15541-6
Palacios, Orsolya M; Carmona, Juan J; Michan, Shaday et al. (2009) Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle. Aging (Albany NY) 1:771-83
Rockl, Katja S C; Witczak, Carol A; Goodyear, Laurie J (2008) Signaling mechanisms in skeletal muscle: acute responses and chronic adaptations to exercise. IUBMB Life 60:145-53
Koh, Ho-Jin; Brandauer, Josef; Goodyear, Laurie J (2008) LKB1 and AMPK and the regulation of skeletal muscle metabolism. Curr Opin Clin Nutr Metab Care 11:227-32
Fujii, Nobuharu; Ho, Richard C; Manabe, Yasuko et al. (2008) Ablation of AMP-activated protein kinase alpha2 activity exacerbates insulin resistance induced by high-fat feeding of mice. Diabetes 57:2958-66

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