Open Access Open Access  Restricted Access Subscription Access
fatty acid metabolism control

Calmodulin dependent protein kinase (CaMK)-II activation by exercise regulates omega-3 polyunsaturated fatty acids biosynthesis in rat skeletal muscle

Jitcy S Joseph, Emmanuel Mukwevho


Calmodulin dependent protein kinase(CaMK)-II activation has been associated with many cellular functions beneficial to human health, especially metabolic syndrome and type 2 diabetes. Omega-3 polyunsaturated fatty acids shown to have positive effects on metabolic syndrome and type 2 diabetes;especiallydocosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) which are synthesized from alpha-linolenic acid (ALA) acquired from diet. Using Gas chromatography-mass spectrometry, we found that exercise induced CaMKII activation regulate the biosynthesis of DHA and EPA. Addition of N-[2-[N-(4-Chlorocinnamyl)-N-methylaminomethyl] phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide (KN93) (CaMKII inhibitor) in the exercised rats group resulted in the biosynthesis attenuated to levels similar to the control group. Furthermore, of Peroxisome proliferator-activated receptor gamma coactivator 1(PGC-1), a co-activator also involved in lipid metabolism was found to have been increased with CaMKII activation.  Here we show for the first time that CaMKII activation controls the metabolism of omega-3 fatty acids, DHA and EPA which has significant implications in the regulation of metabolic diseases. Therefore, CaMKII can be a target to design therapeutic modalities required to cure or better manage metabolic syndrome and type 2 diabetes.


Omega-3 polyunsaturated; CaMKII; Exercise; DHA; EPA, Type 2 Diabetes

Full Text:



R.C. Eva. Role of CAMKII in skeletal muscle plasticity. J. Appl. Physiol. 2005, 99, 414-423.

K. Baar, A.R. Wende, T.E. Jones, M. Marison, L.A. Nolte, M. Chen, D.P. Kelly, J.O. Holloszy. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 2002, 16, 1879–1886.

P.Z. Zimmet, K. Alberti, J.E. Shaw. Mainstreaming the metabolic syndrome: a definitive definition. S Med. J. 2005,183, 175–6.

K.G. Alberti, R.H. Eckel, S.M. Grundy, P.Z. Zimmet, J.I. Cleeman, K.A. Donato. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009, 120, 1640–1645.

W.M. Ratnayake, C.Galli. Fat and fatty acid terminology, methods of analysis and fat digestion and metabolism: a background. Ann. Nutr. Metab. 2009, 55, 8-43.

A.P. Simopoulos. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp. Biol. Med. (Maywood), 2008,233, 674–688.

P. Flachs, O. Horakova, P. Brauner, M. Rossmeisl, P. Pecina, et al. Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce beta-oxidation in white fat. Diabetologia. 2005, 48, 2365-75.

D. Fedor, D.S. Kelley. Prevention of insulin resistance by n-3 polyunsaturated fatty acids. Curr. Opin. Clin. Nutr. Metab. Care. 2009, 12, 138–146.

I. Baik, R.D. Abbott, J.D. Curb. Intake of ï¬sh and n-3 fatty acids and future risk of metabolic syndrome. J. Am. Dietetic Assoc. 2010, 110, 1018–1026.

Y.A. Carpentier, L. Portois, W.J. Malaisse. n-3 fatty acids and the metabolic syndrome. Am. J. Clin. Nutr. 2006, 83, 1499S–1504S.

M.C. Morris, F. Sacks, B. Rosne. Does fish oil lower blood pressure? A meta-analysis of controlled trial. Circulation. 1993, 88, 523–533.

L.J. Appel, E.R. Miller, A.J. Seidler, P.K. Whelton. Does supplementation of diet with ‘fish oil’ reduce blood pressure? A meta-analysis of controlled clinical trial. Arch. Intern. Med.1993, 153, 1429–1438.

J. M. Geleijnse, E.J. Giltay, D.E. Grobbee, A.R. Donders, F.J. Kok,. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J. Hypertens. 2002, 20, 1493–1499.

J.T. Brenna. Efficiency of conversion of alpha-linolenic acid to long chain n−3 fatty acids in man. Curr. Opin. Clin. Nutr. Metab. Care. 2002, 5, 127–32.

A.J. Sinclair, N.M. Attar-Bashi, D. Li. What is the role of alpha-linolenic acid for mammals. Lipid. 2002, 37, 1113–23.

P.T. Price, C.M. Nelson, S.D. Clarke. Omega-3 polyunsaturated fatty acid regulation of gene expression. Curr. Opin. Lipidol. 2000,11, 3-7.

Z. Wu, P. Puigserver, U. Andersson, C. Zhang, G. Adelmant, V. Mootha, A. Troy, S. Cinti, B. Lowell, R.C. Scarpulla, B.M. Spiegelman. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogeniccoactivator PGC-1. Cell.1999, 98, 115–124.

A. Safdar, P.J. Little, A.J. Stokl, B.P. Hettinga, M. Akhtar, and M. Tamopolsky. Exercise Increases Mitochondrial PGC-1Content and Promotes Nuclear-Mitochondrial Cross-talk to Coordinate Mitochondrial Biogenesis. Biol. Chem. 2011, 286, 10605–1061.

S. Terada, T. Yokozeki, K. Kawanaka, K. Ogawa, M. Higuchi, O. Ezaki, I. Tabata. Effects of High-intensity Swimming Training on GLUT-4 and Glucose Transport Activity in Rat Skeletal Muscle. J. Appl. Physiol. 2001, 90, 2019-2024.

H. Pilegaard, B. Saltin, P.D. Neufer. Exercise induces transient transcriptional activation of the PGC-1α gene in human skeletal muscle. J. Physiol. 2003, 546, 851–858.

J.A.H. Smith, M. Collins, L.A. Grobler, C.J. Magee, E.O. Ojuka. Exercise and CaMKII activation both Increase the Binding of MEF2A to the GLUT4 promoter in Skeletal Muscle in vivo. Am. J. Endocrinol. Metab. 2007, 292, 413-420.

J. Folch, M. Lees, G.H. SolaneStanely. A simple method for the isolation and purification of total lipids from animal tissue. J. Biol. 1957, 226, 497-509.

K. Ichihara, A. Shibahara, K. Yamamoto, T. Nakayama. An improved method for rapid analysis of fatty acids of glycerolipids. Lipids. 1996, 31, 535-9.

K.L. Moreau, R. Degarmo, J. Langley. Increasing daily walking lowers blood pressure in postmenopausal women. Med. Sci. Sports. Exerc. 2001, 33,1825-1831.

T.D. Miller, G.J. Balady, G.F. Fletcher. Exercise and its role in the prevention and rehabilitation of cardiovascular disease. Ann. Behav. Med. 1997, 19, 220-229.

A. Alevizos, J. Lentzas, S. Kokkoris, A. Mariolis, P. Korantzopoulos. Physical activity and stroke risk. Int. J. Clin. Pract. 2005, 59, 922-930.

D.B. Panagiotakos, C. H. Pitsavos, C. Chrysohoou, J. Skoumas, etal. The Impact of Lifestyle Habits on the Prevalence of the Metabolic Syndrome among Greek adults from the ATTICA study. Am. Heart. J. 2004, 147, 106-112.

C. Pitsavos, D.B. Panagiotakos, C. Chrysohoou, S. Kavouras, C. Stefanadis. The associations between physical activity, inflammation, and coagulation markers, in people with metabolic syndrome: the ATTICA study. Eur. J. Cardiovasc. Prev. 2005, 12, 151-158.

J.M. Jakicic, C. Winters, W. Lang, R.R. Wing. Effects of intermittent exercise and use of home exercise equipment on adherence, weight loss, and fitness in overweight women. JAMA 1999, 282, 1554-1560.

L.H. Storlien, A.B. Jenkins, D.J. Chisholm, et al. Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipids. Diabetes. 1991, 40, 280-9.

R. Saremi. The utility of omega-3 fatty acids in cardiovascular disease. Am. J. Ther. 2009, 16,421-436.

J.H. Lee, J. O’Keefe, C.J. Lavie, W.S. Harris. Omega-3 fatty acids: cardiovascular benefits, sources and sustainability. Nat. Rev. Cardiol. 2009, 6, 753-758.

J.G. Warner, I.H. Ullrich, M.J. Albrink, R.A. Yeater. Combined effects of aerobic exercise and omega-3 fatty acids in hyperlipidemic persons. MSSE. 1989, 21, 498-505.

A.M. Hill, J.D. Buckley, K.J. Murphy, P.R. Howe. Combining fish-oil supplements with regular aerobic exercise improves body composition and cardiovascular disease risk factors. AJCN. 2007, 85, 1267–1274.

H.O. Bang, J. Dyerberg, A.B. Nielsen. Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet. 1971, 1, 1143- 45.

S. Grimsgaard, K.H. Bonaa, J.B. Hansen, E.S.P. Myrhe. Effects of highly purified eicosapentaenoic acid and docosahexaenoic acid on hemody- namics in humans. Am. J. Clin. Nutr. 1998, 68, 52-9.

D.F. Horrobin. Fatty acid metabolism in health and diseases, the role delta 6 desaturase. Am. J. Clin. Nutr. 1993, 57, 732S-736S.

N. Zamaria. Alternation of polyunsaturated fatty acid status and metabolism in health and diseases. Reprod. Nut. Dev. 2004, 44, 273-282.

G. Li, H. Hidaka, C.B. Wollheim. Inhibition of voltage-gated Ca2+ channels and insulin secretion in HIT cells by the Ca2+/calmodulin-dependent protein kinase II inhibitor KN-62, comparison with antagonists of calmodulin and L-type Ca2+ channels. Mol. Pharmacol. 1992, 42, 489-49.

ISSN 2347–9825

Authors/visitors are advised to use Firefox browser for better experience of journal site.

Open Access: Researcher from developing/low economy countries can access the jorunal contents through WHO-HINARI .