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Tutkimuksen johtaja ja suorituspaikka:
Mustafa Atalay, Kuopion yliopisto, Fysiologian laitos
Tutkimusryhmä; M. Atalay, N. Oksala, J. Lappalainen, Z. Lappalainen, K. Kaarniranta, S. Hyyppä, Z. Radak, C.K.
Tutkimuksen nimi ja asiasanat:
Protective and anti-apoptotic role of thioredoxin system: effect of endurance training and alpha-lipoic acid
Opetusministeriöltä saatu rahoitus tutkimukseen yhteensä (€): 133.000
Tutkimuksen alkamis- ja päättymisajankohta: 1.1.2007 - 31.12.2009

- Tutkimuksen tieteenala: Liikuntafysiologia
- Tavoite: Our hypothesis in this study was that tissue protection could be up-regulated by thioredoxin (TRX) system
in diabetic and non-diabetic conditions. We aim to enhance the cytoprotective, anti-apoptotic and regulative role of
TRX system in diabetic as well as in non-diabetic conditions using endurance training and -lipoic acid
supplementation strategies.

- Keskeiset tieteelliset tulokset ja julkaisut: In animal studies, we showed that at high doses (150 mg/kg), alpha-
lipoic acid (LA) increased cellular protection as observed in biochemical and histological analyses in a tissue-specific
manner. We found that endurance training increased TRX levels and TRX activity, but not thioredoxin interacting
protein (Tx-Nip), a protein which has pro-apoptotic and anti-TRX effects. We observed these effects widely in skeletal
muscle, in heart as well as in several tissues, including kidney and brain, which do not actively participate to the
metabolic processes during prolonged exercise. Lower doses of LA supplementation (25 mg/kg) in trained horses
reduced the rate of free radical formation in skeletal muscle, activated stress protein induction and simultaneously
decreased the concentrations of oxidised protein and lipid peroxidation products. The activities of thioredoxin
reductase and glutathione reductase in muscle were significantly increased in LA-treated horses, while LA increased
the concentration of total glutathione in muscle at rest and during recovery.
Previous studies have reported that supplementation of particular micronutrients may attenuate the normal physiological responses to exercise and blunt the training-induced adaptations. In our studies we have not observed any attenuation of muscle oxidative capacity or overall physical performance in response to LA supplementation. In apoptosis studies, we found that in non-diabetic animals both training and LA-supplementation decreased activity of caspase-3, an effecter enzyme of apoptotic processes. However, only endurance training effect was significant in diabetic animals. Similarly, cell death assay based on the immunoassays of DNA fragments showed that endurance training is an effective tool to decrease strenuous exercise- and diabetes-induced apoptosis. As a major outcome of our OKM projects, two of our PhD students completed their PhD studies with the contribution of these studies: 1) Mika Venojärvi, Roles of exercise training with dietary counselling and muscle fibre composition in the regulation of glucose metabolism in middle-aged subjects with impaired glucose tolerance, 28.6.2011. 2) Susanna Kinnunen, Oxidative stress in skeletal muscle after acute exercise, 26,8,2011, Julkaisut, joissa tämän tutkimuksen tulokset on raportoitu:
1. Lappalainen Z, Lappalainen J, Oksala NKJ, Laaksonen DE, Khanna S, Sen CK, Atalay M. Diabetes impairs
exercise training-associated thioredoxin response and glutathione status in rat brain, J Appl Physiol, 106(2):461-7, 2009. 2. Kinnunen S, Oksala NKJ, Hyyppä S, Sen CK, Radak Z, Szabó B, Jakus J, Atalay M. Alpha-Lipoic acid
modulates thiol antioxidant defences and decreases exercise-induced oxidative stress in standardbred trotters, Free Radical Research, 43(8):697-705, 2009. 3. Kinnunen S, Hyyppä S, Oksala NKJ, Sen CK, Atalay M: Alpha-lipoic acid supplementation enhances tissue
protection and oxidative capacity in exercised trotters, Research in Veterinary Science, Res Vet Sci, 87(3):462-7, 2009. 4. Lappalainen Z, Lappalainen J, Laaksonen DE, Oksala NKJ, Khanna S, Sen CK, Atalay M. Acute exhaustive
exercise induces thioredoxin-1 transcription in rat brain and alpha-lipoic acid modulates thioredoxin-interacting protein response in diabetes, International Journal of Sport Nutrition & Exercise Metabolism, 20(3):206-15.2010. 5. Tanskanen M, Atalay M, Uusitalo A. Oxidative stress and antioxidant capacity in overtrained athletes, Journal
6. Lappalainen Z, Lappalainen J, Oksala N.K.J, Laaksonen DE, Khanna S, Sen CK, Atalay M. Alpha-lipoic acid
does not alter stress protein response to acute exercise in diabetic brain, Cell Biochemistry & Function, 28:644650, 2010. 7. Atalay M, Bilginoglu A, Kokkola T, Oksala N, Turan B. Treatments with sodium selenate or doxycycline offset
diabetes-induced perturbations of thioredoxin levels and antioxidant capacity, Molecular and Cellular Biochemistry, 351 (1-2):125-31, 2011. 8. Tanskanen M., Uusitalo A.L., Kinnunen H., Häkkinen H., Kyröläinen H., Atalay M. Oxidative stress and
antioxidant status are associated with overreaching, Medicine & Science in Sports & Exercise, 43(8):1552-60, 2011. Tutkimusryhmän julkaisuja, jotka ovat liittyneet tähän tutkimuksen aiheeseen ja menetelmiin:
9. Oksala NKJ, Laaksonen D, Lappalainen J, Khanna S, Sen CK, Atalay M.: Kidney heat shock protein
response to exercise in streptozotocin-induced diabetes: effects of -lipoic acid supplementation, Antioxidant and Redox Signalling, 9(4):497-506, 2007. 10. Venojärvi M, Aunola S, Puhke R, Marniemi J, Glad M, Hämäläinen H, Halonen JP, Lindström J, Rastas M, Nuutila P, Hänninen O, Atalay M. Long-term exercise training and dietary intervention modulates heat
shock protein expression in middle-aged subjects with impaired glucose tolerance, BioMed Central,
Endocrine Disorders, 27(8):3, 2008.
11. Mager U, Kolehmainen M, de Mello V. D. F, Schwab U, Laaksonen DE, Rauramaa R, Gylling H, Atalay M,
Pulkkinen L, Uusitupa M. Clinical and genetic determinants of plasma Ghrelin in subjects with metabolic syndrome - the Genobin study, European Journal of Endocrinology, 158(4):499-510, 2008. 12. Ryhänen T, Mannermaa E, Oksala N, Salminen A, Atalay M, Kaarniranta K. Effects of geldanamycin and
radicicol on oxidative stress and cell damage in retinal pigment epithelial cells, European journal of pharmacology, 584: 229 236, 2008. 13. Venojärvi M, Aunola S, Puhke R, Marniemi J, Glad M, Hämäläinen H, Halonen JP, Lindström J, Rastas M, Kallio P, Kolehmainen M, Laaksonen D, Pulkkinen L, Atalay M, Mykkänen H, Uusitupa M, Poutanen K. and
Niskanen L. Inflammation markers are modulated by response to diets differing in postprandial insulin
responses in individuals with metabolic syndrome, The American Journal of Clinical Nutrition, 87(5):1497-
503, 2008.
14. de Mello VDF, Kolehmainen M, Pulkkinen L., Schwab U., Mager U., Laaksonen DE, Niskanen L, Gylling H, Atalay M, Rauramaa R, Uusitupa M. Improvement of insulin sensitivity in subjects with the metabolic
syndrome after weight loss is associated with the decrease in mRNA expression of genes from the nuclear
factor-kappa-B (NF B) pathway in peripheral blood mononuclear cells, Diabetolgia, 51(11):2060-7, 2008.
15. Radak Z, Atalay M, Jakus J, Davies K, Goto S. Exercise improves import of 8-oxoguanine DNA glycosylase
for efficient repair of mitochondrial DNA of skeletal muscle, Free Radical Biology Medicine, 46(2):238-43, 2009. 16. Toldy A, Stadler K, Sasvari M, Jakus J, Atalay M, Jung KJ, Chung HY, Radak Z. The beneficial effects of
nettle supplementation and exercise on brain lesion and memory in rat, Journal of Nutritional Biochemistry, J Nutr Biochem. 20(12):974-81, 2009. 17. Lappalainen Z, Lappalainen J, Oksala N.K.J, Laaksonen DE, Khanna S, Sen CK, Atalay M. Exercise
training and experimental diabetes modulate heat shock protein response in brain, Scandinavian Journal of Medicine and Science in Sports, 20(1):83-9, 2010. 18. Koltai E, Szabo Z., Atalay M., Boldogh I., Naito H., Goto S., Nyakas C., Radak Z. Physical exercise
increases SIRT1 relative activity that was lost in response to aging of skeletal muscle, Mechanisms of Ageing and Development, Mech Ageing Dev, 131(1):21-28, 2010. 19. Radak Z, Hart N, Sarga L, Koltai E, Atalay M, Ohno H, Boldogh I Exercise plays a preventive role against
Alzheimer disease. J Alzheimer Diseases, 20(3):777-83, 2010. 20. Guéraud F, Atalay M, Bresgen N, Cipak A, Eckl PM, Huc L, Jouanin I, Siems W, Uchida K. Chemistry and
biochemistry of lipid peroxidation. Free Radical Research, 44(10): 1098 1124, 2010. 21. Breusing N., Grune T., Andrisic L., Atalay M., et al. Results of an interlaboratory validation of methods of
lipid peroxidation measurements, Free Radical Research, 44(10):1203-15, 2010.
Tutkimuksen vaikutukset liikuntatieteellisesti ja tieteenalan kannalta:

Endurance training enhances thioredoxin defense and over all tissue protection not only in the tissues participating
actively to physical exercise, but also in non-participating tissues in both diabetic and non-diabetic conditions. In
addition, our results gave new mechanistic evidence on the protection of endurance training and thiol redox
regulation against tissue damage in diabetic and non-diabetic conditions.
(ks. liikuntahallinnollinen kehys):

Our studies showed endurance training enhances antioxidant defense and tissue protection not only in the tissues
actively contributing to physical exercise but also in non-active tissues during exercise even in diabetic conditions.
Previous studies showed that as a side effect, supplementation with particular micronutrients attenuated the
normal physiological response of tissues to exercise and blunted the training-induced adaptations. In this study we
showed that complimentary to endurance training, particular dietary antioxidant micronutrients may be used safely
to reduce exercise-induced oxidative stress without impairing the physical performance.

Source: http://www.liikuntaneuvosto.fi/files/150/Protective_and_anti-apoptotic_role_of_thioredoxin_system_effect_of_endurance_training_and_alpha-lipoic_acid.pdf


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