Volume 28, Issue 2 (July 2024)                   Physiol Pharmacol 2024, 28(2): 157-168 | Back to browse issues page

XML Print

Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Nabilpour M, Seifi-Skishahr F, PourRahim A, Nobari H. Impact of two-month sodium citrate supplementation along with moderate-intensity continuous training on PGC-1α and Nrf2 expression in diabetic rats. Physiol Pharmacol 2024; 28 (2) : 6
URL: http://ppj.phypha.ir/article-1-2187-en.html
Abstract:   (552 Views)

Introduction: Sports activity increases PGC1α and Nrf2, the regulatory factors of mitochondrial biogenesis. This paper aims to study the impact of two-month sodium citrate supplementation with Moderate-Intensity Continuous Training (MICT) on PGC-1α and Nrf2 expression in diabetic rats.
Methods: Forty-five three-month-old male Wistar rats were haphazardly assigned to one of five equal groups (N=9): (1) healthy; (2) diabetic; (3) diabetes + exercise (DE); (4) diabetes+ supplementation (DS); and (5) diabetic + exercise + supplementation (DSE), matched according to their weights. After induction, exercises began on a treadmill for 8 weeks, five days a week. The MICT protocol ran at 70% of their maximum speed for 36 minutes. The rats supplemented with sodium-citrate- at 15 mmol/L in drinking water for two months. PGC-1α and Nrf2 expression were measured through Western blotting in the soleus muscle. Data were analyzed using univariate analysis of variance (ANOVA) and the Tukey post-hoc test. Cohen’s D effect size (ES) was calculated to compare the groups.
Results: The results showed that induction of diabetes significantly reduced the expression of PGC-1α (P< 0.001; ES=1.36) and Nrf2 (P<0.088; ES=0.24), while exercise increased PGC-1α expression (P<0.001; ES=0.68). Sodium citrate supplementation, either alone or in combination with MICT activity, did not show a clear advantage for Nrf2 expression.
Conclusion: MICT activity and sodium citrate supplementation, by increasing PGC-1α expression, can be considered therapeutic strategies for diabetic patients. However, to increase Nrf2 expression, further studies with different exercise intensities and doses of sodium citrate supplementation are needed.

Article number: 6
Full-Text [PDF 942 kb]   (17 Downloads)    

1. Bengal E, Aviram S, Hayek T. p38 MAPK in glucose metabolism of skeletal muscle: Beneficial or harmful? International Journal of Molecular Sciences 2020; 21: 6480. [DOI:10.3390/ijms21186480]
2. Chavanelle V, Boisseau N, Otero Y F, Combaret L, Dardevet D, Montaurier C, et al. Effects of high-intensity interval training and moderate-intensity continuous training on glycaemic control and skeletal muscle mitochondrial function in db/db mice. Scientific Reports 2017; 7: 204. [DOI:10.1038/s41598-017-00276-8]
3. Chen X, Ji Y, Liu R, Zhu X, Wang K, Yang X, et al. Mitochondrial dysfunction: roles in skeletal muscle atrophy. Journal of Translational Medicine 2023; 21: 503. [DOI:10.1186/s12967-023-04369-z]
4. Chen Y, Zhang J, Li P, Liu C, Li L. N1 methylnicotinamide ameliorates insulin resistance in skeletal muscle of type 2 diabetic mice by activating the SIRT1/PGC 1α signaling pathway. Molecular Medicine Reports 2021; 23: 1-1. [DOI:10.3892/mmr.2020.11666]
5. Cho N H, Shaw J E, Karuranga S, Huang Y, da Rocha Fernandes J D, Ohlrogge A W, et al. IDF diabetes atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Research and Clinical Practice 2018; 138: 271-281. [DOI:10.1016/j.diabres.2018.02.023]
6. Corona J C, Duchen M R. PPARγ and PGC-1α as therapeutic targets in Parkinson’s. Neurochemical Research 2015; 40: 308-316. [DOI:10.1007/s11064-014-1377-0]
7. Cunha V C R, Aoki M S, Zourdos M C, Gomes R V, Barbosa W P, Massa M, et al. Sodium citrate supplementation enhances tennis skill performance: A crossover, placebo-controlled, double blind study. Journal of the International Society of Sports Nutrition 2019; 16: 32. [DOI:10.1186/s12970-019-0297-4]
8. Deng X, Lin N, Fu J, Xu L, Luo H, Jin Y, et al. The Nrf2/PGC1α pathway regulates antioxidant and proteasomal activity to alter cisplatin sensitivity in ovarian cancer. Oxidative Medicine and Cellular Longevity 2020; 2020: 4830418-4830418. [DOI:10.1155/2020/4830418]
9. Dinkova-Kostova A T, Abramov A Y. The emerging role of Nrf2 in mitochondrial function. Free Radical Biology and Medicine 2015a; 88: 179-188. [DOI:10.1016/j.freeradbiomed.2015.04.036]
10. Gounder S S, Kannan S, Devadoss D, Miller C J, Whitehead K S, Odelberg S J, et al. Impaired transcriptional activity of Nrf2 in age-related myocardial oxidative stress is reversible by moderate exercise training. PLoS One 2012. [DOI:10.1371/annotation/8690bb36-3c5d-48a6-b3be-39a2b50896e1]
11. Granata C, Oliveira R S, Little J P, Renner K, Bishop D J. Sprint-interval but not continuous exercise increases PGC-1α protein content and p53 phosphorylation in nuclear fractions of human skeletal muscle. Scientific Reports 2017; 7: 44227. [DOI:10.1038/srep44227]
12. Halling J F, Pilegaard H. PGC-1α-mediated regulation of mitochondrial function and physiological implications. Applied Physiology, Nutrition, and Metabolism 2020; 45: 927-936. [DOI:10.1139/apnm-2020-0005]
13. Handschin C, Rhee J, Lin J, Tarr P T, Spiegelman B M. An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proceedings of the National Academy of Sciences 2003; 100: 7111-7116. [DOI:10.1073/pnas.1232352100]
14. Heiat F, Ghanbarzadeh M, Ranjbar R, Shojaeifard M. Continuous swimming training arises a remarkable effect on some longevity biomarkers in rat skeletal muscles. Annals of Applied Sport Science 2020; 8.
15. Holmström K M, Baird L, Zhang Y, Hargreaves I, Chalasani A, Land J M, et al. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biology Open 2013; 2: 761-770. [DOI:10.1242/bio.20134853]
16. Hood D A. Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle. Applied Physiology, Nutrition, and Metabolism 2009; 34: 465-472. [DOI:10.1139/H09-045]
17. Kim B. Western blot techniques. Molecular profiling: Methods and Protocols 2017: 133-139. [DOI:10.1007/978-1-4939-6990-6_9]
18. Kobayashi M, Yamamoto M. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Advances in Enzyme Regulation 2006; 46: 113-140. [DOI:10.1016/j.advenzreg.2006.01.007]
19. Konopka A R, Suer M K, Wolff C A, Harber M P. Markers of human skeletal muscle mitochondrial biogenesis and quality control: effects of age and aerobic exercise training. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 2014; 69: 371-378. [DOI:10.1093/gerona/glt107]
20. Kramer H F, Witczak C A, Fujii N, Jessen N, Taylor E B, Arnolds D E, et al. Distinct signals regulate AS160 phosphorylation in response to insulin, AICAR, and contraction in mouse skeletal muscle. Diabetes 2006; 55: 2067-2076. [DOI:10.2337/db06-0150]
21. Lancha Junior A H, Painelli Vde S, Saunders B, Artioli G G. Nutritional strategies to modulate intracellular and extracellular buffering capacity during high-intensity exercise. Sports Medicine 2015; 45 Suppl 1: 71-81. [DOI:10.1007/s40279-015-0397-5]
22. Lira V A, Benton C R, Yan Z, Bonen A. PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity. American Journal of Physiology-Endocrinology and Metabolism 2010; 299: 145-161. [DOI:10.1152/ajpendo.00755.2009]
23. McGee S L, Hargreaves M. Exercise and myocyte enhancer factor 2 regulation in human skeletal muscle. Diabetes 2004; 53: 1208-1214. [DOI:10.2337/diabetes.53.5.1208]
24. McGinley C, Bishop D J. Rest interval duration does not influence adaptations in acid/base transport proteins following 10 wk of sprint-interval training in active women. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 2017; 312: 702-717. [DOI:10.1152/ajpregu.00459.2016]
25. Mootha V K, Lindgren C M, Eriksson K-F, Subramanian A, Sihag S, Lehar J, et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics 2003; 34: 267-273. [DOI:10.1038/ng1180]
26. Mora S, Pessin J E. The MEF2A isoform is required for striated muscle-specific expression of the insulin-responsive GLUT4 glucose transporter. Journal of Biological Chemistry 2000; 275: 16323-16328. [DOI:10.1074/jbc.M910259199]
27. Narasimhan M, Hong J, Atieno N, Muthusamy V R, Davidson C J, Abu-Rmaileh N, et al. Nrf2 deficiency promotes apoptosis and impairs PAX7/MyoD expression in aging skeletal muscle cells. Free Radical Biology and Medicine 2014; 71: 402-414. [DOI:10.1016/j.freeradbiomed.2014.02.023]
28. Neufer P D. The bioenergetics of exercise. Cold Spring Harbor perspectives in medicine 2018; 8. [DOI:10.1101/cshperspect.a029678]
29. Nielsen O B, Ørtenblad N, Lamb G D, Stephenson D G. Excitability of the T-tubular system in rat skeletal muscle: roles of K+ and Na+ gradients and Na+-K+ pump activity. Journal of Physiology 2004a; 557: 133-146. [DOI:10.1113/jphysiol.2003.059014]
30. Ou Y, Hou W, Li S, Zhu X, Lin Y, Han J, et al. Sodium citrate inhibits endoplasmic reticulum stress in rats with adenine-induced chronic renal failure. American Journal of Nephrology 2015; 42: 14-21. [DOI:10.1159/000437235]
31. Park S, Kim B, Kang S. Interaction effect of PGC-1α rs10517030 variants and energy intake in the risk of type 2 diabetes in middle-aged adults. European Journal of Clinical Nutrition 2017; 71: 1442-1448. [DOI:10.1038/ejcn.2017.68]
32. Parry-Billings M, MacLaren D P. The effect of sodium bicarbonate and sodium citrate ingestion on anaerobic power during intermittent exercise. European Journal of Applied Physiology 1986; 55: 524-529. [DOI:10.1007/BF00421648]
33. Pilegaard H, Saltin B, Neufer P D. Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. Journal of Physiology 2003; 546: 851-858. [DOI:10.1113/jphysiol.2002.034850]
34. Rabah H M, Mohamed D A, Mariah R A, Abd El-Khalik S R, Khattab H A, AbuoHashish N A, et al. Novel insights into the synergistic effects of selenium nanoparticles and metformin treatment of letrozole-induced polycystic ovarian syndrome: targeting PI3K/Akt signalling pathway, redox status and mitochondrial dysfunction in ovarian tissue. Redox Report 2023; 28: 2160569. [DOI:10.1080/13510002.2022.2160569]
35. Raciti G A, Iadicicco C, Ulianich L, Vind B F, Gaster M, Andreozzi F, et al. Glucosamine-induced endoplasmic reticulum stress affects GLUT4 expression via activating transcription factor 6 in rat and human skeletal muscle cells. Diabetologia 2010; 53: 955-965. [DOI:10.1007/s00125-010-1676-1]
36. Ramachandran B, Yu G, Gulick T. Nuclear respiratory factor 1 controls myocyte enhancer factor 2A transcription to provide a mechanism for coordinate expression of respiratory chain subunits. Journal of Biological Chemistry 2008; 283: 11935-11946. [DOI:10.1074/jbc.M707389200]
37. Requena B, Zabala M, Padial P, Feriche B. Sodium bicarbonate and sodium citrate: ergogenic aids? The Journal of Strength & Conditioning Research 2005; 19: 213-224. [DOI:10.1519/00124278-200502000-00036]
38. Rius-Pérez S, Torres-Cuevas I, Millán I, Ortega Á L, Pérez S. PGC-1α, inflammation, and oxidative stress: an integrative view in metabolism. Oxidative Medicine and Cellular Longevity 2020; 2020. [DOI:10.1155/2020/1452696]
39. Ruhee R T, Suzuki K. The integrative role of sulforaphane in preventing inflammation, oxidative stress and fatigue: A review of a potential protective phytochemical. Antioxidants (Basel) 2020; 9. [DOI:10.3390/antiox9060521]
40. Sergi D, Naumovski N, Heilbronn L K, Abeywardena M, O’Callaghan N, Lionetti L, et al. Mitochondrial (Dys)function and Insulin resistance: From pathophysiological molecular mechanisms to the impact of diet. Frontiers in Physiology 2019; 10: 532. [DOI:10.3389/fphys.2019.00532]
41. Sundberg C W, Fitts R H. Bioenergetic basis of skeletal muscle fatigue. Current Opinion in Physiology 2019; 10: 118-127. [DOI:10.1016/j.cophys.2019.05.004]
42. Suwa M, Nakano H, Radák Z, Kumagai S. A comparison of chronic AICAR treatment-induced metabolic adaptations in red and white muscles of rats. The Journal of Physiological Sciences 2014; 65: 121-130. [DOI:10.1007/s12576-014-0349-0]
43. Taylor E B, Lamb J D, Hurst R W, Chesser D G, Ellingson W J, Greenwood L J, et al. Endurance training increases skeletal muscle LKB1 and PGC-1alpha protein abundance: Effects of time and intensity. American Journal of Physiology-Endocrinology and Metabolism 2005; 289: 960-968. [DOI:10.1152/ajpendo.00237.2005]
44. Urwin C S, Snow R J, Condo D, Snipe R, Wadley G D, Carr A J. Factors influencing blood alkalosis and other physiological responses, gastrointestinal symptoms, and exercise performance following sodium citrate supplementation: A review. International Journal of Sport Nutrition and Exercise Metabolism 2021; 31: 168-186. [DOI:10.1123/ijsnem.2020-0192]
45. Urwin C S, Snow R J, Orellana L, Condo D, Wadley G D, Carr A J. Sodium citrate ingestion protocol impacts induced alkalosis, gastrointestinal symptoms, and palatability. Physiological Reports 2019; 7: 14216. [DOI:10.14814/phy2.14216]
46. Wu H, Deng X, Shi Y, Su Y, Wei J, Duan H. PGC-1α, glucose metabolism and type 2 diabetes mellitus. Journal of Endocrinology 2016; 229: 99-115. [DOI:10.1530/JOE-16-0021]
47. Yavari A, Javadi M, Mirmiran P, Bahadoran Z. Exercise-induced oxidative stress and dietary antioxidants. Asian Journal of Sports Medicine 2015; 6: 24898. [DOI:10.5812/asjsm.24898]
48. Zaccardi F, Webb D R, Yates T, Davies M J. Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective. Postgraduate Medical Journal 2016; 92: 63-69. [DOI:10.1136/postgradmedj-2015-133281]
49. Zhang M, Lv X-Y, Li J, Xu Z-G, Chen L. The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Journal of Diabetes Research 2008; 2008. [DOI:10.1155/2008/704045]

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.