Research in Sports Medicine and Technology

The effect of a period of high intensity interval maternal exercise training on expression of PGC1α and SIRT1 of skeletal muscle in offspring male rats

Articles in Press

Authors

hadi habibi 1
Ali Asghar Ravasi 2
neda khaledi 1

1 kharazmi university

2 Tehran university

Abstract
The impact of maternal physical activity on offspring health and phenotypic changes due to exercise has emerged as a significant area of interest in exercise physiology in recent years. Therefore, the aim of this study was to determine the effect of a maternal high-intensity interval training (HIIT) program on the expression of PGC1α and SIRT1 genes in the skeletal muscle of first-generation offspring in Wistar rats. Twenty-four 8-week-old female Wistar rats were acclimatized to the environment and then divided into three groups: a maternal control group, a maternal pre-pregnancy exercise group, and a maternal exercise group that trained both before and during pregnancy. The pre-pregnancy exercise regimen lasted 6 weeks, while the exercise during pregnancy lasted 3 weeks. The exercise protocol involved treadmill running, consisting of 5 days per week, with each session including 1 minute of running at 85-100% of VO2peak and a 10% incline, followed by 2 minutes of rest at 65% of VO2peak and 0% incline. The number of intervals started at 10 and increased based on the overload principle. The control group remained sedentary during this period. After the exercise period and the birth of the offspring, male offspring were categorized according to their maternal groups, and the expression levels of PGC1α and SIRT1 genes in their skeletal muscle were evaluated at 10 weeks of age. Data were analyzed using ANOVA and Tukey's post-hoc test.

The results indicated that after the 6-week HIIT program, both the pre-pregnancy exercise group and the group that exercised before and during pregnancy showed significant differences in speed and distance in the functional performance test compared to the control group (P < 0.05). Additionally, significant differences were observed in the expression of PGC1α and SIRT1 genes among the groups after the birth of the offspring. These differences were significant between the pre-pregnancy exercise group, the pre- and during-pregnancy exercise group, and the control group (P < 0.05). It appears that maternal exercise before and during pregnancy induces changes in the mitochondrial genotype of the offspring, with a more pronounced effect on the expression of mitochondrial genes such as PGC1α and SIRT1 when exercise occurs both before and during pregnancy compared to exercise before pregnancy alone.

Keywords

High-intensity interval training
maternal exercise
mitochondria
epigenetics
SIRT1
PGC-1α
1. Borodulin K, Evenson KR, Wen F, Herring AH, Benson A. Physical activity patterns during pregnancy. Medicine and science in sports and exercise. 2008;40(11):1901. doi: 10.1249/MSS.0b013e31817f1957
2. Domenjoz I, Kayser B, Boulvain M. Effect of physical activity during pregnancy on mode of delivery. American journal of obstetrics and gynecology. 2014;211(4):401. e1-. e11. https://doi.org/10.1016/j.ajog.2014.03.030
3. Jevtovic F, May L. Influence of maternal exercise on maternal and offspring metabolic outcomes. Maternal and child health: IntechOpen; 2022. DOI: 10.5772/intechopen.106566
4. Pinckard KM, Félix-Soriano E, Hamilton S, Terentyeva R, Baer LA, Wright KR, et al. Maternal exercise preserves offspring cardiovascular health via oxidative regulation of the ryanodine receptor. Molecular Metabolism. 2024;82:101914. https://doi.org/10.1016/j.molmet.2024.101914
5. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell. 2006;127(6):1109-22. DOI: 10.1016/j.cell.2006.11.013
6. Mohammadkhani R, Khaledi N, Rajabi H, Komaki A, Salehi I. The Influence of Maternal High Intensity Interval Training before and during Pregnancy on the Heart Genes of Adult Female Wistar Offspring. 2023.
7. Maghbooli Z, Emamgholipour S, Aliakbar S, Amini M, Gorgani-Firuzjaee S, Hossein-Nezhad A. Differential expressions of SIRT1, SIRT3, and SIRT4 in peripheral blood mononuclear cells from patients with type 2 diabetic retinopathy. Archives of Physiology and Biochemistry. 2020;126(4):363-8. https://doi.org/10.1080/13813455.2018.1543328
8. Rasmussen L, Knorr S, Antoniussen CS, Bruun JM, Ovesen PG, Fuglsang J, et al. The impact of lifestyle, diet and physical activity on epigenetic changes in the offspring—A systematic review. Nutrients. 2021;13(8):2821. https://doi.org/10.3390/nu13082821
9. Zhang L, Lu Q, Chang C. Epigenetics in health and disease. Epigenetics in allergy and autoimmunity. 2020:3-55. https://doi.org/10.1007/978-981-15-3449-2_1
10. Gibala MJ. Physiological adaptations to low-volume high-intensity interval training. Sports Science Exchange. 2015;28(139):1-6. https://doi.org/10.1113/jphysiol.2011.224725
11. Ahmadi A, Rajabi H, Baker J. High-intensity interval training improves fat oxidation during submaximal exercise in active young men. Comparative Exercise Physiology. 2022;18(3):229-38. https://doi.org/10.3920/CEP210028
12. Axsom JE, Libonati JR. Impact of parental exercise on epigenetic modifications inherited by offspring: A systematic review. Physiol Rep. 2019;7(22):e14287. https://doi.org/10.14814/phy2.14287
13. Laker RC, Lillard TS, Okutsu M, Zhang M, Hoehn KL, Connelly JJ, et al. Exercise prevents maternal high-fat diet–induced hypermethylation of the Pgc-1α gene and age-dependent metabolic dysfunction in the offspring. Diabetes. 2014;63(5):1605-11. https://doi.org/10.2337/db13-1614
14. Panagiotidou A, Chatzakis C, Ververi A, Eleftheriades M, Sotiriadis A. The Effect of Maternal Diet and Physical Activity on the Epigenome of the Offspring. Genes. 2024;15(1):76. https://doi.org/10.3390/genes15010076
15. Heiat F, Ghanbarzadeh M, Shojaeifard M, Ranjbar R. The effect of high-intensity interval training on the expression levels of PGC-1α and SIRT3 proteins and aging index of slow-twitch and fast-twitch of healthy male rats. Science & Sports. 2021;36(2):170-5. https://doi.org/10.1016/j.scispo.2020.06.002
16. Bishop DJ, Botella J, Genders AJ, Lee MJ, Saner NJ, Kuang J, et al. High-intensity exercise and mitochondrial biogenesis: current controversies and future research directions. Physiology. 2019;34(1):56-70. https://doi.org/10.1152/physiol.00038.2018
17. Geng T, Li P, Okutsu M, Yin X, Kwek J, Zhang M, et al. PGC-1α plays a functional role in exercise-induced mitochondrial biogenesis and angiogenesis but not fiber-type transformation in mouse skeletal muscle. American Journal of Physiology-Cell Physiology. 2010;298(3):C572-C9. https://doi.org/10.1152/ajpcell.00481.2009
18. Christiansen D, Murphy RM, Bangsbo J, Stathis CG, Bishop DJ. Increased FXYD1 and PGC‐1α mRNA after blood flow‐restricted running is related to fibre type‐specific AMPK signalling and oxidative stress in human muscle. Acta physiologica. 2018;223(2):e13045. https://doi.org/10.1111/apha.13045
19. Little JP, Safdar A, Bishop D, Tarnopolsky MA, Gibala MJ. An acute bout of high-intensity interval training increases the nuclear abundance of PGC-1α and activates mitochondrial biogenesis in human skeletal muscle. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2011. https://doi.org/10.1152/ajpregu.00538.2010
20. Lochmann TL, Thomas RR, Bennett JP, Jr., Taylor SM. Epigenetic Modifications of the PGC-1α Promoter during Exercise Induced Expression in Mice. PLOS ONE. 2015;10(6):e0129647. https://doi.org/10.1371/journal.pone.0129647
21. Juan CG, Matchett KB, Davison GW. A systematic review and meta-analysis of the SIRT1 response to exercise. Scientific Reports. 2023;13(1):14752. https://doi.org/10.1038/s41598-023-38843-x
22. Bakhtiyari A, Gaeni A, Chobineh S, Kordi MR, Hedayati M. Effect of 12-weeks high-intensity interval training on SIRT1, PGC-1α and ERRα protein expression in aged rats. Journal of Applied Health Studies in Sport Physiology. 2018;5(2):95-102. 10.22049/jassp.2019.26555.1223
23. Barres R, Yan J, Egan B, Treebak JT, Rasmussen M, Fritz T, et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell metabolism. 2012;15(3):405-11. DOI: 10.1016/j.cmet.2012.01.001
24. Kanzleiter T, Jähnert M, Schulze G, Selbig J, Hallahan N, Schwenk RW, et al. Exercise training alters DNA methylation patterns in genes related to muscle growth and differentiation in mice. American Journal of Physiology-Endocrinology and Metabolism. 2015;308(10):E912-E20. https://doi.org/10.1152/ajpendo.00289.2014
25. Høydal M, Kaurstad G, Rolim NP, Johnsen AB, Alves M, Koch LG, et al. High inborn aerobic capacity does not protect the heart following myocardial infarction. Journal of Applied Physiology. 2013;115(12):1788-95. https://doi.org/10.1152/japplphysiol.00312.2013
26. Freitas DA, Soares BA, Nonato LF, Fonseca SR, Martins JB, Mendonça VA, et al. High intensity interval training modulates hippocampal oxidative stress, BDNF and inflammatory mediators in rats. Physiology & behavior. 2018;184:6-11. https://doi.org/10.1016/j.physbeh.2017.10.027
27. Mohammadkhani R, Khaledi N, Rajabi H, Salehi I, Komaki A. Influence of the maternal high-intensity-interval-training on the cardiac Sirt6 and lipid profile of the adult male offspring in rats. PloS one. 2020;15(8):e0237148.
28. Mohammadkhani R, Komaki A, Karimi SA, Behzad M, Heidarisasan S, Salehi I. Maternal high-intensity interval training as a suitable approach for offspring's heart protection in rat: evidence from oxidative stress and mitochondrial genes. Front Physiol. 2023;14:1117666. https://doi.org/10.1371/journal.pone.0237148
29. Son JS, Zhao L, Chen Y, Chen K, Chae SA, de Avila JM, et al. Maternal exercise via exerkine apelin enhances brown adipogenesis and prevents metabolic dysfunction in offspring mice. Science advances. 2020;6(16):eaaz0359. DOI: 10.1126/sciadv.aaz035
30. Park J-w, Kim M-H, Eo S-J, Lee E-H, Kang J-S, Chang H-K, et al. Maternal exercise during pregnancy affects mitochondrial enzymatic activity and biogenesis in offspring brain. International Journal of Neuroscience. 2013;123(4):253-64. https://doi.org/10.3109/00207454.2012.755969
31. Lochmann TL, Thomas RR, Bennett Jr JP, Taylor SM. Epigenetic modifications of the PGC-1α promoter during exercise induced expression in mice. PLoS One. 2015;10(6):e0129647. https://doi.org/10.1371/journal.pone.0129647
32. Chung E, Joiner HE, Skelton T, Looten KD, Manczak M, Reddy PH. Maternal exercise upregulates mitochondrial gene expression and increases enzyme activity of fetal mouse hearts. Physiological reports. 2017;5(5):e13184. https://doi.org/10.14814/phy2.13184
33. Stanford KI, Takahashi H, So K, Alves-Wagner AB, Prince NB, Lehnig AC, et al. Maternal exercise improves glucose tolerance in female offspring. Diabetes. 2017;66(8):2124-36. https://doi.org/10.2337/db17-0098
34. Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders—A step towards mitochondria based therapeutic strategies. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2017;1863(5):1066-77. https://doi.org/10.1016/j.bbadis.2016.11.010
35. Cobley JN, Bartlett JD, Kayani A, Murray SW, Louhelainen J, Donovan T, et al. PGC-1alpha transcriptional response and mitochondrial adaptation to acute exercise is maintained in skeletal muscle of sedentary elderly males. Biogerontology. 2012;13(6):621-31. https://doi.org/10.1007/s10522-012-9408-1
36. Derbre F, Ferrando B, Gomez-Cabrera MC, Sanchis-Gomar F, Martinez-Bello VE, Olaso-Gonzalez G, et al. Inhibition of xanthine oxidase by allopurinol prevents skeletal muscle atrophy: role of p38 MAPKinase and E3 ubiquitin ligases. PLoS One. 2012;7(10):e46668. https://doi.org/10.1371/journal.pone.0046668
37. Kasper P, Breuer S, Hoffmann T, Vohlen C, Janoschek R, Schmitz L, et al. Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers. Cells. 2021;10(5):1247. https://doi.org/10.3390/cells10051247
38. Shan M, Qiu F, Li P, Zhang Y, Shi L. Maternal exercise represses FGF21 via SIRT1 to improve the phenotypic transformation of vascular smooth muscle in hypertensive offspring. Hypertens Res. 2025;48(1):353-65. https://doi.org/10.1038/s41440-024-01991-2
39. Zhang Y, Shan M, Ding X, Sun H, Qiu F, Shi L. Maternal exercise represses Nox4 via SIRT1 to prevent vascular oxidative stress and endothelial dysfunction in SHR offspring. Front Endocrinol (Lausanne). 2023;14:1219194. https://doi.org/10.3389/fendo.2023.1219194
40. Hardie DG. AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function. Genes & development. 2011;25(18):1895-908. doi:10.1101/gad.17420111
41. Hinchy EC, Gruszczyk AV, Willows R, Navaratnam N, Hall AR, Bates G, et al. Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly. Journal of Biological Chemistry. 2018;293(44):17208-17. DOI: 10.1074/jbc.RA118.002579
42. McGee SL, Hargreaves M. Epigenetics and exercise. Trends in Endocrinology & Metabolism. 2019;30(9):636-45. DOI: 10.1016/j.tem.2019.06.002
Research in Sports Medicine and Technology

Articles in Press, Accepted Manuscript
Available Online from 23 October 2019