Abstract
Purpose
Type 2 diabetes is associated with a higher risk of cardiovascular diseases, lowering the quality of life and increasing mortality rates of affected individuals. Circulating monocytes are tightly involved in the atherosclerosis process leading to cardiovascular diseases (CVD), and their inflammatory profile can be modified by exercise. The objective was to exploratory identify genes associated with CVD that could be regulated by high-intensity interval training (HIIT) in monocytes of type 2 diabetes patients.
Methods
Next-generation RNA sequencing (RNA-seq) analyses were conducted on isolated circulating monocytes (CD14+) of six women aged 60 and over with type 2 diabetes who completed a 12-week supervised HIIT intervention on a treadmill.
Results
Following the intervention, a reduction of resting diastolic blood pressure was observed. Concomitant with this result, 56 genes were found to be downregulated following HIIT intervention in isolated monocytes. A large proportion of the regulated genes was involved in cellular adhesion, migration and differentiation into an “atherosclerosis-specific” macrophage phenotype.
Conclusion
The downregulation of transcripts in monocytes globally suggests a favorable cardiovascular effect of the HIIT in older women with type 2 diabetes. In the context of precision medicine and personalized exercise prescription, shedding light on the fundamental mechanisms underlying HIIT effects on the gene profile of immune cells is essential to develop efficient nonpharmacological strategies to prevent CVD in high-risk population.
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References
Alack K, Weiss A, Kruger K, Horet M, Schermuly R, Frech T, Eggert M, Mooren FC (2020) Profiling of human lymphocytes reveals a specific network of protein kinases modulated by endurance training status. Sci Rep 10(1):888. https://doi.org/10.1038/s41598-020-57676-6
Al-Mossawi H, Yager N, Taylor CA, Lau E, Danielli S, de Wit J, Gilchrist J, Nassiri I, Mahe EA, Lee W, Rizvi L, Makino S, Cheeseman J, Neville M, Knight JC, Bowness P, Fairfax BP (2019) Context-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele. Nat Commun 10(1):4575. https://doi.org/10.1038/s41467-019-12393-1
Arslan S, Berkan O, Lalem T, Ozbilum N, Goksel S, Korkmaz O, Cetin N, Devaux Y (2017) Long non-coding RNAs in the atherosclerotic plaque. Atherosclerosis 266:176–181. https://doi.org/10.1016/j.atherosclerosis.2017.10.012
Bartlett DB, Willis LH, Slentz CA, Hoselton A, Kelly L, Huebner JL, Kraus VB, Moss J, Muehlbauer MJ, Spielmann G, Kraus WE, Lord JM, Huffman KM (2018) Ten weeks of high-intensity interval walk training is associated with reduced disease activity and improved innate immune function in older adults with rheumatoid arthritis: a pilot study. Arthritis Res Ther 20(1):127. https://doi.org/10.1186/s13075-018-1624-x
Baturcam E, Abubaker J, Tiss A, Abu-Farha M, Khadir A, Al-Ghimlas F, Al-Khairi I, Cherian P, Elkum N, Hammad M, John J, Kavalakatt S, Lehe C, Warsame S, Behbehani K, Dermime S, Dehbi M (2014) Physical exercise reduces the expression of RANTES and its CCR5 receptor in the adipose tissue of obese humans. Mediat Inflamm 2014:627150. https://doi.org/10.1155/2014/627150
Blin MG, Bachelier R, Fallague K, Moussouni K, Aurrand-Lions M, Fernandez S, Guillet B, Robert S, Foucault-Bertaud A, Bardin N, Blot-Chabaud M, Dignat-George F, Leroyer AS (2019) CD146 deficiency promotes plaque formation in a mouse model of atherosclerosis by enhancing RANTES secretion and leukocyte recruitment. J Mol Cell Cardiol 130:76–87. https://doi.org/10.1016/j.yjmcc.2019.03.017
Borrell-Pages M, Romero JC, Badimon L (2014) LRP5 negatively regulates differentiation of monocytes through abrogation of Wnt signalling. J Cell Mol Med 18(2):314–325. https://doi.org/10.1111/jcmm.12190
Chavez-Galan L, Olleros ML, Vesin D, Garcia I (2015) Much more than M1 and M2 macrophages, there are also CD169(+) and TCR(+) macrophages. Front Immunol 6:263. https://doi.org/10.3389/fimmu.2015.00263
Cornelissen VA, Smart NA (2013) Exercise training for blood pressure: a systematic review and meta-analysis. J Am Heart Assoc 2(1):e004473. https://doi.org/10.1161/JAHA.112.004473
Davis FM, Gallagher KA (2019) Epigenetic mechanisms in monocytes/macrophages regulate inflammation in cardiometabolic and vascular disease. Arterioscler Thromb Vasc Biol 39(4):623–634. https://doi.org/10.1161/ATVBAHA.118.312135
Dimitrov S, Hulteng E, Hong S (2017) Inflammation and exercise: Inhibition of monocytic intracellular TNF production by acute exercise via beta2-adrenergic activation. Brain Behav Immun 61:60–68. https://doi.org/10.1016/j.bbi.2016.12.017
Fiatal S, Adany R (2017) Application of single-nucleotide polymorphism-related risk estimates in identification of increased genetic susceptibility to cardiovascular diseases: a literature review. Front Public Health 5:358. https://doi.org/10.3389/fpubh.2017.00358
Fuchs T, Puellmann K, Emmert A, Fleig J, Oniga S, Laird R, Heida NM, Schafer K, Neumaier M, Beham AW, Kaminski WE (2015) The macrophage-TCRalphabeta is a cholesterol-responsive combinatorial immune receptor and implicated in atherosclerosis. Biochem Biophys Res Commun 456(1):59–65. https://doi.org/10.1016/j.bbrc.2014.11.034
Galvez I, Martin-Cordero L, Hinchado MD, Alvarez-Barrientos A, Ortega E (2019) Anti-inflammatory effect of beta2 adrenergic stimulation on circulating monocytes with a pro-inflammatory state in high-fat diet-induced obesity. Brain Behav Immun 80:564–572. https://doi.org/10.1016/j.bbi.2019.04.042
Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, Guo Y, Stephens R, Baseler MW, Lane HC, Lempicki RA (2007) DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res 35(Web Server issue):W169-175. https://doi.org/10.1093/nar/gkm415
Iberg-Badeaux A, Collombet S, Laurent B, van Oevelen C, Chin KK, Thieffry D, Graf T, Shi Y (2017) A transcription factor pulse can prime chromatin for heritable transcriptional memory. Mol Cell Biol. https://doi.org/10.1128/MCB.00372-16
Kita T, Kume N, Minami M, Hayashida K, Murayama T, Sano H, Moriwaki H, Kataoka H, Nishi E, Horiuchi H, Arai H, Yokode M (2001) Role of oxidized LDL in atherosclerosis. Ann N Y Acad Sci 947:199–205. https://doi.org/10.1111/j.1749-6632.2001.tb03941.x (discussion 205–196)
Kubota Y, Evenson KR, Maclehose RF, Roetker NS, Joshu CE, Folsom AR (2017) Physical activity and lifetime risk of cardiovascular disease and cancer. Med Sci Sports Exerc 49(8):1599–1605. https://doi.org/10.1249/MSS.0000000000001274
Libby P, Ridker PM, Hansson GK (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473(7347):317–325. https://doi.org/10.1038/nature10146
Lizotte F, Denhez B, Guay A, Gevry N, Cote AM, Geraldes P (2016) Persistent insulin resistance in podocytes caused by epigenetic changes of SHP-1 in diabetes. Diabetes 65(12):3705–3717. https://doi.org/10.2337/db16-0254
Marcotte-Chenard A, Tremblay D, Mony MM, Brochu M, Dionne IJ, Langlois MF, Mampuya W, Morais J, Tessier D, Riesco E (2021) Low-volume walking HIIT: efficient strategy to improve physical capacity and reduce the risk of cardiovascular disease in older women with type 2 diabetes. Diabetes Metab Syndr 15(5):102233. https://doi.org/10.1016/j.dsx.2021.102233
Marcotte-Chénard A, Tremblay D, Mony M-M, Boulay P, Brochu M, Morais J, Dionne I, Langlois M-F, Mampuya W, Tessier D, Boulé N, Riesco E (2021) Acute and chronic effects of low-volume high-intensity interval training compared to moderate-intensity continuous training on glycemic control and body composition in older women with type 2 diabetes. Obesities 1(2):72–87. https://doi.org/10.3390/Obesities1020007
Martinez-Hervas S, Sanchez-Garcia V, Herrero-Cervera A, Vinue A, Real JT, Ascaso JF, Burks DJ, Gonzalez-Navarro H (2019) Type 1 diabetic mellitus patients with increased atherosclerosis risk display decreased CDKN2A/2B/2BAS gene expression in leukocytes. J Transl Med 17(1):222. https://doi.org/10.1186/s12967-019-1977-1
Molmen-Hansen HE, Stolen T, Tjonna AE, Aamot IL, Ekeberg IS, Tyldum GA, Wisloff U, Ingul CB, Stoylen A (2012) Aerobic interval training reduces blood pressure and improves myocardial function in hypertensive patients. Eur J Prev Cardiol 19(2):151–160. https://doi.org/10.1177/1741826711400512
Muniyappa R, Sowers JR (2013) Role of insulin resistance in endothelial dysfunction. Rev Endocr Metab Disord 14(1):5–12. https://doi.org/10.1007/s11154-012-9229-1
Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377(12):1119–1131. https://doi.org/10.1056/NEJMoa1707914
Roberto Carlos B, Elizabeth A, Durstine JL, James AC (2020) Inflammation, physical activity, and chronic disease: an evolutionary perspective. Sports Med Health Sci 2(1):1–6. https://doi.org/10.1016/j.smhs.2020.03.004
Rodriguez-Iturbe B, Pons H, Johnson RJ (2017) Role of the immune system in hypertension. Physiol Rev 97(3):1127–1164. https://doi.org/10.1152/physrev.00031.2016
Ross LM, Porter RR, Durstine JL (2016) High-intensity interval training (HIIT) for patients with chronic diseases. J Sport Health Sci 5(2):139–144. https://doi.org/10.1016/j.jshs.2016.04.005
Rudemiller N, Lund H, Jacob HJ, Geurts AM, Mattson DL (2014) CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. Hypertension 63(3):559–564. https://doi.org/10.1161/HYPERTENSIONAHA.113.02191
Sakharov DA, Maltseva DV, Riabenko EA, Shkurnikov MU, Northoff H, Tonevitsky AG, Grigoriev AI (2012) Passing the anaerobic threshold is associated with substantial changes in the gene expression profile in white blood cells. Eur J Appl Physiol 112(3):963–972. https://doi.org/10.1007/s00421-011-2048-3
Schjerve IE, Tyldum GA, Tjonna AE, Stolen T, Loennechen JP, Hansen HE, Haram PM, Heinrich G, Bye A, Najjar SM, Smith GL, Slordahl SA, Kemi OJ, Wisloff U (2008) Both aerobic endurance and strength training programmes improve cardiovascular health in obese adults. Clin Sci (lond) 115(9):283–293. https://doi.org/10.1042/CS20070332
Shalev V, Chodick G, Heymann AD, Kokia E (2005) Gender differences in healthcare utilization and medical indicators among patients with diabetes. Public Health 119(1):45–49. https://doi.org/10.1016/j.puhe.2004.03.004
Sievenpiper JL, Chan CB, Dworatzek PD, Freeze C, Williams SL (2018) Nutrition therapy. Can J Diabetes 42(Suppl 1):S64–S79. https://doi.org/10.1016/j.jcjd.2017.10.009
Sigal RJ, Armstrong MJ, Bacon SL, Boule NG, Dasgupta K, Kenny GP, Riddell MC (2018) Physical activity and diabetes. Can J Diabetes 42(Suppl 1):S54–S63. https://doi.org/10.1016/j.jcjd.2017.10.008
Sun C, Huang L, Li Z, Leng K, Xu Y, Jiang X, Cui Y (2018) Long non-coding RNA MIAT in development and disease: a new player in an old game. J Biomed Sci 25(1):23. https://doi.org/10.1186/s12929-018-0427-3
Terada T, Wilson BJ, Myette-Cote E, Kuzik N, Bell GJ, McCargar LJ, Boule NG (2016) Targeting specific interstitial glycemic parameters with high-intensity interval exercise and fasted-state exercise in type 2 diabetes. Metab Clin Exp 65(5):599–608. https://doi.org/10.1016/j.metabol.2016.01.003
Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M (2016) Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J 37(42):3232–3245. https://doi.org/10.1093/eurheartj/ehw334
Trikkalinou A, Papazafiropoulou AK, Melidonis A (2017) Type 2 diabetes and quality of life. World J Diabetes 8(4):120–129. https://doi.org/10.4239/wjd.v8.i4.120
Van Craenenbroeck AH, Van Ackeren K, Hoymans VY, Roeykens J, Verpooten GA, Vrints CJ, Couttenye MM, Van Craenenbroeck EM (2014) Acute exercise-induced response of monocyte subtypes in chronic heart and renal failure. Mediators Inflamm 2014:216534. https://doi.org/10.1155/2014/216534
Vinu EA, MartInez-Hervas S, Herrero-Cervera A, Ánchez-García VS, Andres-Blasco I, Piqueras L, Sanz MJ, Real JT, Ascaso JF, Burks DJ, Gonzalez-Navarro H (2019) Changes in CDKN2A/2B expression associate with T-cell phenotype modulation in atherosclerosis and type 2 diabetes mellitus. Transl Res 203:31–48. https://doi.org/10.1016/j.trsl.2018.08.003
Wang D, Cai F, Ge J, Yin L (2015) Brief exercises affect gene expression in circulating monocytes. Scand J Immunol 82(5):429–435. https://doi.org/10.1111/sji.12345
Wenzel P (2019) Monocytes as immune targets in arterial hypertension. Br J Pharmacol 176(12):1966–1977. https://doi.org/10.1111/bph.14389
Winding KM, Munch GW, Iepsen UW, Van Hall G, Pedersen BK, Mortensen SP (2018) The effect on glycaemic control of low-volume high-intensity interval training versus endurance training in individuals with type 2 diabetes. Diabetes Obes Metab 20(5):1131–1139. https://doi.org/10.1111/dom.13198
Zhong X, Ma X, Zhang L, Li Y, Li Y, He R (2018) MIAT promotes proliferation and hinders apoptosis by modulating miR-181b/STAT3 axis in ox-LDL-induced atherosclerosis cell models. Biomed Pharmacother 97:1078–1085. https://doi.org/10.1016/j.biopha.2017.11.052
Funding
This work was supported by grants from the Canadian Institute of Health Research (CIHR) [PTJ159627 to P.G.]. This work was performed at the CHUS research center and at the research Center on Aging (CdRV). It was funded by the “Fonds de Recherche du Québec-Santé” (FRQ-S), CEUS-DOCC, the Quebec Network for Research on Aging and the Faculty of Physical Activity Sciences of the University of Sherbrooke. P Geraldes is the holder of the Canada Research Chair in Vascular Complication of Diabetes. A. Marcotte-Chénard and D. Tremblay are supported by FRQ-S and by the CIHR.
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DT, AM-C and FL performed experiments. JHM, DT, AM-C, FL, MAB, BL, ER and PG analyzed the data. JHM, ER and PG wrote the manuscript. MAB, BL and ER reviewed the manuscript and provided comments.
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Communicated by Fabio Fischetti.
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Hamelin Morrissette, J., Tremblay, D., Marcotte-Chénard, A. et al. Transcriptomic modulation in response to high-intensity interval training in monocytes of older women with type 2 diabetes. Eur J Appl Physiol 122, 1085–1095 (2022). https://doi.org/10.1007/s00421-022-04911-9
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DOI: https://doi.org/10.1007/s00421-022-04911-9