Time-dependent Effects of Moderate- and High-intensity Exercises on Myocardial Transcriptomics

Abstract

The heart is a highly adaptable organ that responds to changes in functional requirements due to exposure to internal and external stimuli. Physical exercise has unique stimulatory effects on the myocardium in both healthy individuals and those with health disorders, where the effects are primarily determined by the intensity and recovery time of exercise. We investigated the time-dependent effects of different exercise intensities on myocardial transcriptional expression in rats. Moderate intensity exercise induced more differentially expressed genes in the myocardium than high intensity exercise, while 16 differentially expressed genes were down-regulated by moderate intensity exercise but up-regulated by high intensity exercise at 12 h post- exercise. Both Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis indicated that moderate intensity exercise specifically regulated gene expression related to heart adaptation, energy metabolism, and oxidative stress, while high intensity exercise specifically regulated gene expression related to immunity, inflammation, and apoptosis. Moreover, there was increased expression of Tbx5, Casq1, Igsf1, and Ddah1 at all time points after moderate intensity exercise, while there was increased expression of Card9 at all time points after high intensity exercise. Our study provides a better understanding of the intensity dependent effects of physical exercise of the molecular mechanisms of cardiac adaptation to physical exercise.

Key words

moderate-intensity exercise - high-intensity exercise - transcriptomics - differentially expressed genes - myocardium

• References

• 1 Burtscher M. The bi- (or multi-) phasic response of cardiac remodelling to endurance exercise related to the article: 'From talented child to elite athlete: The development of cardiac morphology and function in a cohort of endurance athletes from age 12 to 18' by Bjerring and colleagues. Eur J Prev Cardiol 2020;
• 2 Mitchell JH. How to recognize 'athlete's heart'. Phys Sportsmed 1992; 20: 86-96
• 3 D'Andrea A, Formisano T, Riegler L. et al. Acute and chronic response to exercise in athletes: the “supernormal heart”. Adv Exp Med Biol 2017; 999: 21-41
• 4 Vettor R, Valerio A, Ragni M. et al. Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism. Am J Physiol Endocrinol Metab 2014; 306: E519-E528
• 5 Dopheide JF, Geissler P, Rubrech J. et al. Influence of exercise training on proangiogenic TIE-2 monocytes and circulating angiogenic cells in patients with peripheral arterial disease. Clin Res Cardiol 2016; 105: 666-676
• 6 Koppe-Schmeißer F, Schwaderlapp M, Schmeißer J. et al. Influence of peripheral transluminal angioplasty alongside exercise training on oxidative stress and inflammation in patients with peripheral arterial disease. J Clin Med 2021; 10: 5851
• 7 Li S, Liang M, Pan Y. et al. Exercise modulates heat shock protein 27 activity in diabetic cardiomyopathy. Life Sci 2020; 243: 117251
• 8 Li S, Liang M, Gao D. et al. Changes in titin and collagen modulate effects of aerobic and resistance exercise on diabetic cardiac function. J Cardiovasc Transl Res 2019; 12: 404-414
• 9 Dangardt FJ, McKenna WJ, Lüscher TF. et al. Exercise: friend or foe. Nat Rev Cardiol 2013; 10: 495-507
• 10 Li S, Laher I. Rethinking “Exercise is Medicine”. EXCLI J 2020; 19: 1169-1171
• 11 Yang YJ. An overview of current physical activity recommendations in primary care. Korean J Fam Med 2019; 40: 135-142
• 12 Cao M, Tang Y, Li S. et al. Effects of high-intensity interval training and moderate-intensity continuous training on cardiometabolic risk factors in overweight and obesity children and adolescents: a meta-analysis of randomized controlled trials. Int J Environ Res Public Health 2021; 18: 11905
• 13 Rugbeer N, Constantinou D, Torres G. Comparison of high-intensity training versus moderate-intensity continuous training on cardiorespiratory fitness and body fat percentage in persons with overweight or obesity: a systematic review and meta-analysis of randomized controlled trials. J Phys Act Health 2021; 18: 610-623
• 14 Muise ES, Guan HP, Liu J. et al. Pharmacological AMPK activation induces transcriptional responses congruent to exercise in skeletal and cardiac muscle, adipose tissues and liver. PLoS One 2019; 14: e0211568
• 15 Gomes C, Almeida JA, Franco OL. et al. Omics and the molecular exercise physiology. Adv Clin Chem 2020; 96: 55-84
• 16 Contrepois K, Wu S, Moneghetti KJ. et al. Molecular choreography of acute exercise. Cell 2020; 181: 1112-1130.e1116
• 17 Bonafiglia JT, Menzies KJ, Gurd BJ. Gene expression variability in human skeletal muscle transcriptome responses to acute resistance exercise. Exp Physiol 2019; 104: 625-629
• 18 Melouane A, Ghanemi A, Aubé S. et al. Differential gene expression analysis in ageing muscle and drug discovery perspectives. Ageing Res Rev 2018; 41: 53-63
• 19 Ropka-Molik K, Stefaniuk-Szmukier M, ZU K. et al. Exercise-induced modification of the skeletal muscle transcriptome in Arabian horses. Physiol Genomics 2017; 49: 318-326
• 20 Bryan K, McGivney BA, Farries G. et al. Equine skeletal muscle adaptations to exercise and training: evidence of differential regulation of autophagosomal and mitochondrial components. BMC Genomics 2017; 18: 595
• 21 Laughlin MH, Padilla J, Jenkins NT. et al. Exercise-induced differential changes in gene expression among arterioles of skeletal muscles of obese rats. J Appl Physiol (1985) 2015; 119: 583-603
• 22 Kim KH, Kim HM. Differential transcriptome profile and exercise capacity in cardiac remodeling by pressure overload versus volume overload. J Cardiovasc Imaging 2019; 27: 50-63
• 23 Benito B, Gay-Jordi G, Serrano-Mollar A. et al. Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation 2011; 123: 13-22
• 24 Bedford TG, Tipton CM, Wilson NC. et al. Maximum oxygen consumption of rats and its changes with various experimental procedures. J Appl Physiol Respir Environ Exerc Physiol 1979; 47: 1278-1283
• 25 Li S, Wang M, Ma J. et al. MOTS-c and Exercise Restore Cardiac Function by Activating of NRG1-ErbB Signaling in Diabetic Rats. Front Endocrinol (Lausanne) 2022; 13: 812032
• 26 Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 2010; 26: 139-140
• 27 Yu G, Wang LG, Han Y. et al. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 2012; 16: 284-287
• 28 Dickinson JM, D'Lugos AC. Transcriptome response of human skeletal muscle to divergent exercise stimuli. J Appl Physiol (1985) 2018; 124: 1529-1540
• 29 Hatcher CJ, Kim MS, Mah CS. et al. TBX5 transcription factor regulates cell proliferation during cardiogenesis. Dev Biol 2001; 230: 177-188
• 30 Tani H, Sadahiro T, Ieda M. Direct cardiac reprogramming: a novel approach for heart regeneration. Int J Mol Sci 2018; 19: 2629
• 31 Volpe P, Martini A, Furlan S. et al. Calsequestrin is a component of smooth muscles: the skeletal- and cardiac-muscle isoforms are both present, although in highly variable amounts and ratios. Biochem J 1994; 301: 465-469
• 32 Carneiro-Júnior MA, Quintão-Júnior JF, Drummond LR. et al. Effect of exercise training on Ca²+ release units of left ventricular myocytes of spontaneously hypertensive rats. Braz J Med Biol Res 2014; 47: 960-965
• 33 Bonilla IM, Belevych AE, Sridhar A. et al. Endurance exercise training normalizes repolarization and calcium-handling abnormalities, preventing ventricular fibrillation in a model of sudden cardiac death. J Appl Physiol (1985) 2012; 113: 1772-1783
• 34 Frattini A, Faranda S, Redolfi E. et al. Identification and genomic organization of a gene coding for a new member of the cell adhesion molecule family mapping to Xq25. Gene 1998; 214: 1-6
• 35 Joustra SD, Meijer OC, Heinen CA. et al. Spatial and temporal expression of immunoglobulin superfamily member 1 in the rat. J Endocrinol 2015; 226: 181-191
• 36 Kostourou V, Robinson SP, Cartwright JE. et al. Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis. Br J Cancer 2002; 87: 673-680
• 37 Chen Y, Li Y, Zhang P. et al. Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing hearts. Am J Physiol Heart Circ Physiol 2005; 289: H2212-H2219
• 38 Sun GC, Wong TY, Chen HH. et al. Angiotensin II inhibits DDAH1-nNOS signaling via AT1R and μOR dimerization to modulate blood pressure control in the central nervous system. Clin Sci (Lond) 2019; 133: 2401-2413
• 39 Xu X, Zhang P, Kwak D. et al. Cardiomyocyte dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays an important role in attenuating ventricular hypertrophy and dysfunction. Basic Res Cardiol 2017; 112: 55
• 40 Zang MX, Li Y, Xue LX. et al. Cooperative activation of atrial naturetic peptide promoter by dHAND and MEF2C. J Cell Biochem 2004; 93: 1255-1266
• 41 Sun L, Yu J, Qi S. et al. Bone morphogenetic protein-10 induces cardiomyocyte proliferation and improves cardiac function after myocardial infarction. J Cell Biochem 2014; 115: 1868-1876
• 42 Li F, Xia K, Sheikh SA. et al. Involvement of RBP4 in hyperinsulinism-induced vascular smooth muscle cell proliferation. Endocrine 2015; 48: 472-482
• 43 Cao L, Qin X, Peterson MR. et al. CARD9 knockout ameliorates myocardial dysfunction associated with high fat diet-induced obesity. J Mol Cell Cardiol 2016; 92: 185-195
• 44 Qin X, Peterson MR, Haller SE. et al. Caspase recruitment domain-containing protein 9 (CARD9) knockout reduces regional ischemia/reperfusion injury through an attenuated inflammatory response. PLoS One 2018; 13: e0199711
• 45 Peterson MR, Haller SE, Ren J. et al. CARD9 as a potential target in cardiovascular disease. Drug Des Devel Ther 2016; 10: 3799-3804
• 46 Peterson JM, Trappe TA, Mylona E. et al. Ibuprofen and acetaminophen: effect on muscle inflammation after eccentric exercise. Med Sci Sports Exerc 2003; 35: 892-896
• 47 Raveendran VV, Al-Haffar K, Kunhi M. et al. Protein arginine methyltransferase 6 mediates cardiac hypertrophy by differential regulation of histone H3 arginine methylation. Heliyon 2020; 6: e03864
• 48 Hsu SF, Chao CM, Chang CP. et al. Heat shock protein 72 may improve hypotension by increasing cardiac mechanical efficiency and arterial elastance in heatstroke rats. Int J Cardiol 2016; 219: 63-69
• 49 Ohno Y, Yamada S, Sugiura T. et al. A possible role of NF-kappaB and HSP72 in skeletal muscle hypertrophy induced by heat stress in rats. Gen Physiol Biophys 2010; 29: 234-242
• 50 Liu W, Kuang H, Xia Y. et al. Regular aerobic exercise-ameliorated troponin I carbonylation to mitigate aged rat soleus muscle functional recession. Exp Physiol 2019; 104: 715-728
• 51 Peng W, Li M, Li H. et al. Dysfunction of myosin light-chain 4 (myl4) leads to heritable atrial cardiomyopathy with electrical, contractile, and structural components: evidence from genetically-engineered rats. J Am Heart Assoc 2017; 6: e007030
• 52 Yerra VG, Batchu SN, Kabir G. et al. Empagliflozin disrupts a tnfrsf12a-mediated feed forward loop that promotes left ventricular hypertrophy. Cardiovasc Drugs Ther 2022; 36: 619-632
• 53 Shah H, Hacker A, Langburt D. et al. Myocardial infarction induces cardiac fibroblast transformation within injured and noninjured regions of the mouse heart. J Proteome Res 2021; 20: 2867-2881
• 54 Li W, Park H, Guo E. et al. Aerobic exercise training inhibits neointimal formation via reduction of PCSK9 and LOX-1 in atherosclerosis. Biomedicines 2020; 8: 92
• 55 Srikanth K, Kumar H, Park W. et al. Cardiac and skeletal muscle transcriptome response to heat stress in kenyan chicken ecotypes adapted to low and high altitudes reveal differences in thermal tolerance and stress response. Front Genet 2019; 10: 993
• 56 Pattamaprapanont P, Garde C, Fabre O. et al. Muscle contraction induces acute hydroxymethylation of the exercise-responsive gene Nr4a3. Front Endocrinol (Lausanne) 2016; 7: 165
• 57 Solskov L, Magnusson NE, Kristiansen SB. et al. Microarray expression analysis in delayed cardioprotection: the effect of exercise, AICAR, or metformin and the possible role of AMP-activated protein kinase (AMPK). Mol Cell Biochem 2012; 360: 353-362
• 58 Kawasaki E, Hokari F, Sasaki M. et al. The effects of β-adrenergic stimulation and exercise on NR4A3 protein expression in rat skeletal muscle. J Physiol Sci 2011; 61: 1-11
• 59 Pillon NJ, Gabriel BM. Transcriptomic profiling of skeletal muscle adaptations to exercise and inactivity. Nat Commun 2020; 11: 470
• 60 Pearen MA, Goode JM, Fitzsimmons RL. et al. Transgenic muscle-specific Nor-1 expression regulates multiple pathways that effect adiposity, metabolism, and endurance. Mol Endocrinol 2013; 27: 1897-1917
• 61 Pearen MA, Eriksson NA, Fitzsimmons RL. et al. The nuclear receptor, Nor-1, markedly increases type II oxidative muscle fibers and resistance to fatigue. Mol Endocrinol 2012; 26: 372-384
• 62 Avery J, Etzion S, DeBosch BJ. et al. TRB3 function in cardiac endoplasmic reticulum stress. Circ Res 2010; 106: 1516-1523
• 63 Siltanen A, Nuutila K, Imanishi Y. et al. The paracrine effect of skeletal myoblasts is cardioprotective against oxidative stress and involves EGFR-ErbB4 signaling, cystathionase, and the unfolded protein response. Cell Transplant 2016; 25: 55-69
• 64 Yaghoob Nezhad F, Verbrugge SAJ, Schönfelder M. et al. Genes whose gain or loss-of-function increases endurance performance in mice: a systematic literature review. Front Physiol 2019; 10: 262
• 65 Luo W, Zhou Y, Tang Q. et al. Modulation of TRIB3 and macrophage phenotype to attenuate insulin resistance after downhill running in mice. Front Physiol 2021; 12: 637432
• 66 Suzuki N, Ando S, Sumida K. et al. Analysis of altered gene expression specific to embryotoxic chemical treatment during embryonic stem cell differentiation into myocardiac and neural cells. J Toxicol Sci 2011; 36: 569-585
• 67 Lattanzio FA, Tiangco D, Osgood C. et al. Cocaine increases intracellular calcium and reactive oxygen species, depolarizes mitochondria, and activates genes associated with heart failure and remodeling. Cardiovasc Toxicol 2005; 5: 377-390
• 68 Ma F, Li W, Tang R. et al. Long non-coding rna expression profiling in obesity mice with folic acid supplement. Cell Physiol Biochem 2017; 42: 416-426
• 69 Helenius M, Hänninen M, Lehtinen SK. et al. Changes associated with aging and replicative senescence in the regulation of transcription factor nuclear factor-kappa B. Biochem J 1996; 318: 603-608
• 70 Niu X, Zhang J, Zhang L. et al. Weighted gene co-expression network analysis identifies critical genes in the development of heart failure after acute myocardial infarction. Front Genet 2019; 10: 1214
• 71 Prasongsukarn K, Dechkhajorn W, Benjathummarak S. et al. TRPM2, PDLIM5, BCL3, CD14, GBA genes as feasible markers for premature coronary heart disease risk. Front Genet 2021; 12: 598296
• 72 Ye H, Zhao Q, Huang Y. et al. Meta-analysis of low density lipoprotein receptor (LDLR) rs2228671 polymorphism and coronary heart disease. Biomed Res Int 2014; 2014: 564940
• 73 Patel M, Rodriguez D, Yousefi K. et al. Osteopontin and LDLR are upregulated in hearts of sudden cardiac death victims with heart failure with preserved ejection fraction and diabetes mellitus. Front Cardiovasc Med 2020; 7: 610282
• 74 Zhao P, Wang Y, Zhang L. et al. Mechanism of long non‑coding RNA metastasis‑associated lung adenocarcinoma transcript 1 in lipid metabolism and inflammation in heart failure. Int J Mol Med 2021; 47: 5
• 75 Hemnes AR, Luther JM, Rhodes CJ. et al. Human PAH is characterized by a pattern of lipid-related insulin resistance. JCI Insight 2019; 4: e123611
• 76 Zhao J, Song Y, Zeng Y. et al. Improvement of hyperlipidemia by aerobic exercise in mice through a regulatory effect of miR-21a-5p on its target genes. Sci Rep 2021; 11: 11966
• 77 Huo M, Wang Z, Wu D. et al. Using coexpression protein interaction network analysis to identify mechanisms of danshensu affecting patients with coronary heart disease.. Int J Mol Sci 2017; 18: 1298