Top

Journal of Cardiovascular Translational Research

Published in:

01-10-2019 | Original Article

Changes in Titin and Collagen Modulate Effects of Aerobic and Resistance Exercise on Diabetic Cardiac Function

Authors: Shunchang Li, Min Liang, Derun Gao, Quansheng Su, Ismail Laher

Published in: Journal of Cardiovascular Translational Research | Issue 5/2019

Abstract

Diastolic dysfunction is a common complication that occurs early in diabetes mellitus. Titin and collagen are two important regulators of myocardial passive tension, which contributes to diabetic myocardial diastolic dysfunction. Exercise therapy significantly improves the impaired diabetic cardiac function, but its benefits appear to depend on the type of exercise used. We investigated the effect of aerobic and resistance exercise on cardiac diastolic function in diabetic rats induced by high-fat diet combined with low-dose streptozotocin injection. Interestingly, although resistance training had a more pronounced effect on blood glucose control than did aerobic training in type 2 diabetic rats, improvements in cardiac diastolic parameters benefited more from aerobic training. Moreover, aerobic exercise did significantly increase the expression levels of titin and decrease collagen I, TGFβ1 expression level. In summary, out data suggest that aerobic exercise may improve diabetic cardiac function through changes in titin-dependent myocardial stiffness rather than collagen-dependent interstitial fibrosis.

Zile, M. R., Baicu, C. F., Ikonomidis, J. S., Stroud, R. E., Nietert, P. J., Bradshaw, A. D., Slater, R., Palmer, B. M., Van Buren, P., Meyer, M., Redfield, M. M., Bull, D. A., Granzier, H. L., & LeWinter, M. M. (2015). Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation., 131, 1247–1259. https://doi.org/10.1161/CIRCULATIONAHA.114.013215. CrossRefPubMedPubMedCentral

LeWinter, M. M., & Granzier, H. L. (2014). Cardiac titin and heart disease. Journal of Cardiovascular Pharmacology, 63, 207–212. https://doi.org/10.1097/FJC.0000000000000007. CrossRefPubMedPubMedCentral

Ricard-Blum, S. (2016). The collagen family. Cold Spring Harbor Perspectives in Biology, 3, a004978. https://doi.org/10.1101/cshperspect.a004978.CrossRef

Franssen, C., & González Miqueo, A. (2016). The role of titin and extracellular matrix remodelling in heart failure with preserved ejection fraction. Netherlands Heart Journal, 24, 259–267. https://doi.org/10.1007/s12471-016-0812-z.CrossRefPubMedPubMedCentral

Granzier, H. L., & Irving, T. C. (1995). Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophysical Journal, 68, 1027–1044. https://doi.org/10.1016/S0006-3495(95)80278-X.CrossRefPubMedPubMedCentral

Goyal, B., & Mehta, A. (2013). Diabetic cardiomyopathy: pathophysiological mechanisms and cardiac dysfuntion. Human & Experimental Toxicology, 32, 571–590. https://doi.org/10.1177/0960327112450885.CrossRef

Hölscher, M., Bode, C., & Bugger, H. (2016). Diabetic cardiomyopathy: does the type of diabetes matter? International Journal of Molecular Sciences, 17, 2136. https://doi.org/10.3390/ijms17122136. CrossRefPubMedCentral

Schannwell, C. M., Schneppenheim, M., Perings, S., Plehn, G., & Strauer, B. E. (2002). Left ventricular diastolic dysfunction as an early manifestation of diabetic cardiomyopathy. Cardiology., 98, 33–39. https://doi.org/10.1159/000064682.CrossRefPubMed

Yilmaz, S., Canpolat, U., Aydogdu, S., & Abboud, H. E. (2015). Diabetic cardiomyopathy; summary of 41 years. Korean Circulation Journal, 45, 266–272. https://doi.org/10.4070/kcj.2015.45.4.266.CrossRefPubMedPubMedCentral

10.

Brunvand, L., Fugelseth, D., Stensaeth, K. H., Dahl-Jørgensen, K., & Margeirsdottir, H. D. (2016). Early reduced myocardial diastolic function in children and adolescents with type 1 diabetes mellitus a population-based study. BMC Cardiovascular Disorders, 16, 103. https://doi.org/10.1186/s12872-016-0288-1. CrossRefPubMedPubMedCentral

11.

Hamdani, N., Franssen, C., Lourenço, A., Falcão-Pires, I., Fontoura, D., Leite, S., Plettig, L., López, B., Ottenheijm, C. A., Becher, P., González, A., Tschöpe, C., Díez, J., Linke, W., Leite Moreira, A., & Paulus, W. (2013). Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model. Circulation. Heart Failure, 6, 1239–1249. https://doi.org/10.1161/CIRCULATIONAHA.114.013215. CrossRefPubMed

12.

Krüger, M., Babicz, K., von Frieling-Salewsky, M., & Linke, W. A. (2010). Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy. Journal of Molecular and Cellular Cardiology, 48, 910–916. https://doi.org/10.1016/j.yjmcc.2010.02.012.CrossRefPubMed

13.

Tokudome, T., Horio, T., Yoshihara, F., Suga, S.-i., Kawano, Y., Kohno, M., & Kangawa, K. (2004). Direct effects of high glucose and insulin on protein synthesis in cultured cardiac myocytes and DNA and collagen synthesis in cardiac fibroblasts. Metabolism., 53, 710–715. https://doi.org/10.1016/j.metabol.2004.01.006. CrossRefPubMed

14.

Souders, C. A., Bowers, S. L. K., & Baudino, T. A. (2009). Cardiac fibroblast: the renaissance cell. Circulation Research, 105, 1164–1176. https://doi.org/10.1161/CIRCRESAHA.109.209809. CrossRefPubMedPubMedCentral

15.

Bacchi, E., Negri, C., Zanolin, M. E., Milanese, C., Faccioli, N., Trombetta, M., Zoppini, G., Cevese, A., Bonadonna, R. C., Schena, F., Bonora, E., Lanza, M., & Moghetti, P. (2012). Metabolic effects of aerobic training and resistance training in type 2 diabetic subjects: a randomized controlled trial (the RAED2 study). Diabetes Care, 35, 676–682. https://doi.org/10.2337/dc11-1655.CrossRefPubMedPubMedCentral

16.

Hidalgo, C., Saripalli, C., & Granzier, H. L. (2014). Effect of exercise training on post-translational and post-transcriptional regulation of titin stiffness in striated muscle of wild type and IG KO mice. Archives of Biochemistry and Biophysics, 552–553, 100–107. https://doi.org/10.2337/dc11-1655.CrossRefPubMed

17.

Hayashi, T., Wojtaszewski, F. P., & Goodyear, L. J. (1997). Execise regulation of glucose transport in skeletal muscle. American Journal of Physiology. Endocrinology and Metabolism, 273, E1039–E1051. https://doi.org/10.1152/ajpendo.1997.273.6.E1039.CrossRef

18.

Ribeiro, C., Cambri, L. T., Dalia, R. A., de Araújo, M. B., Botezelli, J. D., Sponton, A. C. S., & de Mello, M. A. R. (2012). Effects of physical training with different intensities of effort on lipid metabolism in rats submitted to the neonatal application of alloxan. Lipids in Health and Disease, 11, 138. https://doi.org/10.1186/1476-511X-11-138.CrossRefPubMedPubMedCentral

19.

Sylow, L., Kleinert, M., Richter, E., & Jensen, T. (2017). Exercise-stimulated glucose uptake — regulation and implications for glycaemic control. Nature Reviews. Endocrinology, 13, 133–148. https://doi.org/10.1038/nrendo.2016.162.CrossRefPubMed

20.

Cauza, E., Hanusch-Enserer, U., Strasser, B., Ludvik, B., Metz-Schimmerl, S., Pacini, G., Wagner, O., Georg, P., Prager, R., Kostner, K., Dunky, A., & Haber, P. (2005). The relative benefits of endurance and strength training on the metabolic factors and muscle function of people with type 2 diabetes mellitus. Archives of Physical Medicine and Rehabilitation, 86, 1527–1533. https://doi.org/10.1016/j.apmr.2005.01.007. CrossRefPubMed

21.

Ishiguro, H., Kodama, S., Horikawa, C., Fujihara, K., Sugawara Hirose, A., Hirasawa, R., Yachi, Y., Ohara, N., Shimano, H., Hanyu, O., & Sone, H. (2015). Search of the ideal resistance training program to improve glycemic control and its indication for patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Sports Medicine, 46, 67–77. https://doi.org/10.1007/s40279-015-0379-7. CrossRef

22.

Ivy, J. (1997). Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus. Sports Medicine, 24, 321–336. https://doi.org/10.2165/00007256-199724050-00004. CrossRefPubMed

23.

Weeks, D. L. (2007). Exercise interventions for diabetes control: do we really know that strength training is better than endurance training? Archives of Physical Medicine and Rehabilitation, 88, 397. https://doi.org/10.1016/j.apmr.2007.01.008. CrossRefPubMed

24.

Stalin, A., Irudayaraj, S. S., Gandhi, G. R., Balakrishna, K., Ignacimuthu, S., & Al-Dhabi, N. A. (2016). Hypoglycemic activity of 6-bromoembelin and vilangin in high-fat diet fed-streptozotocin-induced type 2 diabetic rats and molecular docking studies. Life Sciences, 153, 100–117. https://doi.org/10.1016/j.lfs.2016.04.016. CrossRefPubMed

25.

Epp, R. A., Susser, S. E., Morissette, M. P., Kehler, D. S., Jassal, D. S., & Duhamel, T. A. (2012). Exercise training prevents the development of cardiac dysfunction in the low-dose streptozotocin diabetic rats fed a high-fat diet. Canadian Journal of Physiology and Pharmacology, 91, 80–89. https://doi.org/10.1139/cjpp-2012-0294.CrossRefPubMed

26.

Gu, H., Xia, X., Chen, Z., Liang, H., Yan, J., Xu, F., & Weng, J. (2014). Insulin therapy improves islet functions by restoring pancreatic vasculature in high-fat diet-fed streptozotocin-diabetic rats. Journal of Diabetes, 6, 228–236. https://doi.org/10.1111/1753-0407.12095. CrossRefPubMed

27.

Bedford, T. G., Tipton, C. M., Wilson, N. C., Oppliger, R. A., & Gisolfi, C. V. (1979). Maximum oxygen consumption of rats and its changes with various experimental procedures. Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology, 47, 1278–1283. https://doi.org/10.1152/jappl.1979.47.6.1278.CrossRef

28.

Hornberger, T. A., Jr., & Farrar, R. P. (2004). Physiological hypertrophy of the FHL muscle following 8 weeks of progressive resistance exercise in the rat. Canadian Journal of Applied Physiology, 29, 16–31. https://doi.org/10.1139/h04-002. CrossRefPubMed

29.

Fang, Z. Y., Prins, J. B., & Marwick, T. H. (2004). Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocrine Reviews, 25, 543–567. https://doi.org/10.1210/er.2003-0012.CrossRefPubMed

30.

Jia, G., Whaley-Connell, A., & Sowers, J. R. (2018). Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia., 61, 21–28. https://doi.org/10.1007/s00125-017-4390-4. CrossRefPubMed

31.

Astorri, E., Fiorina, P., Astorri, A., Contini, G. A., Albertini, D., Magnati, G., & Lanfredini, M. (1997). Isolated and preclinical impairment of left ventricular filling in insulin-dependent and non-insulin-dependent diabetic patients. Clinical Cardiology, 20, 536–540. https://doi.org/10.1002/clc.4960200606. CrossRefPubMed

32.

Aziz, F., Tk, L.-A., Enweluzo, C., Dutta, S., & Zaeem, M. (2013). Diastolic heart failure: a concise review. Journal of Clinical Medical Research, 5, 327–334. https://doi.org/10.4021/jocmr1532w. CrossRef

33.

Boyer, J. K., Thanigaraj, S., Schechtman, K. B., & Pérez, J. E. (2004). Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. The American Journal of Cardiology, 93, 870–875. https://doi.org/10.1016/j.amjcard.2003.12.026.CrossRefPubMed

34.

Böhm, A., Weigert, C., Staiger, H., & Häring, H.-U. (2016). Exercise and diabetes: relevance and causes for response variability. Endocrine., 51, 390–401. https://doi.org/10.1007/s12020-015-0792-6. CrossRefPubMed

35.

Rees, J. L., Johnson, S. T., & Boulé, N. (2017). Aquatic exercise for adults with type 2 diabetes: a meta-analysis. Acta Diabetologica, 54, 895–904. https://doi.org/10.1007/s00592-017-1023-9. CrossRefPubMed

36.

Ried-Larsen, M., MacDonald, C. S., Johansen, M. Y., Hansen, K., Christensen, R., Almdal, T. P., Pedersen, B. K., & Karstoft, K. (2018). Why prescribe exercise as therapy in type 2 diabetes? We have a pill for that! Diabetes/Metabolism Research and Reviews, 34, e2999. https://doi.org/10.1002/dmrr.2999. CrossRefPubMed

37.

Solene Le Douairon, L., Francoise Rannou, B., & Tom, B. (2014). Physical activity and diabetic cardiomyopathy: myocardial adaptation depending on exercise load. Current Diabetes Reviews, 10, 371–390. https://doi.org/10.2174/1573399811666141229151421. CrossRef

38.

Brown, B., Somauroo, J., Green, D., Wilson, M., Drezner, J., George, K., & Oxborough, D. (2017). The complex phenotype of the athlete’s heart: implications for preparticipation screening. Exercise and Sport Sciences Reviews, 45, 96–104. https://doi.org/10.1249/JES.0000000000000102. CrossRefPubMed

39.

Morganroth, J., Maron, B. J., Henry, W. L., & Epstein, S. E. (1975). Comparative left ventricular dimensions in trained athletes. Annals of Internal Medicine, 82, 521–524. https://doi.org/10.7326/0003-4819-82-4-521. CrossRefPubMed

40.

Eliane Hopf, A., Andresen, C., Kötter, S., Isic, M., Ulrich, K., Salcan, S., Bongardt, S., Roell, W., Drove, F., Scheerer, N., Vandekerckhove, L., Keulenaer, G., Hamdani, N., Linke, W., & Krüger, M. (2018). Diabetes-induced cardiomyocyte passive stiffening is caused by impaired insulin-dependent titin modification and can be modulated by neuregulin-1. Circulation Research, 123, 342–355. https://doi.org/10.1161/CIRCRESAHA.117.312166}.CrossRef

41.

Røe, Å. T., Aronsen, J. M., Skårdal, K., Hamdani, N., Linke, W. A., Danielsen, H. E., Sejersted, O. M., Sjaastad, I., & Louch, W. E. (2017). Increased passive stiffness promotes diastolic dysfunction despite improved Ca2+ handling during left ventricular concentric hypertrophy. Cardiovascular Research, 113, 1161–1172. https://doi.org/10.1093/cvr/cvx087. CrossRefPubMedPubMedCentral

42.

Krüger, M., Kötter, S., Grützner, A., Lang, P., Andresen, C., Redfield, M. M., Butt, E., dos Remedios, C. G., & Linke, W. A. (2009). Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circulation Research, 104, 87–94. https://doi.org/10.1016/j.bpj.2008.12.2003.CrossRefPubMed

43.

Nagueh, S. F., Shah, G., Wu, Y., Torre-Amione, G., King, N. M. P., Lahmers, S., Witt, C. C., Becker, K., Labeit, S., & Granzier, H. L. (2004). Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation., 110, 155–162. https://doi.org/10.1161/01.CIR.0000135591.37759.AF. CrossRefPubMed

44.

Warren, C. M., Jordan, M. C., Roos, K. P., Krzesinski, P. R., & Greaser, M. L. (2003). Titin isoform expression in normal and hypertensive myocardium. Cardiovascular Research, 59, 86–94. https://doi.org/10.1016/S0008-6363(03)00328-6. CrossRefPubMed

45.

Wu, Y., Bell, S. P., Trombitas, K., Witt, C. C., Labeit, S., LeWinter, M. M., & Granzier, H. (2002). Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness. Circulation., 106, 1384–1389. https://doi.org/10.1161/01.CIR.0000029804.61510.02. CrossRefPubMed

46.

Yamasaki, R., Wu, Y., McNabb, M., Greaser, M., Labeit, S., & Granzier, H. (2002). Protein kinase A phosphorylates titin’s cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes. Circulation Research, 90, 1181–1188. https://doi.org/10.1161/01.RES.0000021115.24712.99.CrossRefPubMed

47.

Neagoe, C., Kulke, M., del Monte, F., Gwathmey, J. K., de Tombe, P. P., Hajjar, R. J., & Linke, W. A. (2002). Titin isoform switch in ischemic human heart disease. Circulation., 106, 1333–1341. https://doi.org/10.1161/01.CIR.0000029803.93022.93. CrossRefPubMed

48.

Hsu, K. L., Tsai, C. H., Chiang, F.-T., Lo, H., Tseng, C. D., Wang, S. M., Chen, C. F., & Tseng, Y. Z. (1997). Myocardial mechanics and titin in experimental insulin-resistant rats. Japanese Heart Journal, 38, 717–728. https://doi.org/10.1536/ihj.38.717.CrossRefPubMed

49.

Lehti, M., Silvennoinen, M., Kivelä, R., Kainulainen, H., & Komulainen, J. (2006). Effects of streptozotocin-induced diabetes and physical training on gene expression of extracellular matrix proteins in mouse skeletal muscle. American Journal of Physiology. Endocrinology and Metabolism, 290, E900–E9E7. https://doi.org/10.1152/ajpendo.00444.2005. CrossRefPubMed

50.

Shah, M. S., & Brownlee, M. (2016). Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circulation Research, 118, 1808–1829. https://doi.org/10.1161/CIRCRESAHA.116.306923.CrossRefPubMedPubMedCentral

51.

Teran-Garcia, M., Rankinen, T., Koza, R. A., Rao, D. C., & Bouchard, C. (2005). Endurance training-induced changes in insulin sensitivity and gene expression. American Journal of Physiology. Endocrinology and Metabolism, 288, 1168–1178. https://doi.org/10.1152/ajpendo.00467.2004. CrossRef

52.

Mcguigan, M. R., Sharman, M. J., Newton, R. U., Davie, A. J., Murphy, A. J., & Mcbride, J. M. (2003). Effect of explosive resistance training on titin and myosin heavy chain isoforms in trained subjects. Journal of Strength and Conditioning Research, 17, 645–651. https://doi.org/10.1519/00124278-200311000-00004.CrossRefPubMed

53.

Kwak, H. B. (2013). Aging, exercise, and extracellular matrix in the heart. Journal of Exercise Rehabilitation., 9, 338–347. https://doi.org/10.12965/jer.130049. CrossRefPubMedPubMedCentral

54.

Russo, I., & Frangogiannis, N. G. (2016). Diabetes-associated cardiac fibrosis: cellular effectors, molecular mechanisms and therapeutic opportunities. Journal of Molecular and Cellular Cardiology, 90, 84–93. https://doi.org/10.1016/j.yjmcc.2015.12.011.CrossRefPubMed

55.

Calligaris, S. D., Lecanda, M., Solis, F., Ezquer, M., Gutiérrez, J., Brandan, E., Leiva, A., Sobrevia, L., & Conget, P. (2013). Mice long-term high-fat diet feeding recapitulates human cardiovascular alterations: an animal model to study the early phases of diabetic cardiomyopathy. PLoS One, 8, e60931. https://doi.org/10.1371/journal.pone.0060931.CrossRefPubMedPubMedCentral

56.

Namba, T., Tsutsui, H., Tagawa, H., Takahashi, M., & Takeshita, A. (1997). Regulation of fibrillar collagen gene expression and protein accumulation in volume-overloaded cardiac hypertrophy. Circulation, 95, 2448–2454. https://doi.org/10.1161/01.CIR.95.10.2448.CrossRefPubMed

57.

Norambuena-Soto, I., Núñez-Soto, C., Sanhueza Olivares, F., Cancino-Arenas, N., Mondaca-Ruff, D., Vivar, R., Diaz-Araya, G., Mellado, R., & Chiong, M. (2017). Transforming growth factor-beta and Forkhead box O transcription factors as cardiac fibroblast regulators. Bioscience Trends, 11, 154–162. https://doi.org/10.5582/bst.2017.01017. CrossRefPubMed

58.

Serralheiro, P., Cairrao, E., Maia, C. J., Joao, M., Almeida, C. M. C., & Verde, I. (2017). Effect of TGF-beta1 on MMP/TIMP and TGF-beta1 receptors in great saphenous veins and its significance on chronic venous insufficiency. Phlebology., 32, 334–341. https://doi.org/10.1177/0268355516655067.CrossRefPubMed

59.

Xu, H., He, Y., Feng, J. Q., Shu, R., Liu, Z., Li, J., Wang, Y., Xu, Y., Zeng, H., Xu, X., Xiang, Z., Xue, C., Bai, D., & Han, X. (2017). Wnt3α and transforming growth factor-β induce myofibroblast differentiation from periodontal ligament cells via different pathways. Experimental Cell Research, 353, 55–62. https://doi.org/10.1016/j.yexcr.2016.12.026.CrossRefPubMed

Title: Changes in Titin and Collagen Modulate Effects of Aerobic and Resistance Exercise on Diabetic Cardiac Function
Authors: Shunchang Li
Min Liang
Derun Gao
Quansheng Su
Ismail Laher
Publication date: 01-10-2019
Publisher: Springer US
Published in: Journal of Cardiovascular Translational Research / Issue 5/2019
Print ISSN: 1937-5387
Electronic ISSN: 1937-5395
DOI: https://doi.org/10.1007/s12265-019-09875-4

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Changes in Titin and Collagen Modulate Effects of Aerobic and Resistance Exercise on Diabetic Cardiac Function

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2019

Exercise Improves the Function of Endothelial Cells by MicroRNA

TLR2-Dependent Reversible Oxidation of Connexin 43 at Cys260 Modifies Electrical Coupling After Experimental Myocardial Ischemia/Reperfusion

Protection of Myocardial Ischemia–Reperfusion by Therapeutic Hypercapnia: a Mechanism Involving Improvements in Mitochondrial Biogenesis and Function

Plasma Complement Protein C3a Level Was Associated with Abdominal Aortic Calcification in Patients on Hemodialysis

Identification of miR-143 as a Major Contributor for Human Stenotic Aortic Valve Disease

Long Noncoding RNA-CERNA1 Stabilized Atherosclerotic Plaques in apolipoprotein E−/− Mice

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page