Endurance training induces fiber type-specific revascularization in hindlimb skeletal muscles of rats with chronic heart failure

Document Type: Original Article


1 Department of Physical Education and Sport Science, Bandar Abbas branch, Islamic Azad University, Bandar Abbas, Iran

2 School of Humanities, Department of Sport Science, Damghan University, Damghan, Iran

3 Department of Sports Physiology, Faculty of Physical Education and Sports Sciences, Bu-Ali Sina University, Hamedan, Iran


Objective(s): Previous studies showed that skeletal muscle microcirculation was reduced in chronic heart failure. The aim of this study was to investigate the effects of endurance training on capillary and arteriolar density of fast and slow twitch muscles in rats with chronic heart failure.
Materials and Methods: Four weeks after surgeries (left anterior descending (LAD) artery occlusion), chronic heart failure rats were divided into 3 groups: Sham (Sham, n=10); Sedentary (Sed, n=10); Exercise training (Ex, n=10). Ex group rats were subjected to endurance training in the form of treadmill running with moderate intensity for 10 weeks.
Results: Exercise training significantly increased capillary density and capillary to fiber ratio (P<0.05) in slow twitch muscle, but didn’t change fast twitch muscle capillary density and capillary to fiber ratio. Furthermore, arteriolar density in fast twitch muscle increased remarkably (P<0.05) in response to training, but slow twitch muscle arteriolar density did not change in response to exercise in chronic heart failure rats. HIF-1 increased (P<0.01) but VEGF and FGF-2 mRNA did not change in slow twitch muscle after training. In fast twitch muscle, HIF-1 mRNA increased (P<0.05), and VEGF and angiostatin decreased (P<0.01) significantly after training.
Conclusion: Endurance training ameliorates fast and slow twitch muscle revascularization non-uniformly in chronic heart failure rats by increasing capillary density in slow twitch muscle and arteriolar density in fast twitch muscle. The difference in revascularization at slow and fast twitch muscles may be induced by the difference in angiogenic and angiostatic gene expression response to endurance training.


1. Castillero E, Akashi H, Wang C, Najjar M, Ji R, Kennel P, et al. Cardiac myostatin upregulation occurs immediately after myocardial ischemia and is involved in skeletal muscle activation of atrophy. Biochem Biophys Res Commun  2014; 457:106-111.

2. Thomas DP, Hudlická O. Arteriolar reactivity and capillarization in chronically stimulated rat limb skeletal muscle post-MI. J Appl Physiol 1999; 87:2259-2265.

3. Laughlin M, Roseguini B. Mechanisms for exercise training-induced increases in skeletal muscle blood flow capacity: differences with interval sprint training versus aerobic endurance training. J Physiol Pharmacol  2008; 59:71-88.

4. Ogoh S, Hirai T, Nohara R, Taguchi S. Adaptation in properties of skeletal muscle to coronary artery occlusion/reperfusion in rats. Nihon Seirigaku Zasshi 2002; 64:225-236.

5. Benest AV, Stone OA, Miller WH, Glover CP, Uney JB, Baker AH, et al. Arteriolar genesis and angiogenesis induced by endothelial nitric oxide synthase overexpression results in a mature vasculature. Arterioscler Thromb Vasc Biol 2008; 28:1462-1468.

6. White FC, Bloor CM, McKirnan MD, Carroll SM. Exercise training in swine promotes growth of arteriolar bed and capillary angiogenesis in heart. J  Appl Physiol 1998; 85:1160-1168.

7. Roudier E, Forn P, Perry ME, Birot O. Murine double minute-2 expression is required for capillary maintenance and exercise-induced angiogenesis in skeletal muscle. FASEB J 2012; 26:4530-4539.

8. Waters RE, Rotevatn S, Li P, Annex BH, Yan Z. Voluntary running induces fiber type-specific angiogenesis in mouse skeletal muscle. Am J Physiol Cell Physiol 2004; 287:1342-1348.

9. Gute D, Laughlin MH, Amann JF. Regional changes in capillary supply in skeletal muscle of interval-sprint and low-intensity, endurance-trained rats. Microcirculation 1994; 1:183-193.

10. Lundby C, Pilegaard H, Andersen JL, van Hall G, Sander M, Calbet JA. Acclimatization to 4100 m does not change capillary density or mRNA expression of potential angiogenesis regulatory factors in human skeletal muscle. J Exp Biol 2004; 207:3865-3871.

11. Jin K, Mao X, Nagayama T, Goldsmith P, Greenberg D. Induction of vascular endothelial growth factor and hypoxia-inducible factor-1α by global ischemia in rat brain. Neuroscience 2000; 99:577-585.

12. Tsai S, Hollenbeck ST, Ryer EJ, Edlin R, Yamanouchi D, Kundi R, et al. TGF-β through Smad3 signaling stimulates vascular smooth muscle cell proliferation and neointimal formation. Am J Physiol Heart Circ Physiol 2009; 297:540-549.

13. Chantrain CF, Henriet P, Jodele S, Emonard H, Feron O, Courtoy PJ, et al. Mechanisms of pericyte recruitment in tumour angiogenesis: a new role for metalloproteinases. Eur J Cancer 2006; 42:310-318.

14. Nyberg P, Xie L, Kalluri R. Endogenous inhibitors of angiogenesis. Cancer Res 2005; 65:3967-3979.

15. Walter JJ, Sane DC. Angiostatin binds to smooth muscle cells in the coronary artery and inhibits smooth muscle cell proliferation and migration in vitro. Arterioscler Thromb Vasc Biol 1999; 19:2041-2048.

16. Murakami S. Comparison of capillary architecture between slow and fast muscles in rats using a confocal laser scanning microscope. Acta Med Okayama 2010; 64:11-18.

17. Sun Y, Zhang J, Zhang JQ, Weber KT. Renin expression at sites of repair in the infarcted rat heart. J Mol Cell Cardiol 2001; 33:995-1003.

18. Bansal A, Dai Q, Chiao YA, Hakala KW, Zhang JQ, Weintraub ST, et al. Proteomic analysis reveals late exercise effects on cardiac remodeling following myocardial infarction. J Proteomics 2010; 73:2041-2049.

19. Wisløff U, Brubakk AO. Aerobic endurance training reduces bubble formation and increases survival in rats exposed to hyperbaric pressure. J Physiol 2001; 537:607-611.

20. Wagatsuma A, Tamaki H, Ogita F. Capillary supply and gene expression of angiogenesis-related factors in murine skeletal muscle following denervation. Exp Physiol 2005; 90:403-409.

21. Fernandes T, Roque FR, Magalhães FdC, Carmo ECd, Oliveira EMd??. Aerobic exercise training corrects capillary rarefaction and alterations in proportions of the muscle fibers types in spontaneously hypertensive rats. Rev Bras Med Esporte 2012; 18:267-272.

22. Lloyd PG, Prior BM, Yang HT, Terjung RL. Angiogenic growth factor expression in rat skeletal muscle in response to exercise training. Am J Physiol Heart Circ Physiol 2003; 284:1668-1678.

23. Gustafsson T, Puntschart A, Kaijser L, Jansson E, Sundberg CJ. Exercise-induced expression of angiogenesis-related transcrip-tion and growth factors in human skeletal muscle. Am J Physiol Heart Circ Physiol 1999; 276:679-685.

24. Kimura H, Weisz A, Kurashima Y, Hashimoto K, Ogura T, D'Acquisto F, et al. Hypoxia response element of the human vascular endothelial growth factor gene mediates transcriptional regulation by nitric oxide: control of hypoxia-inducible factor-1 activity by nitric oxide. Blood 2000; 95:189-197.

25. Richardson R, Wagner H, Mudaliar S, Saucedo E, Henry R, Wagner P. Exercise adaptation attenuates VEGF gene expression in human skeletal muscle. Am J Physiol Heart Circ Physiol 2000; 279:772-778.

26. Wood R, Sanderson B, Askew C, Walker P, Green S, Stewart I. Effect of training on the response of plasma vascular endothelial growth factor to exercise in patients with peripheral arterial disease. Clin Sci 2006; 111:401-409.

27. Medeiro A, Vanzelli A, Rosa K, Irigoyen M, Brum P. Effect of exercise training and carvedilol treatment on cardiac function and structure in mice with sympathetic hyperactivity-induced heart failure. Braz J Med Biol Res 2008; 41:812-817.

28. Olfert IM, Breen EC, Mathieu-Costello O, Wagner PD. Skeletal muscle capillarity and angiogenic mRNA levels after exercise training in normoxia and chronic hypoxia. J Appl Physiol 2001; 91:1176-1184.

29. Olfert IM, Breen EC, Mathieu-Costello O, Wagner PD. Chronic hypoxia attenuates resting and exercise-induced VEGF, flt-1, and flk-1 mRNA levels in skeletal muscle. J Appl Physiol
2001; 90:1532-1538.

30. Delavar H, Nogueira L, Wagner PD, Hogan MC, Metzger D, Breen EC. Skeletal myofiber VEGF is essential for the exercise training response in adult mice. Am J Physiol Regul Integr Comp Physiol 2014; 306:586-595.

31. Cherwek DH, Hopkins MB, Thompson MJ, Annex BH, Taylor DA. Fiber type-specific differential expression of angiogenic factors in response to chronic hindlimb ischemia. Am J Physiol Heart Circ Physiol 2000;279:932-938.

32. Yan Z, Okutsu M, Akhtar YN, Lira VA. Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle. J Appl Physiol 2011; 110:264-274.

33. Gouspillou G, Sgarioto N, Norris B, Barbat-Artigas S, Aubertin-Leheudre M, Morais JA, et al. The Relationship between Muscle Fiber Type-Specific PGC-1α Content and Mitochondrial Content Varies between Rodent Models and Humans. PLoS One 2014; 9:1-14.

34. Moriyama M, Metzger S, van der Vlies AJ, Uyama H, Ehrbar M, Hasegawa U. Antioxidants: Inhibition of Angiogenesis by Antioxidant Micelles. Adv Healthcare Mater 2015; 4:480-488.

35. Laughlin MH, Cook JD, Tremble R, Ingram D, Colleran PN, Turk JR. Exercise training produces nonuniform increases in arteriolar density of rat soleus and gastrocnemius muscle. Microcirculation 2006; 13:175-186.

36. Guo X, Chen SY. Transforming growth factor-β and smooth muscle differentiation. World J Biol Chem 2012; 3:41-52.

37. Wajih N, Sane DC. Angiostatin selectively inhibits signaling by hepatocyte growth factor in endothelial and smooth muscle cells. Blood 2003; 101:1857-1863.