Abstract
Exercise training could potentially exert beneficial effects on the signaling events associated with cardiac cell apoptosis. Spontaneously hypertensive rats (SHR) were trained 5 days/week on a treadmill (18 m/min for 120 min/day) between the ages of 4 weeks and 1 week, corresponding to the hypertensive accelerating phase. The effect of exercise training on the expression of anti-apoptotic proteins HSP-72, Bcl-2 and protein kinase B (PKB), and the apoptotic proteins Bax and glycogen synthase kinase-3 (GSK-3) was examined. Exercise had a significant acute lowering effect on blood pressure, but this decrease did not attenuate the progressive increase in blood pressure. In the left ventricles of exercised SHR, PKB phosphorylation of both Ser473 and Thr308 residues was significantly increased by 166% and 120%, respectively, compared to sedentary SHR. PKB phosphorylation significantly correlated with GSK-3β phosphorylation. HSP-72 and Bcl-2 protein expression were increased in the left ventricle of exercised SHR, and associated with the concomitant increased expression of the protein Bax. Thus, the Bcl-2/Bax ratio was not changed by exercise training, suggesting that the anti-apoptotic mechanism was effective in compensating the increase in the expression of the pro-apoptotic protein Bax in the myocardium of the SHR.
Similar content being viewed by others
References
Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO 15:6541–6551
Beere HM, Wolf BB, Cain K, Mosser DD, Mahboubi A, Kuwana T, Tailor P, Morimoto RI, Cohen GM, Green DR (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2:469–475
Bialik S, Cryns VL, Drincic A, Miyata S, Wollowick AL, Srinivasan A, Kitsis RN (1999) The mitochondrial apoptotic pathway is activated by serum and glucose deprivation in cardiac myocytes. Circ Res 85:403–414
Bijur GN, Jope RS (2000) Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3beta in the regulation of HSF-1 activity. J Neurochem 75:2401–2408
Bijur GN, Jope RS (2001) Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem 276:37436–37442
Burgess ML, Buggy J, Price RL, Abel FL, Terracio L, Samarel AM, Borg TK (1996) Exercise and hypertension-induced collagen changes are related to left ventricular function in rat hearts. Am J Physiol 270:H151-H159
Bursztyn M, Ben Ishay D, Shochina M, Mekler J, Raz I (1993) Disparate effects of exercise training on glucose tolerance and insulin levels and on ambulatory blood pressure in hypertensive patients. J Hypertens 11:1121–1125
Conlee RK, Tipton CM (1977) Cardiac glycogen repletion after exercise: influence of synthase and glucose 6-phosphate. J Appl Physiol 42:240–244
Crisman RP, Tomanek RJ (1985) Exercise training modifies myocardial mitochondria and myofibril growth in spontaneously hypertensive rats. Am J Physiol 248:H8–H14
Crisman RP, Rittman B, Tomaneck RJ (1985) Exercise-induced myocardial capillary growth in the spontaneously hypertensive rat. Microvasc Res 30:185–194
Dengel DR, Galecki AT, Hagberg JM, Pratley RE (1998) The independent and combined effects of weight loss and aerobic exercise on blood pressure and oral glucose tolerance in older men. Am J Hypertens 11:1405–1412
Dengel DR, Hagberg JM, Pratley RE, Rogus EM, Goldberg AP (1998) Improvements in blood pressure, glucose metabolism, and lipoprotein lipids after aerobic exercise plus weight loss in obese, hypertensive middle-aged men. Metabolism 47:1075–1082
Derave W, Hansen BF, Lund S, Kristiansen S, Richter EA (2000) Muscle glycogen content affects insulin-stimulated glucose transport and protein kinase B activity. Am J Physiol 279:E947–E955
Evenwell R, Struyker-Boudier H (1979) Effect of physical training on the development of hypertension in the spontaneously hypertensive hypertensive rat. Pflugers Arch 381:19–24
Fortuno MA, Ravassa S, Etayo JC, Diez J (1998) Overexpression of Bax protein and enhanced apoptosis in the left ventricule of spontaneously hypertensive rats. Effects of AT1 blockade with Losartan. Hypertension 32:280–286
Friberg P, Hoffmann P, Nordlander M, Thoren P (1988) Effects of voluntary physical exercise on cardiac function and energetics in spontaneously hypertensive rats. Acta Physiol Scand 133:495–500
Golden AL, Bright JM, Lawler JE (1994) Changes in creatine kinase expression induced by exercise in bordeline hypertensive rat hearts. Clin Exp Hypertens 16:577–593
Goodwin GW, Taegtmeyer H (2000) Improved energy homeostasis of the heart in the metabolic state of exercise. Am J Physiol 279:H1490–H1501
Gottlob K, Majewski N, Kennedy S, Kandel E, Brooks Robey R, Hay N (2001) Inhibition of early apoptotic events by Akt/PKB is dependant on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 15:1406–1418
Gross A, Jockel J, Wei MC, Korsmeyer SJ (1998) Enforced dimerization of Bax results in its translocation, mitochondrial dysfunction and apoptosis. EMBO 17:3878–3885
Hagberg JM, Park JJ, Brown MD (2000) The role of exercise training in the treatment of hypertension: an update. Sports Med 30:193–206
Hajduch E, Alessi DR, Hemmings BA, Hundal HS (1998) Constitutive activation of protein kinase B alpha by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells. Diabetes 47:1006–1013
He B, Meng YH, Mivechi NF (1998) Glycogen synthase kinase 3beta and extracellular signal-regulated kinase inactivate heat shock transcription factor 1 by facilitating the disappearance of transcriptionally active granules after heat shock. Mol Cell Biol 18:6624–6633
Higuchi M, Hashimoto I, Yamakawa K (1985) Effect of exercise training on aortic collagen content in spontaneously hypertensive rats (SHR). Eur J Appl Physiol 53:330–333
Kawanaka K, Nolte LA, Han DH, Hansen PA, Holloszy JO (2000) Mechanisms underlying impaired GLUT-4 translocation in glycogen-supercompensated muscles of exercised rats. Am J Physiol 279:E1311–E1318
Kennedy SG, Kandel ES, Cross TK, Hay N (1999) Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol 19:5800–5810
Lajoie C, Trudeau F, Lavoie N, Massicotte G, Gagnon S, Calderone A, Béliveau L (2004) Exercise training attenuated the PKB and GSK-3 dephosphorylation in the myocardium of ZDF rats. J Appl Physiol 96:1606–1612
Lawler JE, Naylor SK, Abel MM, Baldwin DR (1993) A chronic high-salt diet fails to enhance blood pressure reactivity to a tone associated with footshock in SHR, BHR, and WKY rats. Physiol Behav 54:941–946
Li Z, Bing OHL, Long X, Robinson KG, Lakatta EG (1997) Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol 272:H2313–H2319
Liu JJ, Peng L, Bradeley CJ, Zulli A, Shen J, Buxton BF (2000) Increased apoptosis in the heart of genetic hypertension, associated with increased fibroblasts. Cardiovasc Res 45:729–735
Lo S, Russell JC, Taylor AW (1970) Determination of glycogen in small tissue samples. J Appl Physiol 28:234–236
Markuns JF, Wojtaszewski JF, Goodyear LJ (1999) Insulin and exercise decrease glycogen synthase kinase-3 activity by different mechanisms in rat skeletal muscle. J Biol Chem 274:24896–24900
Mikhailov V, Mikhailova M, Pulkrabek DJ, Dong Z, Venkatachalam MA, Saikumar P (2001) Bcl-2 prevents Bax oligomerization in the mitochondrial outer membrane. J Biol Chem 276:18361–18374
Mosser DD, Caron AW, Bourget L, Denis-Larose C, Massie B (1997) Role of the human heat shock protein hsp70 in protection against stress-induced apoptosis. Mol Cell Biol 17:5317–5327
Nguyen QT, Cernacek P, Sirois MG, Calderone A, Lapointe N, Stewart DJ, Rouleau JL (2001) Long-term effects of nonselective endothelin A and B receptor antagonism in postinfarction rat: importance of timing. Circulation 104:2075–2081
Nielsen JN, Vissing J, Wojtaszewski JF, Haller RG, Begum N, Richter EA (2002) Decreased insulin action in skeletal muscle from patients with McArdle’s disease. Am J Physiol 282:E1267–E1275
Noble EG, Moraska A, Mazzeo RS, Roth DA, Olsson MC, Moore RL, Fleshner M (1999) Differential expression of stress proteins in rat myocardium after wheel or treadmill run training. J Appl Physiol 86:1696–1701
Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74:609–619
Pap M, Cooper GM (1998) Role of glycogen synthase kinase-3 in the phosphoinositol 3-kinase/Akt cell survival pathway. J Biol Chem 273:19929–19932
Paternostro G, Clarke K, Heath J, Seymour AM, Radda GK (1995) Decreased GLUT-4 mRNA content and insulin-sensitive deoxyglucose uptake show insulin resistance in the hypertensive rat heart. Cardiovasc Res 30:205–211
Saikumar P, Dong Z, Patel Y, Hall K, Hopfer U, Weinberg JM, Venkatachalam MA (1998) Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury. Oncogene 17:3401–3415
Sharma RM, Tomanek RJ, Bhalla RC (1985) Effect of swimming training on cardiac function and myosin ATPase activity in SHR. J Appl Physiol 59:758–765
Smith L (1955) Spectrophotometric assay of cytochrome c oxidase. In: Glick D (ed) Methods of biochemical analysis. Wiley, New York, pp 427–434
Summers SA, Kao AW, Kohn AD, Backus GS, Roth RA, Pessin JE, Birnbaum MJ (1999) The role of glycogen synthase kinase 3B in insulin-stimulated glucose metabolism. J Biochem Mol Biol 25:17934–17940
Suzuki K, Sawa Y, Kagisaki K, Taketani S, Ichikawa H, Kaneda Y, Matsuda H (2001) Reduction in myocardial apoptosis associated with overexpression of heat shock protein 70. Basic Res Cardiol 95:397–403
Tahar H, Ibrahimi A, Coburn CT, Knapp FF, Kurtz T, Pravenac M, Abumrad (2001) Defective fatty acid uptake in the spontaneously hypertensive rat is a primary determinant of altered glucose metabolism, hyperinsulinemia, and myocardial hypertrophy. J Biol Chem 276:23661–23666
Tipton CM (1991) Exercise, training and hypertension: an update. Exerc Sport Sci Rev 19:447–505
Tipton CM, Matthes RD, Marcus KD, Rowlett KA, Leininger JR (1983) Influences of exercise intensity, age, and medication on resting systolic blood pressure of SHR populations. J Appl Physiol 55:1305–1310
Tomanek RJ, Gisolfi CV, Bauer CA, Palmer PJ (1988) Coronary vasodilator reserve, capillarity, and mitochondria in trained hypertensive rats. J Appl Physiol 64:1179–1185
Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB (2001) Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 21:5899–5912
Véras-Silva AS, Mattos KC, Gava NS, Brum PC, Negrao CE, Krieger EM (1997) Low-intensity exercise training decrease cardiac output and hypertension in spontaneously hypertensive rats. Am J Physiol 273:H2627–H2631
Vogt M, Ott B, Rupp H, Jacob R (1986) Significance of physical exercise in hypertension. Influence of water temperature and beta-blockade on blood pressure, degree of cardiac hypertrophy and cardiac function in swimming training of spontaneously hypertensive rats. Basic Res Cardiol 81:157–169
Wojtazsewski JF, Nielsen P, Kiens B, Richter EA (2001) Regulation of glycogen synthase kinase-3 in human skeletal muscle: effects of food intake and bicycle exercise. Diabetes 50:265–269
Acknowledgements
Dr. A. Calderone is a Chercheur-Boursier Senior of the Fonds de Recherche en Santé du Québec. We thank Dr. Jacques de Champlain for generously providing support for the tail-cuff measurements. The expert technical assistance of Robert Clément from the Montreal Heart Institute was greatly appreciated.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lajoie, C., Calderone, A. & Béliveau, L. Exercise training enhanced the expression of myocardial proteins related to cell protection in spontaneously hypertensive rats. Pflugers Arch - Eur J Physiol 449, 26–32 (2004). https://doi.org/10.1007/s00424-004-1307-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-004-1307-0