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Cardioprotective effects of exercise training on myofilament calcium activation in ovariectomized rats

Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand

Submitted 17 November 2003 ; accepted in final form 11 December 2003

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION GRANTS ACKNOWLEDGMENTS REFERENCES

 
The risks associated with hormone replacement therapy, especially cardiac diseases in postmenopausal women, have prompted extensive studies for other preventive or therapeutic alternatives. We investigated the cardioprotective effects of exercise training on the changes in cardiac myofilament Ca²⁺ activation in 10-wk-old ovariectomized rats. The exercise groups were subjected to a 9-wk running program on a motor-driven treadmill 1 wk after surgery. The relationship between pCa (-log molar free Ca²⁺ concentration) and myofibrillar MgATPase activity of exercise-sham myofibrils or exercise-ovariectomized myofibrils was the same and could not be distinguished from that of sedentary-sham control hearts. In contrast, a significant suppression in maximum MgATPase activity and a leftward shift of pCa₅₀ (half-maximally activating pCa) in the pCa-ATPase activity relationship were detected in sedentary-ovariectomized rats. Exercise training also prevented the shift in myosin heavy chain (MHC) isoforms toward -MHC in ovariectomized hearts. The upregulation of ₁-adrenergic receptors in the left ventricular membranes of ovariectomized rat hearts, as measured by receptor binding and immunoblot analyses, was no longer observed in exercise-ovariectomized hearts. Immunoblot analyses of heat shock protein (HSP) 72, an inducible form of HSP70, demonstrated a significant downregulation in ovariectomized hearts. Exercise training in ovariectomized rats completely reversed the expression of HSP72 to the same level as sham controls. Our results clearly indicate the cardioprotective effects of exercise training on changes in cardiac myofilament Ca²⁺ activation in ovariectomized rats. Alterations in expression of ₁-adrenergic receptors and HSP72 may, in part, play a mechanistic role in the cardioprotective effects.

myofilament calcium activation; ovarian sex hormones; myosin heavy chain; ₁-adrenergic receptors; heat shock protein

Exercise training offers one approach to minimize changes in cardiac myofilament Ca²⁺ activation induced by ovarian sex hormone deprivation. Exercise training has been shown to elicit positive adaptations in the cardiovascular system that results in improved functional capacity and quality of life. A favorable beneficial outcome of exercise training has been indicated in patients with heart failure (3). Moreover, a number of studies examining the effect of exercise training on the contractile performance of cardiac muscle cells demonstrated the increased tension-generating capacity of the myocardium (7-9, 15, 39). Rats exposed to a regimen of treadmill exercise for 13 wk showed significant increases in indexes of cardiac function (15). The improved cardiac function after exercise training was detected without evidence of cardiac apoptosis and with a pattern of cardiac gene expression distinct from pathological cardiac adaptation. In ovariectomized rats, swimming exercise was able to prevent the shift in cardiac myosin isoenzymes from a predominant V₁, the highest Ca²⁺-ATPase activity isoenzyme, to a predominant V₃, the lowest Ca²⁺-ATPase activity isoenzyme (19). These beneficial adaptations indicate the probability that the introduction of exercise training may be an alternative mode of prevention for those changes in cardiac myofilament Ca²⁺ activation induced by ovariectomy.

It is not yet clear how exercise training, a physical stress, improves or protects cardiac function. Generally, two major stress signals, including sympathetic outflow and heat production, are induced during exercise. It is the enhanced inotropic response to -adrenergic stimulation that underlies the adaptive increase in ventricular performance after exercise training (29, 30). In addition, exercise training reverses the downregulation of ₁-adrenergic receptors in chronic hypoxic hearts (12). For the heat signal, the heat-induced endogenous protective protein heat shock protein (HSP) 70 has been documented to be a cardioprotective factor (28). An increased expression of HSP72, the inducible form of HSP70, by exercise training has been reported (13). It was, therefore, of interest to investigate whether exercise training exerts cardioprotective effects on myofilament Ca²⁺ activation in ovariectomized rats through possible alterations in expression of ₁-adrenergic receptors and/or HSP72.

Experiments reported here focused on two questions. 1) Can exercise training prevent changes in cardiac myofilament Ca²⁺ activation as well as the switching of MHC isoforms in ovariectomized rat hearts? 2) Does exercise training affect the expression of ₁-adrenergic receptors and HSP in ovariectomized hearts? We approached these questions by subjecting the exercise groups of sham controls and ovariectomized rats 1 wk after surgery to a 9-wk treadmill-running program. Data from these groups were compared with sedentary controls. Results of our studies support the potential use of adequate exercise training as a preventive measure for the changes in cardiac myofilament Ca²⁺ activation induced by ovarian sex hormone deficiency.

	MATERIALS AND METHODS

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Animal preparation. Female Sprague-Dawley rats weighing between 180 and 200 g (8-9 wk old) were sham operated or ovariectomized and then randomly divided into sedentary and exercise groups. Ovariectomy or a sham operation was performed through bilateral skin incision in the flank area of the lower back as previously described (36). Adequacy of ovariectomy was verified by uterine mass on the day the rats were killed. Individual rats were then housed in an 8 x 10 in. hanging cage with rat chow and water ad libitum. The 9-wk running program on a motor-driven treadmill five times per week was introduced to the exercise groups 1 wk after surgery. The rats were trained to run during the first week at a fixed speed of 21 m/min with 0% grade, but running time was varied from 2 x 5 min of running with a 10-min resting interval on the day 1 to reach 2 x 25 min of running on the day 5. From the week 2 until the end of the running program, the rats were subjected to 2 x 30 min of running at a fixed speed of 21 m/min but with 7.5 and 5.5% grade for sham and ovariectomized groups, respectively. These grades were calculated for the work rate of 65-75% maximum oxygen consumption on the basis of the body weight of each group, as previously described (2). Adequacy of the exercise running program was determined by citrate synthase activity of plantaris muscle dissected on the day the rats were killed. The animal protocol was approved by the Experimental Animal Committee, Faculty of Science, Mahidol University, in accordance with National Laboratory Animal Centre, Thailand.

Cardiac myofibrillar actomyosin MgATPase activity. Ten weeks after surgery, hearts were rapidly removed from the rats under ether anesthesia and placed in ice-cold saline. Cardiac myofibrils were prepared from the left ventricles, as described by Pagani and Solaro (23). Ca²⁺-dependent MgATPase activity of isolated myofibrils was assayed by determination of inorganic phosphate released in a 10-min linear reaction at 30°C in 2 mM Mg²⁺, 60 mM imidazole, 5 mM Mg ATP^2-, pH 7.0, and ionic strength of 120 mM. Assays were run at various concentrations of Ca²⁺ ranging from pCa 7.5 to 4.875. Total concentrations of CaCl₂, EGTA, KCl, MgCl₂, and ATP were calculated with a computer program generated from the dissociation constants given by Fabiato (11). The concentration of inorganic phosphate was measured by the method of Carter and Karl (5).

Cardiac membrane preparation. Cardiac membrane was prepared from the left ventricle by the method of Baker and Potter (1) with modifications. Briefly, the left ventricle was homogenized in 10 mM ice-cold Tris·HCl, pH 8.0. The homogenate was incubated in 1 M KCl to dissolve the myofilament proteins and then filtered through layers of cheesecloth. The filtrate was centrifuged at 43,900 g at 4°C for 20 min. The pellet was resuspended in Tris buffer, homogenized, and resedimented. The final pellet was dispersed in ice-cold 50 mM HEPES buffer (pH 8.0) with a Teflon glass homogenizer and was immediately used for receptor binding assay after the protein content was determined by Bradford protein assay kit (Bio-Rad).

₁-Adrenergic receptor binding assay. The binding assay for ₁-adrenergic receptors was conducted under equilibrium condition in various concentrations of [³H]dihydroalprenolol, as previously described (32). Nonspecific binding was performed in a parallel set of experiments with addition of -/- alprenolol, a specific antagonist of ₁-adrenergic receptors. The saturation binding was determined from the relationships between the specific binding and the free ligand by nonlinear least-square regression analysis. Binding parameters, including the density and dissociation constant of the receptors, were determined from a linear transformation of data to the Scatchard plot of bound/free to bound form.

General methods and statistical analyses. Protein contents of ₁-adrenergic receptors and HSP72 in the left ventricular homogenate were examined by Western blot analysis with polyclonal antibodies of ₁-adrenoceptors (Affinity Bioreagents, Golden, CO) and HSP72 (Stressgen, Victoria, BC). MHC isoforms of left ventricular trabeculae were electrophoretically separated as previously described (37). The immunoblots and the silver stained gels were scanned by GS800 densitometer (Bio-Rad). Data are presented as means ± SE. All curve fittings were performed using GraphPad Inplot (ISI Software). The significance of differences among groups was analyzed by one-way ANOVA followed by the Student-Newman-Keuls test for multiple comparisons. A P value of <0.05 was set for the significant difference among groups.

Materials. All chemicals were purchased from Sigma Chemical (St. Louis, MO) and Fisher Scientific (Pittsburgh, PA). [³H]dihydroalprenolol, enhanced chemiluminescence detection kit, and hyperfilm were obtained from Amersham Pharmacia Biotech (Buckinghamshire, UK).

	RESULTS

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Adequacy of ovarian sex hormone deficiency was clearly demonstrated by a significant reduction in the uterine weight in ovariectomized groups when compared with that of sham controls (Table 1). Efficiency of the running program was verified by a significant increase in citrate synthase activities of plantaris muscles isolated from exercised rats. The cardiac hypertrophic effect of exercise training, as determined by the ratio of heart to body weight, was also demonstrated in both groups of exercised rats when compared with sedentary controls. In contrast, neither ovariectomy nor exercise induced hypertrophy of slow skeletal muscle of the hindlimb (soleus), as represented by percent soleus per body weight in the present study.

Results shown in Fig. 1 demonstrate a complete reversal of the suppressed maximum myofibrillar MgATPase activity detected in sedentary ovariectomized hearts by exercise training. The leftward shift in the pCa-ATPase activity relations with an increase in pCa₅₀ demonstrated in ovariectomized hearts was also completely abolished by exercise training (Fig. 2). However, there was no change in the slope or Hill coefficient of the pCa-ATPase activity relations in these hearts (data not shown). Further analyses of MHC isoform shift associated with the changes in myofibrillar activity showed that exercise training was able to prevent the significant reduction in the relative amount of -MHC in ovariectomized hearts (Fig. 3). Exercise training by itself induced no change in the maximum myofibrillar MgATPase activity, the myofibrillar Ca²⁺ sensitivity, and MHC isoforms in the sham hearts. These results indicate a beneficial role of exercise training in conserving the cardiac myofibrillar function in the condition of ovarian sex hormone deprivation.

View larger version (24K): [in this window] [in a new window]   Fig. 1. A: effects of ovariectomy and exercise training on the Ca2+-dependent MgATPase activities of cardiac myofibrils in various calcium concentrations ranging from pCa 7.5 to 4.875, pH 7.0. B: comparisons of maximum MgATPase activities between sham controls (Sham) and ovariectomized rats (OVX) of sedentary and exercise groups. Data are means ± SE from 8-9 preparations with 2-3 rat hearts for each preparation. *Significantly different from sedentary Sham (P < 0.05) using Student-Newman-Keuls test after ANOVA.

View larger version (19K): [in this window] [in a new window]   Fig. 2. A: effects of ovariectomy and exercise training on the % maximum MgATPase activities of cardiac myofibrils in various calcium concentrations ranging from pCa 7.5 to 4.875, pH 7.0. B: comparisons of -log of the calcium concentration producing half-maximal activation (pCa50) determinants between Sham and OVX of sedentary and exercise groups. Data are means ± SE from 8-9 preparations with 2-3 rat hearts for each preparation. *Significantly different from sedentary Sham (P < 0.05) using Student-Newman-Keuls test after ANOVA.

View larger version (31K): [in this window] [in a new window]   Fig. 3. A: myosin heavy chain (MHC) region of SDS gels on which were samples of left ventricular trabeculae from Sham and OVX of sedentary and exercise groups. B: relative amount of -MHC (as a percentage of total MHC) of left ventricular trabeculae from each group. Data are means ± SE from 8 hearts. *Significantly different from sedentary Sham (P < 0.05) using Student-Newman-Keuls test after ANOVA.

To understand better the significance of the preventive role of exercise training in ovariectomized hearts, we determined the possible preventive effect of exercise training on the upregulation of ₁-adrenergic receptors in ovariectomized hearts. As expected, deprivation of ovarian sex hormones for 10 wk induced a significant increase in the density of ₁-adrenoceptors (25%) compared with that of sham controls (Fig. 4A). Although exercise training had no effect on ₁-adrenoceptors in hearts of sham rats, there was a prevention of the upregulation of the receptors in the hearts of exercise-ovariectomized rats (Fig. 4A) without any effect on the receptor binding affinity (Fig. 4B). Further determination of ₁-adrenoceptor proteins with the use of immunoblot analyses of the left ventricular homogenate confirmed the complete prevntion of receptor upregulation (Fig. 5). These results thus indicate the significant preventive role of exercise training in the expression of cardiac ₁-adrenoceptor proteins, which could further modify the myofibrillar activity, in ovariectomized hearts.

View larger version (24K): [in this window] [in a new window]   Fig. 4. Comparisons of density (Bmax; A) and dissociation constant (Kd; B) of cardiac 1-adrenergic receptors in left ventricular membrane preparations from Sham and OVX of sedentary and exercise groups. Data are means ± SE of 8 hearts. *Significantly different from sedentary Sham (P < 0.05) using Student-Newman-Keuls test after ANOVA.

View larger version (21K): [in this window] [in a new window]   Fig. 5. Region of 1-adrenergic receptor (AR) proteins on immunoblots on which were samples of left ventricular homogenates from Sham and OVX of sedentary and exercise groups (top) and comparisons of the relative intensity unit from densitometry of immunoblots from each group (bottom). Data are means ± SE from 4 hearts. *Significantly different from sedentary Sham (P < 0.05) using Student-Newman-Keuls test after ANOVA.

To test for a possible contribution of HSP in the cardioprotective role of exercise training in ovariectomized hearts, HSP72 was examined by blot analysis. There was a downregulation of HSP72 evident in hearts of ovariectomized rats compared with those of sham controls (Fig. 6). The level of HSP72 in hearts of shams was not affected by exercise training. On the other hand, exercise training in ovariectomized rats completely abolished the downregulation of HSP72 protein. These results imply a possibly similar mechanism of female sex hormones and exercise training in protecting changes in cardiac performance.

View larger version (29K): [in this window] [in a new window]   Fig. 6. Region of heat shock protein (HSP) 72 and calsequestrin (CQ) on immunoblots on which were samples of left ventricular homogenates from Sham and OVX of sedentary and exercise groups (top) and comparisons of the relative HSP72 to the relative calsequestrin intensity from densitometry of immunoblots from each group (bottom). Data are means ± SE from 4 hearts. *Significantly different from sedentary Sham (P < 0.05) using Student-Newman-Keuls test after ANOVA.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION GRANTS ACKNOWLEDGMENTS REFERENCES

 
Results from the present study in ovariectomized rats provide important and novel evidence for exercise training as a cardioprotective alternative in ovarian sex hormone-deficient condition. Our study points to a possibility that regular running with moderate intensity could normalize the changes in myofilament Ca²⁺ activation associated with ovariectomy, including suppression and Ca²⁺ hypersensitivity of myofilament Ca²⁺ activation, and shift MHC isoforms toward -MHC. These cardioprotective effects of exercise training may be responsible by alterations in the expression of ₁-adrenergic receptors and HSP72.

It is theoretically possible that HRT provides the best risk-benefit profile for the prevention of cardiovascular disease in postmenopausal women. Many previous studies in animal models provide evidence supporting the idea that estrogen supplementation prevents cardiac contractile changes after chronic deprivation of female sex hormones (27, 32, 38). However, results from the clinical trial in an average 5.2-yr follow-up among healthy postmenopausal US women using a combined regimen of estrogen plus progestin indicate that the treatment is generally not beneficial (42). Our data indicate the potential importance of exercise training as a cost-effective alternative strategy.

Results presented here extend our understanding of the molecular adaptations in ovarian sex hormone-deprived hearts to moderate-intensity regular running. The American Heart Association Scientific Statement recently released for health professionals has summarized the evidence for the benefits of physical activity in the prevention and treatment of cardiovascular disease (33). Although there is sufficient evidence to encourage increased exercise and physical activity for the public and most patient groups, additional physiological and basic research is needed to provide the scientific rationale to support the importance of such a recommendation. Importantly, the underlying mechanisms by which exercise training reduces cardiovascular risk should be addressed as indicated in the present study.

Changes in the sympathetic control of the heart are well known to modify the myofilament Ca²⁺ activation via many protein phosphorylations. Physiologically, adrenergic stimulation induces improvement of cardiac contraction and relaxation cycle. Pharmacologically, administration of -adrenergic agonists has been shown to decrease survival of patients with chronic heart failure (22). It is presently accepted that chronic adrenergic signaling is a harmful compensatory mechanism to the heart (4, 10, 17). A short-lived improvement of cardiac function but a final production of cardiomyopathic phenotype with dilation and depressed contractile function has been demonstrated in transgenic overexpression of human ₁-adrenergic receptors in the heart (4, 10). Despite an unclear conclusion whether the upregulation of ₁-adrenoceptors in ovariectomized hearts was induced by a direct effect or an adaptive response of hormone deficiency, normalization of the receptor level should be a beneficial outcome to the cardiac performance. However, it is not known at this point how exercise training normalizes the upregulation of ₁-adrenergic receptors as well as the consequent activation of myofilament in ovariectomized hearts. Inasmuch as exercise training has no effect on the level of ₁-adrenergic receptors in sham hearts, as shown in the present study and in other previous reports (12, 26), additional studies are needed to better understand the underlying mechanisms of exercise training on the expression of ₁-adrenergic receptors.

Induction of HSP72 by exercise training was also suggested from our results to be a protective factor of molecular alterations in myofilament Ca²⁺ activation in ovariectomized hearts. Upregulation of HSP synthesis is considered to be a powerful physiological route involved in crucial cellular homeostatic mechanisms against a number of stresses (28). The cytoprotective function of HSP in rat ventricle after a global ischemic insult has been demonstrated (6). Furthermore, a direct cardioprotective effect of HSP72 against myocardial trauma has been reported in studies using transgenic models (20, 25, 34). Sufficient enhancement of HSP synthesis in mammalian cells and tissues, including cardiomyocytes, by exercise training has been found (13, 18). It was also shown that female rats have twice as much HSP72 as male hearts and that estrogen is responsible for the sexual dimorphism in the expression of cardiac HSP72 (35). A single bout of exercise was also demonstrated to induce a significant increase in cardiac HSP72 expression in ovariectomized but not estrogen-positive rats (24). In addition, a decrease in Ca²⁺ sensitivity of force generation in dog ventricular trabeculae after an application of HSP coinducer bimoclomol was also reported (31). Our laboratory's previous reports (36, 37) regarding changes in myofilament Ca²⁺ activation and the preventive effects of exercise training demonstrated in the present study thus point to the significance of HSP72 induction by exercise training in the molecular adaptations of cardiac myofilament in ovariectomized rats. However, it is not known at present exactly how exercise signals the upregulation of HSP72. Thermal stress (13) and/or cardiomyocyte stretch sensors may be involved (16).

Results in the present study support the preventive effects of exercise training on the molecular alterations in ovarian sex hormone-deprived rat hearts. Despite the effective outcomes in ovariectomized rats, it would be too early to suggest the use of exercise training for cardiac preventive treatment in postmenopausal women. Yet, prudent application of exercise training as an additional treatment in addition to the regularly used preventive regimen should do no harm.

	GRANTS

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This study was supported by grants from the Thailand Research Fund (to J. Wattanapermpool), the Thailand Research Fund through the Royal Golden Jubilee PhD Program (grant no. PHD/0121/2542 to T. Bupha-Intr and J. Wattanapermpool), and by a grant-in-aid from Mahidol University (to J. Wattanapermpool).

	ACKNOWLEDGMENTS

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We thank Drs. R. John Solaro and Nateetip Krishnamra for critical reading of the manuscript. We also thank Dr. Peter J. Reiser for help with the technique of MHC gel electrophoresis.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. Wattanapermpool, Dept. of Physiology, Faculty of Science, Mahidol Univ., Rama 6 Rd., Bangkok 10400, Thailand (E-mail: tejwt{at}mahidol.ac.th).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION GRANTS ACKNOWLEDGMENTS REFERENCES

 

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