Exercise training improves aging-induced downregulation of VEGF angiogenic signaling cascade in hearts

Exercise training improves aging-induced deterioration of angiogenesis in the heart. However, the mechanisms underlying exercise-induced improvement of capillary density in the aged heart are unclear. Vascular endothelial growth factor (VEGF) is implicated in angiogenesis, which activated angiogenic signaling cascade through Akt and endothelial nitric oxide synthase (eNOS)-related pathway. We hypothesized that VEGF angiogenic signaling cascade in the heart contributes to a molecular mechanism of exercise training-induced improvement of capillary density in old age. With the use of hearts of sedentary young rats (4 mo old), sedentary aged rats (23 mo old), and exercise-trained aged rats (23 mo old, swim training for 8 wk), the present study investigated whether VEGF and VEGF-related angiogenic molecular expression in the aged heart is affected by exercise training. Total capillary density in the heart was significantly lower in the sedentary aged rats compared with the sedentary young rats, whereas that in the exercise-trained rat was significantly higher than the sedentary aged rats. The mRNA and protein expressions of VEGF and of fms-like tyrosine kinase-1 (Flt-1) and fetal liver kinase-1 (Flk-1), which are main VEGF receptors, in the heart were significantly lower in the sedentary aged rats compared with the sedentary young rats, whereas those in the exercise-trained rats were significantly higher than those in the sedentary aged rats. The phosphorylation of Akt protein and eNOS protein in the heart corresponded to the changes in the VEGF protein levels. These findings suggest that exercise training improves aging-induced downregulation of cardiac VEGF angiogenic signaling cascade, thereby contributing to the exercise training-induced improvement of angiogenesis in old age.     

Effects of chronic swimming training on cardiac sarcolemmal function and composition

Cardiac contractile function is dependent on the integrity and function of the sarcolemmal membrane. Swimming exercise training is known to increase cardiac contractile performance. The purpose of the present study was to examine whether a swimming exercise program would alter sarcolemmal enzyme activity, ion flux, and composition in rat hearts. After approximately 11 wk of exercise training, cardiac myosin and actomyosin Ca2+-adenosinetriphosphatase (ATPase) activity was significantly higher in exercised rat hearts than in sedentary control rat hearts. Glycogen content was increased in plantaris and gastrocnemius muscles from exercised animals as was succinic dehydrogenase activity in gastrocnemius muscle of exercised rats in comparison to sedentary rat preparations. Sarcolemmal vesicles were isolated from hearts of exercise-trained and control rats. Sarcolemmal Na+-K+-ATPase and K+-p-nitrophenylphosphatase activities, Na+-Ca2+ exchange, and passive Ca2+ binding did not differ between the two groups. ATP-dependent Ca2+ uptake and 5'-nucleotidase activity were elevated in the cardiac sarcolemmal vesicles isolated from exercised animals compared with sedentary control rats. Sarcolemmal phospholipid composition was not altered by the exercise training. Our results demonstrate that swimming training in rats does not affect most parameters of cardiac sarcolemmal function or composition. However, the elevated sarcolemmal Ca2+ pump activity in exercised rats may help to reduce intracellular Ca2+ and augment cardiac relaxation rates. The enhanced 5'-nucleotidase activity may stimulate adenosine production, which could affect myocardial blood flow. The present results further our knowledge on the subcellular response of the heart to swimming training in the rat.     

Exercise training increases the Ca(2+) sensitivity of tension in rat cardiac myocytes.

The heart is known to respond to a program of chronic exercise in ways that enhance cardiac function. However, the cellular mechanisms involved in training-induced improvements in the contractile function of the myocardium are not known. In this study we tested the hypothesis that increased contractility of the myocardium associated with exercise training is due, in part, to increases in the Ca(2+) sensitivity of steady-state tension. Female Sprague-Dawley rats were randomly divided into sedentary control (C) and exercise-trained (T) groups. The T rats underwent 11 wk of progressive treadmill exercise (1 h/day, 5 days/wk, 26 m/min, 20% grade). Evidence of training effect included a 5.9% increase in heart mass, increases in heart weight-to-body weight ratio, and a 60% increase in skeletal muscle citrate synthase activity in T rats compared with C rats. After the training program, cardiac myocytes were isolated from T and C hearts. Myocytes were chemically skinned (i.e., the sarcolemma was removed) and attached to a force transducer, and steady-state tension was determined in solutions of various Ca(2+) concentrations ([Ca(2+)]). Myocytes isolated from the hearts of T rats showed a significantly (P < 0.01) increased sensitivity of tension to [Ca(2+)]. The [Ca(2+)] giving 50% of maximal tension (pCa(50)) was 5.90 +/- 0.033 and 5.82 +/- 0.023 (SD) in T and C myocytes, respectively (n = 70 myocytes/group). This result suggests that exercise training affects the myofibrillar proteins, such that Ca(2+) sensitivity is increased, and that this may be the mechanism that underlies, at least in part, the effect of training to increase myocardial contractility.     

Untargeted metabolomics analysis of ischemia–reperfusion-injured hearts ex vivo from sedentary and exercise-trained rats

Introduction

The effects of exercise on the heart and its resistance to disease are well-documented. Recent studies have identified that exercise-induced resistance to arrhythmia is due to the preservation of mitochondrial membrane potential.

Objectives

To identify novel metabolic changes that occur parallel to these mitochondrial alterations, we performed non-targeted metabolomics analysis on hearts from sedentary and exercise-trained rats challenged with isolated heart ischemia–reperfusion injury (I/R).

Methods

Eight-week old Sprague–Dawley rats were treadmill trained 5 days/week for 6 weeks (exercise duration and intensity progressively increased to 1 h at 30 m/min up a 10.5% incline, 75–80% VO_2max). The recovery of pre-ischemic function for sedentary rat hearts was 28.8?±?5.4% (N?=?12) compared to exercise trained hearts, which recovered 51.9%?±?5.7 (N?=?14) (p?<?0.001).

Results

Non-targeted GC–MS metabolomics analysis of (1) sedentary rat hearts; (2) exercise-trained rat hearts; (3) sedentary rat hearts challenged with global ischemia–reperfusion (I/R) injury; and (4) exercise-trained rat hearts challenged with global I/R (10/group) revealed 15 statistically significant metabolites between groups by ANOVA using Metaboanalyst (p?<?0.001). Enrichment analysis of these metabolites for pathway-associated metabolic sets indicated a?>?10-fold enrichment for ammonia recycling and protein biosynthesis. Subsequent comparison of the sedentary hearts post-I/R and exercise-trained hearts post-I/R further identified significant differences in three metabolites (oleic acid, pantothenic acid, and campesterol) related to pantothenate and CoA biosynthesis (p?≤?1.24E?05, FDR?≤?5.07E?4).

Conclusions

These studies shed light on novel mechanisms in which exercise-induced cardioprotection occurs in I/R that complement both the mitochondrial stabilization and antioxidant mechanisms recently described. These findings also link protein synthesis and protein degradation (protein quality control mechanisms) with exercise-linked cardioprotection and mitochondrial susceptibility for the first time in cardiac I/R.

     

Castration inhibits exercise-induced accumulation of Hsp70 in male rodent hearts

Intense exercise leads to accumulation of the inducible member of the 70-kDa family of heat shock proteins, Hsp70, in male, but not female, hearts. Estrogen is at least partially responsible for this difference. Because androgen receptors are expressed in the heart and castration leads to decreases in calcium regulatory proteins and altered cardiac function, testosterone (T) or its metabolites could also be involved. We hypothesized that removal of endogenous T production through castration would reduce cardiac Hsp70 accumulation after an acute exercise bout, whereas castrated animals supplemented with 5alpha-dihydrotestosterone (DHT) would show the intact male response. Fifty-four 8-wk-old male Sprague-Dawley rats were divided into intact, castrated, or castrated + DHT groups (n = 18/group). At 11 wk of age, 12 animals in each group undertook a 60-min bout of treadmill running at 30 m/min (2% incline) while the remaining 6 in each group remained sedentary. At 30 min or 24 h after exercise (n = 6/time point), blood and hearts were harvested for analysis. Serum T was undetectable in castrated and DHT-treated castrated rats, whereas serum DHT was significantly reduced in castrated animals only (approximately 60% reduction) (P < 0.05). Although there were no differences in constitutive levels of Hsp70 protein, exercise significantly increased cardiac hsp70 mRNA and protein in intact and DHT-supplemented rats, but not in castrated animals (P < 0.05). To examine whether castration eliminated the ability to respond to stress, another six intact and six castrated animals were subjected to a 15-min period of hyperthermia (core temperature raised to 42 degrees C) and killed 24 h later. As opposed to exercise, castrated animals subjected to heat shock exhibited increases in Hsp70 above nonshocked (i.e., sedentary) animals, similarly to intact males (P < 0.05). These data suggest that androgens, in addition to estrogen, play a role in the sexual dimorphism observed in the stress response to exercise but not heat shock.     

Proteomic adaptation to chronic high intensity swimming training in the rat heart

Cardiac hypertrophy induced by exercise is associated with less cardiac fibrosis and better systolic and diastolic function, suggesting that the adaptive mechanisms may exist in exercise-induced hypertrophy. To identify molecular mechanisms by which exercise training stimulates this favorable phenotype, a proteomic approach was employed to detect rat cardiac proteins that were differentially expressed or modified after exercise training. Sixteen male Sprague–Dawley rats were divided into trained (T) and control(C). T rats underwent eight weeks of swimming training seven days/week, using a high intensity protocol. Hearts were used to generate 2-D electrophoretic proteome maps. Training significantly altered 23 protein spot intensities (P < 0.05), including proteins associated with the mitochondria oxidative metabolism, such as prohibitin, malate dehydrogenase, short-chain acyl-CoA dehydrogenase, triosephosphate isomerase, electron transfer flavoprotein subunit beta, ndufa10 protein, ATP synthase subunit alpha and isocitrate dehydrogenase [NAD] subunit. Additionally, Prohibitin was increased in the exercise-induced hearts. Cytoskeletal, signal pathway, stress and oxidative proteins also increased within T groups. These results strongly support the notion that the observed changes in the expression of energy metabolism proteins resulted in a potential increase in the capacity to synthesise ATP, probably via mitochondrial oxidative metabolism. The observed changes in the expression of these metabolic and structural proteins induced by training may beneficially influence heart metabolism, stress response and signalling paths, and therefore improve the overall cardiac function.     

Activation pattern of MAPK signaling in the hearts of trained and untrained rats following a single bout of exercise.

Since exercise training causes cardiac hypertrophy and a single bout induces mechanical stress to the heart, the present study aimed to characterize the activation patterns of multiple MAPK signaling pathways in the heart after a single bout of exercise or chronic exercises. The hearts of untrained rats received 5, 15, and 30 min of treadmill running exercise (Ex5 to Ex30) and rested for 0.5, 1, 3, 6, 12, and 24 h (PostEx0.5 to PostEx24) before subjecting them to the following different experiments. Activation of MAPKs (ERK, JNK, and p38) and MAPKKs (MEK1/2, SEK, and MKK3/6) increased immediately after acute exercise in a time-dependent manner, with ERK, JNK, and p38 peaking at Ex15, Ex15, and Ex30, respectively. Expression of immediate early genes (c-fos, c-jun, and c-myc) was augmented and activator protein-1 DNA binding activity was enhanced in untrained rats immediately after a single bout of exercise. The elevated levels of MAPKs declined to the resting levels within 24 h after exercise. In another set of experiments, following 4, 8, and 12 wk of exercise training, the rats exhibited significant cardiac hypertrophy by week 12. Activation of MAPKs in the 4-wk-trained rats increased after a 30-min single bout of exercise but decreased in the 8-wk group. Finally, the activity of MAPKs signaling in the 12-wk-trained rats exposed to an acute bout of exercise was unaltered. We conclude that exercise induces the activation of multiple MAPK (ERK, JNK, and p38) pathways in the heart, an effect that gradually declines with the development of exercise-induced cardiac hypertrophy.     

Differential expression of stress proteins in rat myocardium after free wheel or treadmill run training.

High-intensity treadmill exercise increases the expression of a cardioprotective, inducible 72-kDa stress protein (SP72) in cardiac muscle. This investigation examined whether voluntary free wheel exercise training would be sufficient to confer a similar response. Male Sprague-Dawley rats were randomly assigned to either treadmill (TM-Tr) or free wheel (FW-Tr) training groups. By the end of the 8-wk training period, TM-Tr animals ran 1 h/day, 5 days/wk up a 10% grade, covering a distance of 8,282 m/wk. FW-Tr rats ran, on average, 5,300 m/wk, with one-third of the animals covering distances similar to those for the TM-Tr group. At the time of death, hearts of trained and caged sedentary control (Sed) animals were divided into left (LV) and right (RV) ventricles. Citrate synthase activity and the relative immunoblot contents of SP72, SP73 (the constitutive isoform of the SP70 family), and a 75-kDa mitochondrial chaperone (SP75) were subsequently determined. LV and RV did not differ on any measure, and SP73, SP75, and citrate synthase were not affected by training. Cardiac SP72 levels were elevated over fourfold in both ventricles of TM-Tr compared with RV of FW-Sed rats. Despite the animals having run a similar total distance, cardiac SP72 content in FW-Tr rats was not different from that in Sed animals. These data indicate that voluntary exercise training is insufficient to elicit an elevation of SP72 in rat heart and suggest that exercise intensity may be a critical factor in evoking the cardioprotective SP72 response.     

Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy

The receptors for IGF-I (IGF-IR) and insulin (IR) have been implicated in physiological cardiac growth, but it is unknown whether IGF-IR or IR signaling are critically required. We generated mice with cardiomyocyte-specific knockout of IGF-IR (CIGF1RKO) and compared them with cardiomyocyte-specific insulin receptor knockout (CIRKO) mice in response to 5 wk exercise swim training. Cardiac development was normal in CIGF1RKO mice, but the hypertrophic response to exercise was prevented. In contrast, despite reduced baseline heart size, the hypertrophic response of CIRKO hearts to exercise was preserved. Exercise increased IGF-IR content in control and CIRKO hearts. Akt phosphorylation increased in exercise-trained control and CIRKO hearts and, surprisingly, in CIGF1RKO hearts as well. In exercise-trained control and CIRKO mice, expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and glycogen content were both increased but were unchanged in trained CIGF1RKO mice. Activation of AMP-activated protein kinase (AMPK) and its downstream target eukaryotic elongation factor-2 was increased in exercise-trained CIGF1RKO but not in CIRKO or control hearts. In cultured neonatal rat cardiomyocytes, activation of AMPK with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) prevented IGF-I/insulin-induced cardiomyocyte hypertrophy. These studies identify an essential role for IGF-IR in mediating physiological cardiomyocyte hypertrophy. IGF-IR deficiency promotes energetic stress in response to exercise, thereby activating AMPK, which leads to phosphorylation of eukaryotic elongation factor-2. These signaling events antagonize Akt signaling, which although necessary for mediating physiological cardiac hypertrophy, is insufficient to promote cardiac hypertrophy in the absence of myocardial IGF-I signaling.     

Voluntary exercise protects against acute doxorubicin cardiotoxicity in the isolated perfused rat heart

The clinical use of doxorubicin (DOX) is limited by a dose-dependent cardiotoxicity. The purpose of this study was to determine whether voluntary exercise training would confer protection against DOX cardiotoxicity in the isolated perfused rat heart. Female Sprague-Dawley rats were randomly assigned to standard holding cages or cages with running wheels for 8 wk. Twenty-four hours after the sedentary (SED) or voluntary exercise (VEX) running period, rats were anesthetized with pentobarbital sodium, and hearts were isolated and perfused with oxygenated Krebs-Henseleit (KH) buffer at a constant flow of 15 ml/min. After a 20-min stabilization period, hearts were paced at 300 beats per minute and perfused with KH buffer containing 10 microM DOX for 60 min. A set of control hearts from SED and VEX rats were perfused under identical conditions without DOX for the same period. DOX perfusion led to significant decreases in left ventricular developed pressure, +dP/dt, and -dP/dt, and significant increases in LV lipid peroxidation in sedentary rats compared with non-DOX controls (P < 0.05). Prior voluntary exercise training attenuated these DOX-induced effects and was associated with a significant increase (78%, P < 0.05) in heat shock protein (HSP72), but not mitochondrial isoform of SOD (MnSOD) or CuZnSOD protein expression in the hearts of wheel-run animals. These data indicate that chronic physical activity may provide resistance against the cardiac dysfunction and oxidative damage associated with DOX exposure and provide novel evidence of HSP72 induction in the heart after voluntary exercise.     

Delta Opioid Receptors: The Link between Exercise and Cardioprotection

This study investigated the role of opioid receptor (OR) subtypes as a mechanism by which endurance exercise promotes cardioprotection against myocardial ischemia-reperfusion (IR) injury. Wistar rats were randomly divided into one of seven experimental groups: 1) control; 2) exercise-trained; 3) exercise-trained plus a non-selective OR antagonist; 4) control sham; 5) exercise-trained plus a kappa OR antagonist; 6) exercise-trained plus a delta OR antagonist; and 7) exercise-trained plus a mu OR antagonist. The exercised animals underwent 4 consecutive days of treadmill training (60 min/day at ∼70% of maximal oxygen consumption). All groups except the sham group were exposed to an in vivo myocardial IR insult, and the myocardial infarct size (IS) was determined histologically. Myocardial capillary density, OR subtype expression, heat shock protein 72 (HSP72) expression, and antioxidant enzyme activity were measured in the hearts of both the exercised and control groups. Exercise training significantly reduced the myocardial IS by approximately 34%. Pharmacological blockade of the kappa or mu OR subtypes did not blunt exercise-induced cardioprotection against IR-mediated infarction, whereas treatment of animals with a non-selective OR antagonist or a delta OR antagonist abolished exercise-induced cardioprotection. Exercise training enhanced the activities of myocardial superoxide dismutase (SOD) and catalase but did not increase the left ventricular capillary density or the mRNA levels of HSP72, SOD, and catalase. In addition, exercise significantly reduced the protein expression of kappa and delta ORs in the heart by 44% and 37%, respectively. Together, these results indicate that ORs contribute to the cardioprotection conferred by endurance exercise, with the delta OR subtype playing a key role in this response.     

Disruption of estrous cycles in exercise-trained rats

The female Sprague-Dawley rat was evaluated as an animal model for the menstrual irregularities that are common in women athletes. Daily vaginal smears revealed that estrous cycles were markedly disrupted in rats during a 10-week exercise training program, while cycles remained normal in sedentary rats. Compared to 9 sedentary rats, the 10 exercise-trained rats had longer mean cycle lengths and fewer estrus smears. Six of the exercise-trained rats, but none of the sedentary rats, had an "anestrus period" with more than twice the normal interval between estrus smears; one exercise-trained rat became essentially acyclic. Weight gain during the 10-week training program was lower in exercise-trained rats than in sedentary rats. Colonic temperatures, monitored at rest and during 30 min of exercise, were slightly lower in exercise-trained rats with irregular estrous cycles than in exercise-trained rats with regular cycles, indicating that unusually elevated body temperatures during exercise are not responsible for exercise-related reproductive acyclicity. It is concluded that the female Sprague-Dawley rat may be a useful animal model for the study of menstrual irregularities associated with exercise training.     

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

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 beta-MHC in ovariectomized hearts. The upregulation of beta1-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 beta1-adrenergic receptors and HSP72 may, in part, play a mechanistic role in the cardioprotective effects.     

Interactive effect of exercise training and growth hormone administration on glucose tolerance and muscle GLUT4 protein expression in rats

The insulin-resistance effect of growth hormone (GH) administration has been frequently reported. The present study investigated the effect of GH administration on glucose tolerance and muscle GLUT4 protein expression in exercise-trained and untrained rats. Forty-eight rats were weight-matched and assigned to the following 4 groups: control, GH, exercise training, and exercise training + GH groups. After 2 weeks of GH injections (65 µg/kg/day) and exercise training, the glucose tolerance and insulin response were measured in these rats. The GLUT4 protein level, glycogen storage, and citrate synthase activity were determined in red gastrocnemius and plantaris muscles. Daily GH administration elevated the curves of the oral glucose tolerance test and insulin response compared with those of saline-injected control rats. Furthermore, exercise training completely eliminated this GH-induced insulin resistance as determined 18 h after the last bout of exercise training. Additionally, exercise training significantly increased muscle glycogen storage and GLUT4 protein levels. GH administration did not affect the GLUT4 protein and glycogen storage increases induced by exercise training, but the citrate synthase activity in the plantaris muscle was further elevated by GH administration to a level above that induced by training. In conclusion, this is the first study that demonstrates that regular exercise training prevents GH-induced insulin-resistance side effect in rats.     

Myocardial Na+/H+ exchanger-1 (NHE1) content is decreased by exercise training

The effect of exercise training on myocardial Na⁺/H⁺ exchanger-1 (NHE1) protein expression was examined. Adult female Sprague–Dawley rats were randomly divided into sedentary (S; n?=?8) and exercised (E; n?=?9) groups. Twenty-four hours after the last exercise bout, hearts were weighed and connected to an isolated perfused working heart apparatus for evaluation of cardiac functional performance. Heart weight and heart weight/body weight from E rats was significantly increased by 7.1 and 7.2 % (P?<?0.05), respectively, compared with S hearts. The E hearts displayed 15 % greater cardiac output and 35 % external cardiac work compared with the S group at both low and high workloads (P?<?0.05 for both parameters). Left ventricular tissue from the same hearts was homogenized and NHE1 and Na⁺/Ca²⁺ exchanger (NCX) content determined by Western blotting. E hearts had a 38 % (P?<?0.001) reduction in NHE1 content related to S hearts, and there was no difference in NCX content between groups. Cytochrome c oxidase activity in plantaris increased by 100 % (P?<?0.05) and was assessed as a marker of mitochondria content and to verify training status. Our data indicate that exercise training at an intensity that results in cardiac hypertrophy and improved performance is accompanied by decreased NHE1 content in heart.     

Exercise training alters length dependence of contractile properties in rat myocardium.

Myocardial function is enhanced by endurance exercise training, but the cellular mechanisms underlying this improved function remain unclear. Exercise training increases the sensitivity of rat cardiac myocytes to activation by Ca(2+), and this Ca(2+) sensitivity has been shown to be highly dependent on sarcomere length. We tested the hypothesis that exercise training increases this length dependence in cardiac myocytes. Female Sprague-Dawley rats were divided into sedentary control (C) and exercise-trained (T) groups. The T rats underwent 11 wk of progressive treadmill exercise. Heart weight increased by 14% in T compared with C rats, and plantaris muscle citrate synthase activity showed a 39% increase with training. Steady-state tension was determined in permeabilized myocytes by using solutions of various Ca(2+) concentration (pCa), and tension-pCa curves were generated at two different sarcomere lengths for each myocyte (1.9 and 2.3 microm). We found an increased sarcomere length dependence of both maximal tension and pCa(50) (the Ca(2+) concentration giving 50% of maximal tension) in T compared with C myocytes. The DeltapCa(50) between the long and short sarcomere length was 0.084 +/- 0.023 (mean +/- SD) in myocytes from C hearts compared with 0.132 +/- 0.014 in myocytes from T hearts (n = 50 myocytes per group). The Deltamaximal tension was 5.11 +/- 1.42 kN/m(2) in C myocytes and 9.01 +/- 1.28 in T myocytes. We conclude that exercise training increases the length dependence of maximal and submaximal tension in cardiac myocytes, and this change may underlie, at least in part, training-induced enhancement of myocardial function.     

The effect of different types of physical exercise on glucose and citrulline synthesis in isolated rat liver parenchymal cells

Rates of gluconeogenesis from lactate or pyruvate in hepatocytes from untrained rats were not increased by an acute (1 h) bout of exercise (running at 20 m/min). Hepatocytes from rats that had been exercise-trained for 1 month had lower rates of gluconeogenesis from lactate than cells from unexercised controls; the rates with pyruvate were identical. Hepatocytes from livers of trained animals immediately after 1 h of exercise synthesized glucose more rapidly and accumulated more citrulline than cells from resting rats.     

Response of muscle protein turnover to insulin after acute exercise and training.

To determine whether the enhanced insulin-sensitivity of glucose metabolism in muscle after acute exercise also extends to protein metabolism, untrained and exercise-trained rats were subjected to an acute bout of exercise, and the responses of protein synthesis and degradation to insulin were measured in epitrochlearis muscles in vitro. Acute exercise of both untrained and trained rats decreased protein synthesis in muscle in the absence or presence of insulin, but protein degradation was not altered. Exercise training alone had no effect on protein synthesis or degradation in muscle in the absence or presence of insulin. Acute exercise or training alone enhanced the sensitivities of both protein synthesis and degradation to insulin, but the enhanced insulin-sensitivities from training alone were not additive to those after acute exercise. These results indicate that: a decrease in protein synthesis is the primary change in muscle protein turnover after acute exercise and is not altered by prior exercise training, and the enhanced insulin-sensitivities of metabolism of both glucose and protein after either acute exercise or training suggest post-binding receptor events.     

Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity.

Doxorubicin (Dox) is a highly effective antineoplastic antibiotic associated with a dose-limiting cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. The purpose of this study was to examine the effects of low-intensity exercise training (LIET) during the course of Dox treatment on cardiac function, myosin heavy chain expression, oxidative stress, and apoptosis activation following treatment. Male Sprague-Dawley rats either remained sedentary or were exercise trained on a motorized treadmill at 15 m/min, 20 min/day, 5 days/wk (Monday through Friday) for 2 wk. During the same 2-wk period, Dox (2.5 mg/kg) or saline was administered intraperitoneally to sedentary and exercised rats 3 days/wk (Monday, Wednesday, Friday) 1-2 h following the exercise training sessions (cumulative Dox dose: 15 mg/kg). Five days following the final injections, hearts were isolated for determination of left ventricular (LV) function, lipid peroxidation, antioxidant enzyme protein expression, 72-kDa heat shock protein expression, caspase-3 activity, and myosin heavy chain isoform expression. Dox treatment significantly impaired LV function and increased caspase-3 activity in sedentary animals (P < 0.05). LIET attenuated the LV dysfunction and apoptotic signal activation induced by Dox treatment and increased glutathione peroxidase expression, but it had no significant effect on lipid peroxidation, protein expression of myosin heavy chain isoforms, 72-kDa heat shock protein, or superoxide dismutase isoforms. In conclusion, our data suggest that LIET applied during chronic Dox treatment protects against cardiac dysfunction following treatment, possibly by enhancing antioxidant defenses and inhibiting apoptosis.