Haydar A. Demirel

Exercise training improves myocardial tolerance to in vivo ischemia-reperfusion in the rat

Experimental studies examining the effects of regular exercise on cardiac responses to ischemia and reperfusion (I/R) are limited. Therefore, these experiments examined the effects of endurance exercise training on myocardial biochemical and physiological responses during in vivo I/R. Female Sprague-Dawley rats (4 mo old) were randomly assigned to either a sedentary control group or to an exercise training group. After a 10-wk endurance exercise training program, animals were anesthetized and mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was achieved by a ligature around the left coronary artery; occlusion was maintained for 20 min, followed by a 10-min period of reperfusion. Compared with untrained, exercise-trained animals maintained higher ( P < 0.05) peak systolic blood pressure throughout I/R. Training resulted in a significant ( P < 0.05) increase in ventricular nonprotein thiols, heat shock protein (HSP) 72, and the activities of superoxide dismutase (SOD), phosphofructokinase (PFK), and lactate dehydrogenase. Furthermore, compared with untrained controls, left ventricles from trained animals exhibited lower levels ( P < 0.05) of lipid peroxidation after I/R. These data demonstrate that endurance exercise training improves myocardial contractile performance and reduces lipid peroxidation during I/R in the rat in vivo. It appears likely that the improvement in the myocardial responses to I/R was related to training-induced increases in nonprotein thiols, HSP72, and the activities of SOD and PFK in the myocardium.Experimental studies examining the effects of regular exercise on cardiac responses to ischemia and reperfusion (I/R) are limited. Therefore, these experiments examined the effects of endurance exercise training on myocardial biochemical and physiological responses during in vivo I/R. Female Sprague-Dawley rats (4 mo old) were randomly assigned to either a sedentary control group or to an exercise training group. After a 10-wk endurance exercise training program, animals were anesthetized and mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was achieved by a ligature around the left coronary artery; occlusion was maintained for 20 min, followed by a 10-min period of reperfusion. Compared with untrained, exercise-trained animals maintained higher (P < 0.05) peak systolic blood pressure throughout I/R. Training resulted in a significant (P < 0.05) increase in ventricular nonprotein thiols, heat shock protein (HSP) 72, and the activities of superoxide dismutase (SOD), phosphofructokinase (PFK), and lactate dehydrogenase. Furthermore, compared with untrained controls, left ventricles from trained animals exhibited lower levels (P < 0. 05) of lipid peroxidation after I/R. These data demonstrate that endurance exercise training improves myocardial contractile performance and reduces lipid peroxidation during I/R in the rat in vivo. It appears likely that the improvement in the myocardial responses to I/R was related to training-induced increases in nonprotein thiols, HSP72, and the activities of SOD and PFK in the myocardium.

Mitochondrial signaling contributes to disuse muscle atrophy.

It is well established that long durations of bed rest, limb immobilization, or reduced activity in respiratory muscles during mechanical ventilation results in skeletal muscle atrophy in humans and other animals. The idea that mitochondrial damage/dysfunction contributes to disuse muscle atrophy originated over 40 years ago. These early studies were largely descriptive and did not provide unequivocal evidence that mitochondria play a primary role in disuse muscle atrophy. However, recent experiments have provided direct evidence connecting mitochondrial dysfunction to muscle atrophy. Numerous studies have described changes in mitochondria shape, number, and function in skeletal muscles exposed to prolonged periods of inactivity. Furthermore, recent evidence indicates that increased mitochondrial ROS production plays a key signaling role in both immobilization-induced limb muscle atrophy and diaphragmatic atrophy occurring during prolonged mechanical ventilation. Moreover, new evidence reveals that, during denervation-induced muscle atrophy, increased mitochondrial fragmentation due to fission is a required signaling event that activates the AMPK-FoxO3 signaling axis, which induces the expression of atrophy genes, protein breakdown, and ultimately muscle atrophy. Collectively, these findings highlight the importance of future research to better understand the mitochondrial signaling mechanisms that contribute to disuse muscle atrophy and to develop novel therapeutic interventions for prevention of inactivity-induced skeletal muscle atrophy.

Exercise training increases heat shock protein in skeletal muscles of old rats.

PURPOSE The effects of chronic exercise training on the expression of heat shock protein (HSP) in skeletal muscle of senescent animals are unknown. Therefore, the purpose of this study was to investigate the effects of chronic exercise training on skeletal muscle HSP expression in both young and old rats. METHODS Young adult (3 months) and old (23 months) female Fisher 344 rats were assigned to either a sedentary control or an endurance exercise trained group (N = 6 per group). Exercised animals ran (60 min.d-1, 5 d.wk-1) on a treadmill at approximately 77% VO2peak for 10 wk. After completion of the training program, the soleus (SOL), plantaris (PL), and the red (RG) and white portions (WG) of the gastrocnemius muscles were excised, and citrate synthase (CS) activity and the relative levels of HSP72 were determined. RESULTS Training resulted in increases (P < 0.05) in VO2peak in both young (67.6 +/- 3.1 vs 86.9 +/- 1.6 mL.kg-1.min-1) and old animals (54.5 +/- 1.8 vs 68.2 +/- 2.2 mL.kg-1.min-1). Training increased CS activity and the relative levels of HSP72 (P < 0.05) in all four skeletal muscles in both young and old animals. Specifically, compared with age-matched sedentary controls, exercise training resulted in increased (P < 0.05) levels of HSP72 in skeletal muscles of both young (SOL + 22%, PL +94%, RG + 44%, WG + 243%) and old animals (SOL +15%, PL +73%, RG +38%, WG +150%). CONCLUSIONS These findings reveal that the exercise-induced accumulation of HSP72 in skeletal muscle differs between fast and slow muscles. Further, these data indicate that the exercise-induced accumulation of HSP72 in highly oxidative skeletal muscles (SOL and RG) is similar between young and old animals. In contrast, aging is associated with a blunted expression of HSP72 in fast skeletal muscles (PL and WG) in response to chronic exercise.

Exercise, heat shock proteins, and myocardial protection from I-R injury

Heat shock proteins (HSPs) play a critical role in maintaining cellular homeostasis and protecting cells during episodes of acute stress. Specifically, HSPs of the 70 kDa family (i.e., HSP72) are important in preventing ischemia-reperfusion induced apoptosis, necrosis, and oxidative injury in a variety of cell types including the cardiac myocyte. Evidence indicates that HSP72 may contribute to cellular protection against a variety of stresses by preventing protein aggregation, assisting in the refolding of damaged proteins, and chaperoning nascent polypeptides along ribosomes. Endurance exercise is a physiological stress that can be used to elevate myocardial levels of HSP72. It is now clear that endurance exercise training can elevate myocardial HSP72 by 400-500% in young adult animals. Importantly, an exercise-induced elevation in myocardial HSPs is associated with a reduction in ischemia-reperfusion (I-R) injury in the heart. Although it seems likely that exercise-induced elevations in myocardial levels of HSPs play an important role in this protection against an I-R insult, new evidence suggests that other factors may also be involved. This is an important area for future research.

Exercise training reduces myocardial lipid peroxidation following short-term ischemia-reperfusion

PURPOSE The purpose of these experiments was to test the hypothesis that endurance exercise training will reduce myocardial lipid peroxidation following short-term ischemia and reperfusion (I-R). METHODS Female Sprague-Dawley rats (4 months old) were randomly assigned to either a sedentary control group (N = 13) or to an exercise training group (N = 13). The exercise trained animals ran 4 d.wk-1 (90 min.d-1) at approximately 75% V02max. Following a 10-wk training program, animals were anesthetized, mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was achieved by a ligature around the left coronary artery; occlusion was maintained for 5 min followed by a 10-min period of reperfusion. RESULTS Although training did not alter (P > 0.05) myocardial activities of antioxidant enzymes (superoxide dismutase and glutathione peroxidase), training was associated with significant increase (P > 0.05) in heat shock protein (HSP72) in the left ventricle. Compared with controls, trained animals exhibited significantly lower levels (P < 0.05) of myocardial lipid peroxidation following I-R. CONCLUSION These data support the hypothesis that exercise training provides protection against myocardial lipid peroxidation induced by short-term I-R in vivo.

Short-term exercise training improves diaphragm antioxidant capacity and endurance

Abstract These experiments tested the hypothesis that short-term endurance exercise training would rapidly improve (within 5 days) the diaphragm oxidative/antioxidant capacity and protect the diaphragm against contraction-induced oxidative stress. To test this postulate, male Sprague-Dawley rats (6 weeks old) ran on a motorized treadmill for 5 consecutive days (40–60 min · day−1) at approximately 65% maximal oxygen uptake. Costal diaphragm strips were excised from both sedentary control (CON, n=14) and trained (TR, n=13) animals 24 h after the last exercise session, for measurement of in vitro contraction properties and selected biochemical parameters of oxidative/antioxidant capacity. Training did not alter diaphragm force-frequency characteristics over a full range of submaximal and maximal stimulation frequencies (P > 0.05). In contrast, training improved diaphragm resistance to fatigue as contraction forces were better-maintained by the diaphragms of the TR animals during a submaximal 60-min fatigue protocol (P < 0.05). Following the fatigue protocol, diaphragm strips from the TR animals contained 30% lower concentrations of lipid hydroperoxides compared to CON (P < 0.05). Biochemical analysis revealed that exercise training increased diaphragm oxidative and antioxidant capacity (citrate synthase activity +18%, catalase activity +24%, total superoxide dismutase activity +20%, glutathione concentration +10%) (P < 0.05). These data indicate that short-term exercise training can rapidly elevate oxidative capacity as well as enzymatic and non-enzymatic antioxidant defenses in the diaphragm. Furthermore, this up-regulation in antioxidant defenses would be accompanied by a reduction in contraction-induced lipid peroxidation and an increased fatigue resistance.

Gene expression of catecholamine biosynthetic enzymes following exercise: modulation by age

Both age and exercise training are associated with tissue specific alterations in the catecholaminergic system. We examined the effect of short-term exercise training on tyrosine hydroxylase and dopamine beta-hydroxylase gene expression in adrenals and specific brain regions with aging. In addition, we examined activator protein-1 and cyclic AMP response element transcription factor binding activity in the adrenal medulla. Male, six- and 24-month-old F-344 rats were exercised by treadmill running for five consecutive days. One group was killed immediately and a second group was killed 2h after the last training session. Exercise significantly elevated tyrosine hydroxylase messenger RNA equally in adrenals of both young and old rats. Training had no effect on dopamine beta-hydroxylase messenger RNA in adrenals of young, but levels were elevated in old rats. Binding activities of both activator protein-1 and cyclic AMP response element binding protein were diminished with age in the adrenal medulla. Exercise training had no significant effect on the binding activity of cyclic AMP response element binding protein in either young or old animals, whereas activator protein-1 binding activity increased equally in young and old animals. Exercise training revealed divergent changes in tyrosine hydroxylase messenger RNA in brain catecholaminergic neurons. In the locus coeruleus and the ventral tegmental areas, training elevated tyrosine hydroxylase messenger RNA levels only in young rats. In the substantia nigra, there was no change in young, but a 45% increase in tyrosine hydroxylase messenger RNA in old rats. In the ventral tegmental area, training increased tyrosine hydroxylase gene expression 80% in young but not in old rats. These results indicate that short-term exercise training increases tyrosine hydroxylase messenger RNA levels in young animals in the adrenals, the locus coeruleus and the ventral tegmental area. The responses for exercise training of aged animals differed from the young in brain noradrenergic and dopaminergic nuclei, especially in the substantia nigra, and to some extent in the locus coeruleus and the ventral tegmental area.

Exercise training protects against contraction-induced lipid peroxidation in the diaphragm

Abstract Endurance exercise training promotes a small but significant increase in antioxidant enzyme activity in the costal diaphragm (DIA) of rodents. It is unclear if these training-induced improvements in muscle antioxidant capacity are large enough to reduce oxidative stress during prolonged contractile activity. To test the hypothesis that training-related increases in DIA antioxidant capacity reduces contraction-induced lipid peroxidation, we exercise trained adult female Sprague-Dawley (n = 7) rats on a motor-driven treadmill for 12 weeks at ≈ 75% maximal O2 consumption (90 min/day). Control animals (n = 8) remained sedentary during the same 12-week period. After training, DIA strips from animals in both experimental groups were excised and subjected to an in vitro fatigue contractile protocol in which the muscle was stimulated for 60 min at a frequency of 30 Hz, every 2 s, with a train duration of 330 m. Compared to the controls, endurance training resulted in an increase (P < 0.05) in diaphragmatic non-protein thiols and in the activity of the antioxidant enzyme superoxide dismutase. Following the contractile protocol, lipid peroxidation was significantly lower (P < 0.05) in the trained DIA compared to the controls. These data support the hypothesis that endurance exercise training-induced increases in DIA antioxidant capacity protect the muscle against contractile-related oxidative stress.

Exercise-induced improvements in myocardial antioxidant capacity: the antioxidant players and cardioprotection

Abstract Endurance exercise training is known to promote beneficial adaptations to numerous tissues including the heart. Indeed, endurance exercise training results in a cardioprotective phenotype that resists injury during an ischemia–reperfusion (IR) insult. Because IR-induced cardiac injury is due, in part, to increased production of radicals and other reactive oxygen species, many studies have explored the impact of exercise training on myocardial antioxidant capacity. Unfortunately, the literature describing the effects of exercise on the cardiac antioxidant capacity is widely inconsistent. Nonetheless, a growing body of evidence indicates that regular bouts of endurance exercise promote an increase in the expression of both superoxide dismutase 1 and 2 in cardiac mitochondria. Moreover, emerging evidence suggests that exercise also increases accessory antioxidant enzymes in the heart. Importantly, robust evidence indicates that as few as five consecutive days of endurance exercise training results in a cardiac phenotype that resists IR-induced arrhythmias, myocardial stunning, and infarction. Further, mechanistic studies indicate that exercise-induced increases in mitochondrial superoxide dismutase 2 play a key role in this adaptation. Future studies are required to provide a complete picture regarding the cellular adaptations that are responsible for exercise-induced cardioprotection.

Exercise Training-Induced Changes in Respiratory Muscles

SummaryInterest in the adaptive strategies of respiratory muscles in response to exercise training has grown in recent years. Animal studies have clearly demonstrated that regular endurance exercise training results in small but significant increases in oxidative and antioxidant enzyme activities in both inspiratory and expiratory muscles. Further, exercise training has been shown to promote a shift in the fast myosin heavy chain isoforms (e.g. from type IIb to IId) within the costal diaphragm of endurance-trained rodents. Human studies using numerous respiratory muscle training programmes have shown that respiratory muscle training results in an increased work capacity of the ventilatory musculature. However, the issue of whether respiratory muscle training improves whole body endurance capacity remains controversial. Although some authors have reported that ventilatory muscle training results in improved whole body exercise, many investigators argue that respiratory muscle performance does not limit high intensity exercise tolerance or influence maximum oxygen uptake (V̇O2max). The explanation for the divergent findings is unclear but may be due to variance in the exercise tasks used to evaluate exercise endurance. This is an interesting area for future research.