Ischemia-reperfusion-induced calpain activation and SERCA2a degradation are attenuated by exercise training and calpain inhibition

2006 ◽  
Vol 290 (1) ◽  
pp. H128-H136 ◽  
Author(s):  
Joel P. French ◽  
John C. Quindry ◽  
Darin J. Falk ◽  
Jessica L. Staib ◽  
Youngil Lee ◽  
...  
Keyword(s):  
Exercise Training ◽  
Ischemia Reperfusion ◽  
Male Rats ◽  
Calpain Activity ◽  
Cardiac Work ◽  
Calpain Activation ◽  
Protein Levels ◽  
Calpain Inhibition ◽  
Exercise Induced ◽  
Injury Recovery

The Ca2+-activated protease calpain has been shown to play a deleterious role in the heart during ischemia-reperfusion (I/R). We tested the hypothesis that exercise training would minimize I/R-induced calpain activation and provide cardioprotection against I/R-induced injury. Hearts from adult male rats were isolated in a working heart preparation, and myocardial injury was induced with 25 min of global ischemia followed by 45 min of reperfusion. In sedentary control rats, I/R significantly increased calpain activity and impaired cardiac performance (cardiac work during reperfusion = 24% of baseline). Compared with sedentary animals, exercise training prevented the I/R-induced rise in calpain activity and improved cardiac work (recovery = 80% of baseline). Similar to exercise, pharmacological inhibition of calpain activity resulted in comparable cardioprotection against I/R injury (recovery = 86% of baseline). The exercise-induced protection against I/R-induced calpain activation was not due to altered myocardial protein levels of calpain or calpastatin. However, exercise training was associated with increased myocardial antioxidant enzyme activity (Mn-SOD, catalase) and a reduction in oxidative stress. Importantly, exercise training also prevented the I/R-induced degradation of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a. These findings suggest that increases in endogenous antioxidants may diminish the free radical-mediated damage and/or degradation of Ca2+ handling proteins (such as SERCA2a) typically observed after I/R. In conclusion, these results support the concept that calpain activation is an important component of I/R-induced injury and that exercise training provides cardioprotection against I/R injury, at least in part, by attenuating I/R-induced calpain activation.

Loss of exercise-induced cardioprotection after cessation of exercise

2004 ◽  
Vol 96 (4) ◽  
pp. 1299-1305 ◽  
Author(s):  
Shannon L. Lennon ◽  
John Quindry ◽  
Karyn L. Hamilton ◽  
Joel French ◽  
Jessica Staib ◽  
...  
Keyword(s):  
Myocardial Stunning ◽  
Time Course ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Antioxidant Enzyme Activity ◽  
Male Rats ◽  
Sedentary Control ◽  
Cardiac Work ◽  
Exercise Induced ◽  
Working Heart

Endurance exercise provides cardioprotection against ischemia-reperfusion (I/R) injury. Exercise-induced cardioprotection is associated with increases in cytoprotective proteins, including heat shock protein 72 (HSP72) and increases in antioxidant enzyme activity. On the basis of the reported half-life of these putative cardioprotective proteins, we hypothesized that exercise-induced cardioprotection against I/R injury would be lost within days after cessation of exercise. To test this, male rats (4 mo) were randomly assigned to one of five experimental groups: 1) sedentary control, 2) exercise followed by 1 day of rest, 3) exercise followed by 3 days of rest, 4) exercise followed by 9 days of rest, and 5) exercise followed by 18 days of rest. Exercise-induced increases ( P < 0.05) in left ventricular catalase activity and HSP72 were evident at 1 and 3 days postexercise. However, at 9 days postexercise, myocardial HSP72 and catalase levels declined to sedentary control values. To evaluate cardioprotection during recovery from I/R, hearts were isolated, placed in working heart mode, and subjected to 20.5 min of global ischemia followed by 30 min of reperfusion. Compared with sedentary controls, exercised animals sustained less I/R injury as evidenced by maintenance of a higher ( P < 0.05) percentage of preischemia cardiac work during reperfusion at 1, 3, and 9 days postexercise. The exercise-induced cardioprotection vanished by 18 days after exercise cessation. On the basis of the time course of the loss of cardioprotection and the return of HSP72 and catalase to preexercise levels, we conclude that HSP72 and catalase are not essential for exercise-induced protection during myocardial stunning. Therefore, other cytoprotective molecules are responsible for providing protection during I/R.

scholarly journals Exercise: Teaching myocytes new tricks

2017 ◽  
Vol 123 (2) ◽  
pp. 460-472 ◽  
Author(s):  
Scott K. Powers
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Cardiac Myocytes ◽  
Endurance Exercise ◽  
Ischemia Reperfusion ◽  
Muscle Fibers ◽  
Cardiac Phenotype ◽  
Endurance Exercise Training ◽  
Skeletal Muscle Fibers ◽  
Exercise Induced

Endurance exercise training promotes numerous cellular adaptations in both cardiac myocytes and skeletal muscle fibers. For example, exercise training fosters changes in mitochondrial function due to increased mitochondrial protein expression and accelerated mitochondrial turnover. Additionally, endurance exercise training alters the abundance of numerous cytosolic and mitochondrial proteins in both cardiac and skeletal muscle myocytes, resulting in a protective phenotype in the active fibers; this exercise-induced protection of cardiac and skeletal muscle fibers is often referred to as “exercise preconditioning.” As few as 3–5 consecutive days of endurance exercise training result in a preconditioned cardiac phenotype that is sheltered against ischemia-reperfusion-induced injury. Similarly, endurance exercise training results in preconditioned skeletal muscle fibers that are resistant to a variety of stresses (e.g., heat stress, exercise-induced oxidative stress, and inactivity-induced atrophy). Many studies have probed the mechanisms responsible for exercise-induced preconditioning of cardiac and skeletal muscle fibers; these studies are important, because they provide an improved understanding of the biochemical mechanisms responsible for exercise-induced preconditioning, which has the potential to lead to innovative pharmacological therapies aimed at minimizing stress-induced injury to cardiac and skeletal muscle. This review summarizes the development of exercise-induced protection of cardiac myocytes and skeletal muscle fibers and highlights the putative mechanisms responsible for exercise-induced protection in the heart and skeletal muscles.

scholarly journals Moderate exercise prevents impaired Ca2+ handling in heart of CO-exposed rat: implication for sensitivity to ischemia-reperfusion

2010 ◽  
Vol 299 (6) ◽  
pp. H2076-H2081 ◽  
Author(s):  
C. Farah ◽  
G. Meyer ◽  
L. André ◽  
J. Boissière ◽  
S. Gayrard ◽  
...  
Keyword(s):  
Exercise Training ◽  
Antioxidant Status ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Moderate Exercise ◽  
Plasmic Reticulum ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Exercise Induced ◽  
Moderate Exercise Training

Sustained urban carbon monoxide (CO) exposure exacerbates heart vulnerability to ischemia-reperfusion via deleterious effects on the antioxidant status and Ca2+ homeostasis of cardiomyocytes. The aim of this work was to evaluate whether moderate exercise training prevents these effects. Wistar rats were randomly assigned to a control group and to CO groups, living during 4 wk in simulated urban CO pollution (30–100 parts/million, 12 h/day) with (CO-Ex) or sedentary without exercise (CO-Sed). The exercise procedure began 4 wk before CO exposure and was maintained twice a week in standard filtered air during CO exposure. On one set of rats, myocardial ischemia (30 min) and reperfusion (120 min) were performed on isolated perfused rat hearts. On another set of rats, myocardial antioxidant status and Ca2+ handling were evaluated following environmental exposure. As a result, exercise training prevented CO-induced myocardial phenotypical changes. Indeed, exercise induced myocardial antioxidant status recovery in CO-exposed rats, which is accompanied by a normalization of sarco(endo)plasmic reticulum Ca2+-ATPase 2a expression and then of Ca2+ handling. Importantly, in CO-exposed rats, the normalization of cardiomyocyte phenotype with moderate exercise was associated with a restored sensitivity of the myocardium to ischemia-reperfusion. Indeed, CO-Ex rats presented a lower infarct size and a significant decrease of reperfusion arrhythmias compared with their sedentary counterparts. To conclude, moderate exercise, by preventing CO-induced Ca2+ handling and myocardial antioxidant status alterations, reduces heart vulnerability to ischemia-reperfusion.

Exercise induces a cardiac mitochondrial phenotype that resists apoptotic stimuli

2008 ◽  
Vol 294 (2) ◽  
pp. H928-H935 ◽  
Author(s):  
Andreas N. Kavazis ◽  
Joseph M. McClung ◽  
David A. Hood ◽  
Scott K. Powers
Keyword(s):  
Exercise Training ◽  
Endurance Exercise ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Oxygen Species ◽  
Antiapoptotic Proteins ◽  
Exercise Induced

Ischemia-reperfusion-induced calcium overload and production of reactive oxygen species can trigger apoptosis by promoting the release of proapoptotic factors via the mitochondrial permeability transition pore. While it is clear that endurance exercise provides cardioprotection against ischemia-reperfusion-induced injury, it is unknown if exercise training directly alters mitochondria phenotype and confers protection against apoptotic stimuli in both subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria. We hypothesized that exercise training increases expression of endogenous antioxidant enzymes and other antiapoptotic proteins, resulting in a SS and IMF mitochondrial phenotype that resists apoptotic stimuli. Mitochondria isolated from hearts of sedentary ( n = 8) and exercised-trained ( n = 8) adult male rats were studied. Endurance exercise increased the protein levels of primary antioxidant enzymes in both SS and IMF mitochondria. Furthermore, exercise increased the levels of antiapoptotic proteins in the heart, including the apoptosis repressor with a caspase recruitment domain and inducible heat shock protein 70. Importantly, our findings reveal that endurance exercise training attenuates reactive oxygen species-induced cytochrome c release from heart mitochondria. These changes are accompanied by a lower maximal rate of mitochondrial permeability transition pore opening ( Vmax) and prolonged time to Vmax in both SS and IMF cardiac mitochondria. These novel findings reveal that endurance exercise promotes biochemical alterations in cardiac SS and IMF mitochondria, resulting in a phenotype that resists apoptotic stimuli. Furthermore, these results are consistent with the concept that exercise-induced mitochondrial adaptations contribute to exercise-induced cardioprotection.

Effect of birth weight and 12 weeks of exercise training on exercise-induced AMPK signaling in human skeletal muscle

2013 ◽  
Vol 304 (12) ◽  
pp. E1379-E1390 ◽  
Author(s):  
Brynjulf Mortensen ◽  
Janne R. Hingst ◽  
Nicklas Frederiksen ◽  
Rikke W. W. Hansen ◽  
Caroline S. Christiansen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Birth Weight ◽  
Exercise Training ◽  
Acute Exercise ◽  
Mrna Levels ◽  
Ampk Activation ◽  
Ampk Signaling ◽  
Protein Levels ◽  
Before And After ◽  
Exercise Induced

Subjects with a low birth weight (LBW) display increased risk of developing type 2 diabetes (T2D). We hypothesized that this is associated with defects in muscle adaptations following acute and regular physical activity, evident by impairments in the exercise-induced activation of AMPK signaling. We investigated 21 LBW and 21 normal birth weight (NBW) subjects during 1 h of acute exercise performed at the same relative workload before and after 12 wk of exercise training. Multiple skeletal muscle biopsies were obtained before and after exercise. Protein levels and phosphorylation status were determined by Western blotting. AMPK activities were measured using activity assays. Protein levels of AMPKα1 and -γ1 were significantly increased, whereas AMPKγ3 levels decreased with training independently of group. The LBW group had higher exercise-induced AMPK Thr172 phosphorylation before training and higher exercise-induced ACC2 Ser221 phosphorylation both before and after training compared with NBW. Despite exercise being performed at the same relative intensity (65% of V̇o2peak), the acute exercise response on AMPK Thr172, ACC2 Ser221, AMPKα2β2γ1, and AMPKα2β2γ3 activities, GS activity, and adenine nucleotides as well as hexokinase II mRNA levels were all reduced after exercise training. Increased exercise-induced muscle AMPK activation and ACC2 Ser221 phosphorylation in LBW subjects may indicate a more sensitive AMPK system in this population. Long-term exercise training may reduce the need for AMPK to control energy turnover during exercise. Thus, the remaining γ3-associated AMPK activation by acute exercise after exercise training might be sufficient to maintain cellular energy balance.

Abstract 275: Berbamine Confers Cardioprotection Against Ischemia-Reperfusion Injury by Attenuating Ca 2+ Overload and Preventing Calpain Activation Through Protection of Mitochondria

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Huang-Tian Yang ◽  
Cai-Mei Zhang ◽  
Ling Gao ◽  
Yan-Jun Zheng
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Adaptive Responses ◽  
Sprague Dawley ◽  
Calpain Activity ◽  
Calpain Activation ◽  
Rat Hearts ◽  
Intracellular Ca ◽  
Underlying Mechanisms ◽  
Severe Ischemia

Reperfusion is an essential treatment to salvage ischemia myocardium from necrosis. However, the reperfusion can also lead to additional damage. Ischemic preconditioning is a powerful way to initiate intrinsic adaptive responses protecting the heart from subsequent severe ischemia/reperfusion (I/R) injury that can be mimicked by pharmacological preconditioning. However, so far few agents are clinically available for patients with ischemia heart disease. There is a growing interest in exploring effective cardioprotective components extracted from Traditional Chinese Medicine because they have been practiced for thousands of years, providing a vast source of pharmaceutical materials. Berbamine, a kind of bisbenzylisochinoline alkaloids derived from the roots, barks and stems of Barberry , was reported to protect myocardium from ischemia/reperfusion (I/R) injury, but the underlying mechanisms are largely unknown. Here, we investigated whether berbamine confers cardioprotection via preventing calpain activation and protein degradation. We identified here that berbamine pretreatment from 10 to 100 nM concentration-dependently improved post-ischemic myocardial function in isolated Sprague-Dawley rat hearts subjected to 30 min ischemia/45 min reperfusion. Similar protection was confirmed in isolated cardiomyocytes characterized by the attenuation of I/R-induced intracellular Ca 2+ overloading and the depression of Ca 2+ transients and cell shortening. Moreover, I/R-induced decreases of Ca 2+ handling proteins were significantly attenuated by berbamine. Further analysis showed that those protections were related to the suppression of I/R-induced calpain activity and the protection of mitochondrial function by berbamine. These findings suggest that berbamine confers cardioprotections against I/R injury by attenuating Ca 2+ overloading and preventing calpain activation; and the protection of mitochondria is critical for the cardioprotection.

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

2006 ◽  
Vol 291 (3) ◽  
pp. H1290-H1298 ◽  
Author(s):  
Motoyuki Iemitsu ◽  
Seiji Maeda ◽  
Subrina Jesmin ◽  
Takeshi Otsuki ◽  
Takashi Miyauchi
Keyword(s):  
Exercise Training ◽  
Old Age ◽  
Fetal Liver ◽  
Capillary Density ◽  
Signaling Cascade ◽  
Aged Rats ◽  
Protein Levels ◽  
Young Rats ◽  
Exercise Induced ◽  
Endothelial Nitric Oxide

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.

scholarly journals Contribution of IL-6 to the Hsp72, Hsp25, and αβ-crystallin responses to inflammation and exercise training in mouse skeletal and cardiac muscle

2008 ◽  
Vol 105 (6) ◽  
pp. 1830-1836 ◽  
Author(s):  
Kimberly A. Huey ◽  
Benjamin M. Meador
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Cardiac Muscle ◽  
Wheel Running ◽  
Protein Levels ◽  
Cardiac Muscles ◽  
Exercise Induced ◽  
Shock Proteins ◽  
Dependent Mechanism

The heat shock proteins (Hsps) Hsp72, Hsp25, and αβ-crystallin (αβC) may protect tissues during exercise and/or inflammatory insults; however, no studies have investigated whether exercise training increases both basal and inflammation-induced expression of these Hsps in skeletal or cardiac muscle. IL-6 is produced by muscle during both exercise and inflammation and has been shown to modulate Hsp expression. These studies tested the hypothesis that voluntary wheel running (RW) increases basal and inflammation-induced Hsp72, Hsp25, and αβC protein through an IL-6-dependent mechanism. We compared Hsp72, Hsp25, αβC, and IL-6 protein levels 4 h after systemic inflammation induced by lipopolysaccharide (LPS) in skeletal and cardiac muscles of wild-type (IL-6+/+) and IL-6 deficient (IL-6−/−) mice after 2 wk of RW or normal cage activity (Sed). LPS significantly increased skeletal Hsp72 and Hsp25 relative to saline in Sed IL-6+/+, but not IL-6−/− mice. LPS increased Hsp72 relative to saline in Sed IL-6+/+ cardiac muscle. RW increased basal Hsp72, Hsp25, and αβC in skeletal muscle in IL-6+/+ and IL-6−/− mice. However, LPS was not associated with increases in any Hsp in RW IL-6+/+ or IL-6−/− mice. LPS increased IL-6 protein in skeletal muscle and plasma in Sed and RW groups, with a significantly greater response in RW. The major results provide the first in vivo evidence that the absence of IL-6 is associated with reduced skeletal muscle Hsp72 and Hsp25 responses to LPS, but that IL-6 is not required for exercise-induced Hsp upregulation in skeletal or cardiac muscle.

Effect of leucine metabolite β-hydroxy-β-methylbutyrate on muscle metabolism during resistance-exercise training

1996 ◽  
Vol 81 (5) ◽  
pp. 2095-2104 ◽  
Author(s):  
S. Nissen ◽  
R. Sharp ◽  
M. Ray ◽  
J. A. Rathmacher ◽  
D. Rice ◽  
...  
Keyword(s):  
Exercise Training ◽  
Resistance Exercise ◽  
Muscle Metabolism ◽  
Linear Increase ◽  
Fat Free Mass ◽  
Resistance Exercise Training ◽  
Protein Levels ◽  
Linear Decrease ◽  
Exercise Induced ◽  
Leucine Metabolite

Nissen, S., R. Sharp, M. Ray, J. A. Rathmacher, D. Rice, J. C. Fuller, Jr., A. S. Connelly, and N. Abumrad. Effect of leucine metabolite β-hydroxy-β-methylbutyrate on muscle metabolism during resistance-exercise training. J. Appl. Physiol. 81(5): 2095–2104, 1996.—The effects of dietary supplementation with the leucine metabolite β-hydroxy-β-methylbutyrate (HMB) were studied in two experiments. In study 1, subjects ( n = 41) were randomized among three levels of HMB supplementation (0, 1.5 or 3.0 g HMB/day) and two protein levels (normal, 117 g/day, or high, 175 g/day) and weight lifted for 1.5 h 3 days/wk for 3 wk. In study 2, subjects ( n = 28) were fed either 0 or 3.0 g HMB/day and weight lifted for 2–3 h 6 days/wk for 7 wk. In study 1, HMB significantly decreased the exercise-induced rise in muscle proteolysis as measured by urine 3-methylhistidine during the first 2 wk of exercise (linear decrease, P < 0.04). Plasma creatine phosphokinase was also decreased with HMB supplementation ( week 3, linear decrease, P < 0.05). Weight lifted was increased by HMB supplementation when compared with the unsupplemented subjects during each week of the study (linear increase, P < 0.02). In study 2, fat-free mass was significantly increased in HMB-supplemented subjects compared with the unsupplemented group at 2 and 4–6 wk of the study ( P < 0.05). In conclusion, supplementation with either 1.5 or 3 g HMB/day can partly prevent exercise-induced proteolysis and/or muscle damage and result in larger gains in muscle function associated with resistance training.

Detrimental effect of combined exercise training and eNOS overexpression on cardiac function after myocardial infarction

2009 ◽  
Vol 296 (5) ◽  
pp. H1513-H1523 ◽  
Author(s):  
Monique C. de Waard ◽  
Jolanda van der Velden ◽  
Nicky M. Boontje ◽  
Dick H. W. Dekkers ◽  
Rien van Haperen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Exercise Training ◽  
Left Ventricular ◽  
Lv Function ◽  
Enos Expression ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Enos Uncoupling ◽  
Lv Remodeling ◽  
Exercise Induced

It has been reported that exercise after myocardial infarction (MI) attenuates left ventricular (LV) pump dysfunction by normalization of myofilament function. This benefit could be due to an exercise-induced upregulation of endothelial nitric oxide synthase (eNOS) expression and activity. Consequently, we first tested the hypothesis that the effects of exercise after MI can be mimicked by elevated eNOS expression using transgenic mice with overexpression of human eNOS (eNOSTg). Both exercise and eNOSTg attenuated LV remodeling and dysfunction after MI in mice and improved cardiomyocyte maximal force development (Fmax). However, only exercise training restored myofilament Ca2+-sensitivity and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a protein levels and improved the first derivative of LV pressure at 30 mmHg. Conversely, only eNOSTg improved survival. In view of these partly complementary actions, we subsequently tested the hypothesis that combining exercise and eNOSTg would provide additional protection against LV remodeling and dysfunction after MI. Unexpectedly, the combination of exercise and eNOSTg abolished the beneficial effects on LV remodeling and dysfunction of either treatment alone. The latter was likely due to perturbations in Ca2+ homeostasis, as myofilament Fmax actually increased despite marked reductions in the phosphorylation status of several myofilament proteins, whereas the exercise-induced increases in SERCA2a protein levels were lost in eNOSTg mice. Antioxidant treatment with N-acetylcysteine or supplementation of tetrahydrobiopterin and l-arginine prevented these detrimental effects on LV function while partly restoring the phosphorylation status of myofilament proteins and further enhancing myofilament Fmax. In conclusion, the combination of exercise and elevated eNOS expression abolished the cardioprotective effects of either treatment alone after MI, which appeared to be, at least in part, the result of increased oxidative stress secondary to eNOS “uncoupling.”

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