Cardiovascular Research 73 (2007) 10 18 www.elsevier.

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Review

Beneficial effects of endurance training on cardiac and skeletal muscle energy metabolism in heart failure
Rene Ventura-Clapier a,, Bertrand Mettauer b,c , Xavier Bigard d
a

INSERM U-769, Universit Paris-Sud, 5 rue J-B Clment, F-92296, Chtenay-Malabry, France b Dpartement de Physiologie, CHRU Strasbourg, F-67091 France c Service de Cardiologie, Hpitaux Civils de Colmar, F-68024 France d Centre de Recherches du Service de Sant des Armes, F-38702 La Tronche Cedex, France Received 7 April 2006; received in revised form 31 August 2006; accepted 8 September 2006 Available online 16 September 2006 Time for primary review 27 days

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Abstract As endurance training improves symptoms and quality of life and decreases mortality rate and hospitalization, it is increasingly recognized as a beneficial practice for heart failure (HF) patients. However, the mechanisms involved in the beneficial effects of exercise training are far from being understood and need further evaluation. Independent of hemodynamics effects, exercise training participates in tissue remodeling. While heart failure induces a generalized metabolic myopathy, adaptation to endurance training mainly improves energetic aspects of muscle function. In the present review, after presenting the main characteristics of cardiac and skeletal muscle energy metabolism and the effects of exercise training, we will discuss the evidence for the beneficial effects of endurance training on cardiac and skeletal muscle oxidative metabolism and intracellular energy transfer in HF. These beneficial effects of exercise training seen in heart failure patients are also relevant to other chronic diseases (chronic obstructive pulmonary disease, diabetes, and obesity) and even for highly sedentary or elderly individuals [Booth F.W., Chakravathy M.V., Spangenburg E.E. Exercise and gene expression: physiological regulation of the human genome through physical activity. J Physiol (Lond) 2002;543:399411] [1]. Physical rehabilitation is thus a major health issue for populations in industrialized countries. 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Energy metabolism; Mitochondria; Heart failure; Heart; Skeletal muscle; Creatine kinase; Endurance training; Mitochondrial biogenesis

1. Introduction Alterations in cell energy metabolism participate in many pathophysiological processes including chronic heart failure (CHF). This syndrome is characterized by an augmented energy demand due to increased workload, a decreased energetic efficiency, and diminished energy metabolism leading to energetic imbalance of the myocardium [26]. HF is also characterized by a reduced ability to perform aerobic exercise and early fatigue. The reason for fatigue is attributable to persistent vasoconstrictor drive, endothelial dysfunction, and

Corresponding author. Tel.: +331 46 83 57 62; fax: +331 46 83 54 75. E-mail address: renee.ventura@cep.u-psud.fr (R. Ventura-Clapier).

structural and functional abnormalities of skeletal muscle rather than to ventricular dysfunction per se [610]. Fatigue resistance in muscle is largely dependent on oxidative energy production and on control of energy fluxes [1012]. Cardiac and skeletal muscle cells whose energy metabolism is high, fluctuating, and adapting to the special needs of the body exhibit sophisticated pathways for synthesizing, transferring, and utilizing energy in accordance with the needs of the body [11,1315]. Thus, the view that HF is a paradigm of energetic failure of cardiac and skeletal muscles, leading to contractile failure, physical handicap, worsening and ultimately death, should be increasingly considered [2]. On the other hand, exercise training improves endothelial function and coronary perfusion, decreases peripheral resistance, and induces cardiac and skeletal muscle cell remodeling, leading to increased

0008-6363/$ - see front matter 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.cardiores.2006.09.003

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oxygen uptake, substrate oxidation, and resistance to fatigue [1619]. Although physical activity was avoided in CHF patients until the late 1980s, over the last decade, endurance exercise training in CHF patients has proven feasible [20], in terms of increased exercise capacity, quality of life [21,22], and to potentially reduce morbidity and mortality rates [2325]. Adaptation to endurance training mainly involves energetic aspects of muscle function. To what extent endurance training in HF improves cardiac and skeletal muscle metabolism as well as how metabolic improvement contributes to the beneficial effects of exercise training is far from being understood. This review will focus on the effects of exercise training in heart failure with a special emphasis on energy metabolism. We will first briefly summarize the current knowledge on cardiac and skeletal muscle energy metabolism in health and heart failure (see [2,46,26] for extensive reviews). In the second section, we will also summarize the effects of exercise training on muscle energy metabolism (see [11,12,27] for reviews). Finally, current knowledge on the effects of exercise training on energy metabolism in HF will be presented. 2. Cardiac and skeletal muscle energy metabolism in heart failure 2.1. Normal cardiac and skeletal muscle energy metabolism Heart muscle must maintain blood circulation in states of both rest and high peripheral demand such as that triggered by exercise. A trained athlete is able to rapidly increase cardiac output as much as 6-fold from rest to high activity levels [28]. The work done by the heart and hence energy yield must then be permanent, adaptable, rapidly regulated, and highly efficient. The functional and structural diversity of mammalian skeletal muscles allows performances from strenuous fast strength production of locomotor muscles to long-lasting contractile activity of postural muscles. Energy metabolism plays a critical role in muscle function. Schematically, two extreme metabolic patterns have been defined [14,2931]. Fast skeletal muscle fibers mainly rely on quickly mobilisable energy sources to develop strong and fast contractions but this is possible only for short periods of time because of limited cellular metabolic reserves (mainly phosphocreatine (PCr) and glycogen). These muscles are quickly fatigable and exhibit delayed recovery of their energy reserves through anaerobic glycolysis and less importantly mitochondrial oxidations. Slow muscles, on the contrary develop lower contractile force but are able to maintain long-term contractile activity because they rely on oxidative phosphorylations. They should have accurate adjustment of energy production to energy consumption. This metabolic specificity of muscle types generates a fiber-type specificity of substrate utilization, roughly oxidative fibers and cardiac muscle oxidize fatty acids and lactate, while glycolytic fibers mainly use glucose as substrate [29,32].

Creatine kinase (CK) and other phosphotransfer kinases (like myokinase) participate in energy shuttling within cardiac and skeletal muscle cells (reviewed in [14,33,34]). CK isoenzymes for example are located on sites of energy production (mitochondria or glycolytic complexes) and utilization (myosin and sarcoplasmic reticulum ATPases (SERCA)), ensuring fast and efficient energy transfer to ATPases, and signal transfer to energy producing sites (for review see [14,34,35]. This finetuning of energy fluxes in oxidative muscle and heart underlies fatigue resistance. Finally, direct energy channeling between mitochondria and sarcoplasmic reticulum (SR) or myofibrils in slow and cardiac muscle, also produces compartmentation of adenine nucleotides [3638]. Another recent issue in energy metabolism concerns the transcriptional regulation and signaling pathways involved in the maintenance of energy homeostasis and mitochondrial biogenesis (for recent review see [39]). Mitochondrial biogenesis depends on the coordinated function of mitochondrial and nuclear genomes. The mitochondrial transcription factor (mtTFA) is encoded by the nuclear genome and activates transcription and replication of the mitochondrial DNA. MtTFA expression is controlled by nuclear respiratory factors (NRFs) that additionally stimulate expression of numerous nuclear-encoded mitochondrial proteins. NRFs expression and transcriptional activity are under the control of the transcriptional co-activator PGC-1 (transcriptional co-activator of peroxisome-proliferator-activated-receptor (PPAR) gamma) [39,40]. PGC-1 coordinates mitochondrial protein expression with substrate utilization by co-activating respectively PPAR that regulates fatty acid oxidation, and NRFs that activate transcription of nuclear and mitochondria-encoded proteins (Fig. 1). Creatine kinases are highly modulated in response to physiological stimuli, but surprisingly little is known concerning their transcriptional regulation in muscle cells [41]. 2.2. Impacts of heart failure 2.2.1. Cardiac energy metabolism in heart failure Early, the failing heart has been described as energy starved [4]. Indeed, in the stage of heart failure, oxidative capacity of the myocardium decreases [4244]. In addition, HF also impairs energy transfer and utilization. A generalized alteration of the creatine kinase system has long been observed with both cytosolic and mitochondrial isoenzymes being affected (for review see [4,5,26]). Furthermore, the failing heart has reduced mechanical efficiency, increasing the energy cost of contraction [3,45]. This energetic imbalance is the major cause for the lower PCr/ATP ratio that turned out to be a valuable predictor of mortality in CHF patients [46]. Decreased mitochondrial capacity in heart failure seems to be due to alteration in mitochondrial biogenesis, the whole PGC-1/NRFs/Tfam transcription pathway being down-regulated [5,47]. Finally, pressure overload-induced hypertrophy results in deactivation of PPAR and subsequent dysregulation of fatty acid oxidation enzyme gene expression [48,49].

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Fig. 1. Signaling pathways involved in phenotypic genes in mitochondrial gene expression. Exercise training activates a number of signaling pathways including nitric oxide synthase (NOS/cGMP), p38 mitogen-activated-proteinkinase (p38MAPK), calcineurin, calciumcalmodulin-activated kinase IV (CaMKIV), and adenosine-monophosphate-activated kinase (AMPK). These signaling pathways regulate expression of the co-activator of peroxisome proliferator activated receptor (PPAR) (PGC-1) through transcription factors like ATF2 (activating-Transcription-Factor-2), MEF2 (myocyteenhancer-factor-2) and CREB (cyclic-AMP-response-element-binding-protein) or other unknown factors. PGC-1a co-activates nuclear respiratory factors (NRFs), estrogen-related-receptor (ERR) and PPAR, known to regulate mitochondrial biogenesis and fatty acid oxidation.

biochemical studies of vastus lateralis from CHF patients revealed decreased volume density of mitochondria and oxidative enzymes in proportion with the decrease in peak oxygen consumption (VO2 peak) [55,56]. Recent studies have demonstrated however that in situ muscle oxidative capacity, mitochondrial ATP production and the transcriptional cascade PGC-1/NRFs/Tfam is identical in CHF patients and sedentary subjects [53,57,58]. One possible explanation is a beneficial effect of recent HF therapy [53]. Indeed, angiotensin-converting enzymes inhibitors (ACEi) can be protective for mitochondrial function and biogenesis both in heart and skeletal muscle as suggested by results obtained in experimental heart failure [59,60]. Nevertheless, defects in creatine kinase and citrate synthase activity [57] are still observed suggesting the persisting metabolic defects in skeletal muscle in CHF patients. The ageing processes in skeletal muscle shares many aspects in common with heart failure including muscle wasting, endothelial dysfunction, increased oxidative stress and muscle cytokines, apoptosis, and impaired mitochondrial function [61,62] participating in muscle energetic dysfunction. Thus the overlap of aging and CHF-associated changes may partially explain the more severe disabling consequences of the CHF syndrome in elderly patients [62]. 3. Effects of physical training on cardiac and skeletal muscle metabolism Regular exercise positively influences the cardiovascular system and is a determinant of health and quality of life. Endurance training improves heart and skeletal muscle energy metabolism and function. 3.1. Exercise training and cardiac metabolism Adaptive responses of the heart to endurance training include resting and submaximal exercise bradycardia and increase in end-diastolic dimension. This leads to non-pathological cardiac hypertrophy, improved ventricular function and increase in the resistance of the heart to ischemic insult [63]. However, whether changes in energy production and transfer occur to preserve or improve cardiac function is unclear. In animal models, while some studies showed that regular endurance exercise increases glycolysis and oxidative metabolism [64,65], others demonstrated that adaptive responses result from increased muscle mass, rather than mitochondrial gene expression [66,67]. Exercise training in rats may also protect against aging-induced increase in oxidative stress [68]. Data from previous studies suggest that the increase in cardiac mitochondrial capacity with training if any is subtle. Moreover, either increase or no change in fatty acid utilization capacity were reported [69,70]. These findings suggest that the exercise-induced cardiac hypertrophy mostly results in normal energy production from fatty acid metabolism. Little is known concerning creatine kinase expression and function in trained heart. Aerobic exercise training increases total myocardial CK activity and MBCK content in

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Which signals trigger the drop in creatine kinase in heart failure, remain to be established. 2.2.2. Skeletal muscle energy metabolism in heart failure Changes in skeletal muscle morphology, metabolism and function in CHF patients include muscle atrophy, decreased vascularisation, fiber type shift towards faster phenotype, and decreased resistance to fatigue [10]. The skeletal muscle metabolism of CHF patients exhibits greater changes and delayed recovery of PCr/ATP ratio following exercise [50]. In animal models, defects in expression and activity of mitochondrial enzymes lead to decreased muscle oxidative capacity, and altered mitochondrial regulation [51]. This supports that mechanisms underlying these energetic abnormalities could be related to a generalized disturbance of mitochondrial gene expression, and decreased PGC-1 expression as observed in experimental heart failure [47,52]. Creatine kinase expression is altered in skeletal muscles, in experimental heart failure in a muscle-type specific manner with the mi-CK subunit being the most affected [51], and in patients [53]. Thus, metabolic alterations in heart failure affect both cardiac and skeletal muscles, suggesting a generalized metabolic myopathy in this disease [54]. Impairment in skeletal muscle mitochondrial function in patients deserves further consideration. Morphometric and

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canine left ventricular myocardium [71] but the physiological relevance of this observation is not obvious. Thus whether the heart adapts to repeated exercise by improving energy synthesis and energy fluxes or both await further investigation. Whether these results extend to human heart remains to be established. 3.2. Exercise training and skeletal muscle metabolism Skeletal muscles adapt to repeated prolonged exercise by marked quantitative and qualitative changes in mitochondria, capillary supply, but only limited transitions in MHC isoforms [11,15,27]. Endurance training promotes an increase in mitochondrial volume density and mitochondrial proteins, in all three fiber types [72]. A decreased mitochondrial permeability to ADP and enhanced functional role of mi-CK, occurs also in both glycolytic and oxidative fibers, favoring closer coupling between energy production and utilization [73,74]. The specific effects of increased contractile activity are caused by several factors, including nerve-dependent parameters, acute and sustained changes in intracellular free calcium concentration ([Ca2+]i), metabolic factors such as hypoxia, and/or mechanical load [11]. Whereas muscle responses to endurance training are now well described at the phenomenological level, much less is known about the intracellular pathways linking increased functional demand to changes in gene expression. PGC-1 plays a key role in regulating mitochondrial biogenesis in skeletal muscle during endurance training (Fig. 1) [56], and correlates with the training status of healthy individuals [53]. Moreover, proteins involved in mitochondrial dynamics and protein assembly correlate with PGC-1, extending the role of this co-activator to the proper assembly of protein subunits of mitochondrial and nuclear origin [53]. A strong correlation has been observed between calcineurin activation, a calcium regulated phosphatase, and PGC-1 expression, suggesting that this metabolic transcriptional co-activator could be regulated by changes in intracellular calcium levels. However, calcineurin inhibition fails to block the exercise induced PGC-1 expression and activation of mitochondrial biogenesis either in rats [75] or in transplanted patients after cyclosporin treatment [76]. Thus, other pathways like MAPK pathway and CaMKs, also activated during exercise, are likely involved in the control of muscle oxidative capacity [77,78]. The increased energy demand during sustained muscle contraction and the resulting activation of energysensing pathways also seem to be important for the induction of PGC-1 mRNA. The AMP sensitive protein kinase (AM PK), which is a sensitive indicator of reduced cellular energy status in skeletal muscle, is chronically activated during periods of repeated exercise [79], and is involved in PGC-1 transcription and mitochondrial biogenesis as demonstrated in animal models [8082]. However the link between AMPK activation and transcription of PGC-1 remains to be determined. A decrease in intracellular PO2 occurs within the first

seconds of muscle contraction. Local hypoxic areas may thus occur during prolonged exercises and in pathologies affecting peripheral circulation like heart failure. The hypoxia-inducible factor (HIF) family of transcription factors plays a critical role in mediating the hypoxic regulation of several genes [83] including the vascular endothelial growth factor (VEGF). Components of the HIF-1 pathway are activated by physical activity in healthy human skeletal muscle [84]. The exercise-induced increase in VEGF gene transcription occurs especially within type IIb glycolytic myofibers, which are more susceptible to local hypoxia [85]. This fine regulation may be of importance in HF where heart and skeletal muscle are prone to experience episodes of local hypoxia. 4. Relevance of exercise training to heart failure
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Endurance training induces an improvement of muscle resistance to fatigue and justifies that endurance training programs could be considered as countermeasures of muscle weakness in heart failure patients (Fig. 2). Indeed, exercise training is able to oppose the deleterious effects of heart failure on skeletal muscle energy metabolism, although this is less clear for cardiac muscle. 4.1. Effect of exercise training on cardiac metabolism in heart failure Whether consistently observed beneficial effects of exercise training of CHF patients result from cardiac improvements is still an open question [23]. An array of arguments suggests that cardiac energy metabolism may be improved, or at least preserved. Some studies have been performed on animal models of myocardial infarction. A protective effect of training prior to myocardial infarction reduces infarct size [86], ventricular enlargement, improves remodeling, increases systolic function, and improves expression of cytochrome oxidase subunits, ventricular atrial natriuretic peptide, SR calcium ATPase and fatty-acid binding protein [87]. Exercise training decreases apoptotic processes, and protects

Fig. 2. Antagonistic effects of endurance training on muscle oxidative capacity and energy transfer changes in heart failure.

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mitochondrial function from oxidative stress and other cardiac insults [88]. In rats with myocardial infarction, aerobic endurance training attenuates ventricular and cellular hypertrophy and consistently restores contractile function, intracellular Ca2+ handling, and Ca2+-sensitivity in cardiomyocytes [89], thereby possibly increasing energetic efficiency. Observations indirectly suggest that exercise training can improve myocardial energy metabolism. Exercise improves coronary blood flow and endothelium-dependent vasodilatation, and increases resistance vessel sensitivity to the metabolic mediator adenosine, ameliorating oxygen and substrate supply to the failing heart in coronary artery diseases in humans [16] and pacing induced heart failure [90]. In humans, better left ventricular diastolic filling, increased ejection fraction and stroke volume, decreased end diastolic LV dimension and increased cardiac output at peak exercise, suggest improved cardiac load and efficiency for a given work rate [16,23,91,92]. Moreover the deleterious neuro-endocrine and pro-inflammatory cytokine burden of CHF are decreased by exercise training [9395]. This anti-inflammatory effect of exercise training in CHF may further decrease the oxidative stress within cardiac tissue and therefore improve intracellular energetics. However, direct evidences for beneficial effects of exercise training on cardiac energy metabolism are sparse. In experimental heart failure, physically active animals did not modify oxidative capacity, oxidative enzymes and energy transfer enzyme activity compared to their sedentary counterparts, but irreversible aortic stenosis may have precluded the potential beneficial effects of exercise training on cardiac metabolism [96]. One recent study in CHF patients with non-ischemic cardiomyopathy measured oxidative metabolism by [11C] acetate and positron emission tomography [97]. Training induced a coordinated decrease in myocardial O2 uptake indicating improved forward work efficiency. Therefore, exercise training in CHF seems to improve cardiac energetic efficiency. Because clear beneficial effects of training in terms of ventricular remodeling, efficiency and even patients survival has been shown after myocardial infarction [98], exercise rehabilitation has become standard of care in this setting [99], provided that exercise testing and training are not initiated within the first few days of the acute event when arrhythmias and adverse remodeling can occur [100]. It remains to be established whether this results from the effects of training on ventricular geometry and heart rate only, from better energetic efficiency of the cardiomyocyte, or from improved intrinsic oxidative capacity and intracellular energy transfers in human failing cardiomyocytes or a combination of these factors. 4.2. Effect of exercise training on skeletal muscle metabolism in heart failure Effects of exercise training on skeletal muscle of CHF patients are more documented. Increases in VO2 peak have been consistently reported with exercise training, together with improvements in global indices of muscle metabolism like lesser PCr decrease, lower Pi/PCr ratio and higher PCr

resynthesis rates for a given workload after training [101 104]. This improved overall metabolic balance for a given workload can result from improved O2 and substrate supply to skeletal muscle tissue, increased tissue oxidative capacity, and/or more efficient energy utilization. 4.2.1. O2 and substrate supply to skeletal muscle One of the first studies that examined the effects of training in CHF patients showed increased peak leg blood flow to active skeletal muscles and more efficient peripheral oxygen extraction after training, without improved submaximal exercise leg blood flow [105]. Nevertheless, the CHF-induced decrease in capillarity is improved after training [106,107]. Moreover, the decreased endothelium-mediated vasodilatory properties of the skeletal muscle during CHF are at least partly corrected, at the local and systemic levels [8,17,108]. This improvement in flow mediated vasodilatation by exercise training in CHF is accompanied by enhanced expression of eNOS [109] and/or increased activity of vascular antioxidative enzymes [110]. Thus, exercise training has been proposed as an effective antioxidant and antiatherogenic therapy at the vascular level which is able to correct and/or improve endothelial dysfunction [111]. Therefore, despite unchanged leg blood flow, a favorable intramuscular redistribution of nutritive flow and oxygen may occur after training. It remains that these hypotheses still await more conclusive evidence. 4.2.2. Skeletal muscle oxidative capacity and energy transfer In chronic heart failure patients, endurance training reduces phosphocreatine depletion and ADP increase during exercise, and enhances the rate of phosphocreatine resynthesis after exercise indicating a substantial improvement of skeletal muscle oxidative capacity [101]. Increase in mitochondrial volume density positively correlates with changes in VO2 peak and anaerobic threshold exercise [112] or changes in type I fiber percentage, and negatively with muscle venous lactate for a given workload [113]. As exercise training in heart failure patients increases mitochondrial size [114], it is likely that it will also increase muscle oxidative capacity in skeletal muscle, resulting in increased exercise tolerance. In older human skeletal muscle, exercise enhances mitochondrial activity, which is likely related to the concomitant increase in mitochondrial biogenesis [115]. In CHF rats, muscle oxidative capacity increases with physical activity in muscles recruited during exercise [96] and in vastus lateralis muscle of patients after cardiac transplantation [76]. Whether this increase in mitochondrial density and oxidative capacity with training in CHF occurs because of increased coordinated transcription of nuclear and mitochondrial genes is presently undemonstrated. However, this hypothesis is likely because of the coordinated changes in PGC1 expression, muscle oxidative capacity, VO2 peak and the training status in healthy individuals and in CHF patients [53]. In heart failure patients, abnormal local generation of NO by over-expression of iNOS, increases production of reactive oxygen species and enhances cytokine levels creating local

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deleterious conditions for optimal mitochondrial functioning, thus decreasing the functional oxidative capacity of muscle tissue [110,116,117]. Exercise training partially reverses these cellular events by decreasing tissue iNOS, cytokine production, local ROS generation and AngioII-mediaed vasoconstriction [118,119], and by enhancing expression of antioxidative enzymes [110], thus having anticatabolic effects on one hand and restoring better environmental conditions for mitochondrial energy production on the other. Indeed, training decreases local cytokines and partially reconstitutes oxidative defenses, resulting in decreased muscular damage and apoptosis [120]. Nevertheless the direct demonstration of the effects of oxidative stress on functional mitochondrial oxidative capacity is still lacking. As stated above, intracellular energy transfer through creatine kinase is also limited in heart failure [51,57]. These abnormalities persist in ACEi treated patients [53,57]. In heart transplant recipient, a significant increase in mi-CK activity is observed with training without changes in MCK [76]. In rats, voluntary wheel running increases both MCK and mi-CK in soleus muscle, but mi-CK is still lower than in control rats [96]. Interestingly, running performance strongly correlates with mi-CK activity both in rats [96] and CHF patients [116] further underscoring the importance of tight integration between oxidative energy synthesis and energy utilization in determining muscle performance [73,74]. Nevertheless, direct assessment of exercise training on mitochondrial function and energy transfer in heart failure still deserve further consideration. Considering the similarity between muscle disability in aging and heart failure, it is not surprising that healthy or CHF elderly highly benefit from exercise training in terms of exercise tolerance, contractile, mitochondrial and endothelial functions, cardiovascular endurance and oxidative defenses [61,62,115,121]. 5. Conclusions Heart failure induces a metabolic myopathy affecting both heart and skeletal muscles. This manifests itself mainly by decreased oxidative capacity, shift in substrate utilization and altered energy transfer by phosphotransfer kinases. In skeletal muscle, endurance exercise capacity is mainly conditioned by increased oxidative capacity, increased lipid utilization, and improvement of energy fluxes and better coupling between energy production and utilization. Prolonged exercise is thus able to counteract these deleterious effects by improving oxygen and substrate delivery, as well as metabolic remodeling of cardiac and skeletal muscles. Although beneficial effects of endurance training in heart failure are indubitable, further work is needed to delineate the pleiotropic effects of physical activity on cardiac and skeletal muscle functions. This issue is of interest for clinical output, especially for rehabilitation of patients with heart failure. If the beneficial effects of endurance training in CHF patients are well established in terms of exercise capacity,

quality of life and even morbi-mortality, there is increasing evidence that it is at least not harmful and may even be beneficial for the failing heart itself. If by further studies this proves to be true in human patients, training should be implemented in the care standards, together with -blockers and medication antagonizing the reninangiotensinealdosterone system. Further research examining the mechanisms of these beneficial effects at the whole organ and cellular levels will be of vital importance to identify potential advantageous effects of pharmacological and physical therapy. The specific effects of other kinds of exercise such as resistance exercise, alone or in combination with endurance exercise on muscle mass and energy metabolism also should be investigated in the future. Acknowledgements
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R.V.-C. is supported by the Centre National de la Recherche Scientifique. This work was supported by an INSERM PRO GRES, an Association Franaise contre les Myopathies and a Fondation de France grants. References
[1] Booth FW, Chakravathy MV, Spangenburg EE. Exercise and gene expression: physiological regulation of the human genome through physical activity. J Physiol (Lond) 2002;543:399411. [2] Taegtmeyer H. Metabolism the lost child of cardiology. J Am Coll Cardiol 2000;36:13868. [3] Ashrafian H, Redwood C, Blair E, Watkins H. Hypertrophic cardiomyopathy: a paradigm for myocardial energy depletion. Trends Genet 2003;19:2638. [4] Ingwall JS, Weiss RG. Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 2004;95:13545. [5] Ventura-Clapier R, Garnier A, Veksler V. Energy metabolism in heart failure. J Physiol 2004;555:113. [6] Mettauer B, Zoll J, Garnier A, Ventura-Clapier R. Heart failure: a model of cardiac and skeletal muscle energetic failure. Pflugers Arch 2006;452:65366. [7] Minotti JR, Christoph I, Oka R, Weiner MW, Wells L, Massie BM. Impaired skeletal muscle function in patients with congestive heart failure. Relationship to systemic exercise performance. J Clin Invest 1991;88:207782. [8] Linke A, Schoene N, Gielen S, Hofer J, Erbs S, Schuler G, et al. Endothelial dysfunction in patients with chronic heart failure: systemic effects of lower-limb exercise training. J Am Coll Cardiol 2001;37:3927. [9] Massie BM. Exercise tolerance in congestive heart failure. Role of cardiac function, peripheral blood flow, and muscle metabolism and effect of treatment. Am J Med 1988;84:7582. [10] Drexler H, Coats AJ. Explaining fatigue in congestive heart failure. Annu Rev Med 1996;47:24156. [11] Fluck M, Hoppeler H. Molecular basis of skeletal muscle plasticity from gene to form and function. Rev Physiol Biochem Pharmacol 2003;146:159216. [12] Hood DA. Plasticity in skeletal, cardiac, and smooth muscle invited review: contractile activity-induced mitochondrial biogenesis in skeletal muscle. J Appl Physiol 2001;90:113757. [13] Pette D, Staron RS. The molecular diversity of mammalian muscle fibers. News Physiol Sci 1993;8:1537. [14] Ventura-Clapier R, Kuznetsov A, Veksler V, Boehm E, Anflous K. Functional coupling of creatine kinases in muscles: species and tissue specificity. Mol Cell Biochem 1998;184:23147.

16

R. Ventura-Clapier et al. / Cardiovascular Research 73 (2007) 1018 [40] Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 2003;24:7890. [41] Qin WN, Khuchua Z, Cheng J, Boero J, Payne RM, Strauss AW. Molecular characterization of the creatine kinases and some historical perspectives. Mol Cell Biochem 1998;184:15367. [42] De Sousa E, Veksler V, Minajeva A, Kaasik A, Mateo P, Mayoux E, et al. Subcellular creatine kinase alterations implications in heart failure. Circ Res 1999;85:6876. [43] Quigley AF, Kapsa RM, Esmore D, Hale G, Byrne E. Mitochondrial respiratory chain activity in idiopathic dilated cardiomyopathy. J Card Fail 2000;6:4755. [44] Sharov VG, Goussev A, Lesch M, Goldstein S, Sabbah HN. Abnormal mitochondrial function in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol 1998;30:175762. [45] Schipke JD. Cardiac efficiency. Basic Res Cardiol 1994;89:20740. [46] Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W, et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 1997;96:21906. [47] Garnier A, Fortin D, Delomenie C, Momken I, Veksler V, VenturaClapier R. Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J Physiol 2003;551:491501. [48] Barger PM, Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med 2000;10:23845. [49] van Bilsen M, Smeets PJ, Gilde AJ, van der Vusse GJ. Metabolic remodelling of the failing heart: the cardiac burn-out syndrome? Cardiovasc Res 2004;61:21826. [50] Massie BM, Conway M, Yonge R, Frostick S, Sleight P, Ledingham J, et al. 31P nuclear magnetic resonance evidence of abnormal skeletal muscle metabolism in patients with congestive heart failure. Am J Cardiol 1987;60:30915. [51] De Sousa E, Veksler V, Bigard X, Mateo P, Ventura-Clapier R. Heart failure affects mitochondrial but not myofibrillar intrinsic properties of skeletal muscle. Circulation 2000;102:184753. [52] Vescovo G, Ravara B, Gobbo V, Angelini A, Dalla Libera L. Skeletal muscle fibres synthesis in heart failure: role of PGC-1alpha, calcineurin and GH. Int J Cardiol 2005;104:298306. [53] Garnier A, Fortin D, Zoll J, N'Guessan B, Mettauer B, Lampert E, et al. Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle. FASEB J 2005;19:4352. [54] Ventura-Clapier R, De Sousa E, Veksler V. Metabolic myopathy in heart failure. News Physiol Sci 2002;17:1916. [55] Sullivan MJ, Green HJ, Cobb FR. Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 1990;81:51827. [56] Drexler H, Riede U, Munzel T, Konig H, Funke E, Jusu H. Alterations of skeletal muscle in chronic heart failure. Circulation 1992;85:17519. [57] Mettauer B, Zoll J, Sanchez H, Lampert E, Ribera F, Veksler V, et al. Oxidative capacity of skeletal muscle in heart failure patients versus sedentary or active control subjects. J Am Coll Cardiol 2001;38:94754. [58] Williams AD, Selig S, Hare DL, Hayes A, Krum H, Patterson J, et al. Reduced exercise tolerance in CHF may be related to factors other than impaired skeletal muscle oxidative capacity. J Card Fail 2004;10: 1418. [59] Sanbe A, Tanonaka K, Kobayasi R, Takeo S. Effects of long-term therapy with ACE inhibitors, captopril, enalapril and trandolapril, on myocardial energy metabolism in rats with heart failure following myocardial infarction. J Mol Cell Cardiol 1995;27:220922. [60] Zoll J, Monassier L, Garnier A, N'Guessan B, Doutreleau S, Mettauer B, et al. ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction. J Appl Physiol 2006;101:38591. [61] Dirks AJ, Hofer T, Marzetti E, Pahor M, Leeuwenburgh C. Mitochondrial DNA mutations, energy metabolism and apoptosis in aging muscle. Ageing Res Rev 2006;5:17995.

[15] Hood DA, Irrcher I, Ljubicic V, Joseph AM. Coordination of metabolic plasticity in skeletal muscle. J Exp Biol 2006;209:226575. [16] Gielen S, Schuler G, Hambrecht R. Exercise training in coronary artery disease and coronary vasomotion. Circulation 2001;103:E16. [17] Hambrecht R, Fiehn E, Weigl C, Gielen S, Hamann C, Kaiser R, et al. Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure. Circulation 1998;98:270915. [18] Booth FW, Thomason DB. Molecular and cellular adaptation of muscle in response to exercise: perspectives of various models. Physiol Rev 1991;71:54185. [19] Pette D, Staron RS. Myosin isoforms, muscle fiber types, and transitions. Microsc Res Tech 2000;50:5009. [20] Coats AJ, Adamopoulos S, Meyer TE, Conway J, Sleight P. Effects of physical training in chronic heart failure. Lancet 1990;335:636. [21] Belardinelli R, Georgiou D, Cianci G, Purcaro A. Randomized, controlled trial of long-term moderate exercise training in chronic heart failure: effects on functional capacity, quality of life, and clinical outcome. Circulation 1999;99:117382. [22] Cohen-Solal A, Guiti C, Geyer C, Logeart D, Ennezat PV. Exercise training in chronic heart failure; why? Heart Fail Rev 1999;3:111. [23] Coats AJS. Exercise training in heart failure. Curr Control Trials Cardiovasc Med 2000;1:15560. [24] Piepoli MF, Davos C, Francis DP, Coats AJ. Exercise training metaanalysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ 2004;328:18995. [25] Pina IL, Daoud S. Exercise and heart failure. Minerva Cardioangiol 2004;52:53746. [26] Dzeja PP, Redfield MM, Burnett JC, Terzic A. Failing energetics in failing hearts. Curr Cardiol Rep 2000;2:2127. [27] Koulmann N, Bigard AX. Interaction between signalling pathways involved in skeletal muscle responses to endurance exercise. Pflugers Arch 2006:115. [28] Pina LL, Apstein CS, Balady GJ, Belardinelli R, Chaitman BR, Duscha BD, et al. Exercise and heart failure a statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention. Circulation 2003;107:121025. [29] Holloszy JO, Booth FW. Biochemical adaptations to endurance exercise in muscle. Annu Rev Physiol 1976;38:27391. [30] Pette D, Staron RS. Celllular and molecular diversities of mammalian skeletal muscle fibers. Rev Physiol Biochem Pharmacol 1990;116:176. [31] Sahlin K, Tonkonogi M, Soderlund K. Energy supply and muscle fatigue in humans. Acta Physiol Scand 1998;162:2616. [32] Dyck DJ, Glatz PJ, Keizer GH, Kiens B, Liu S, Richter EA, et al. Functional differences in lipid metabolism in resting skeletal muscle of various types. Am J Physiol 1997;272:E34051. [33] Dzeja PP, Terzic A. Phosphotransfer networks and cellular energetics. J Exp Biol 2003;206:203947. [34] Saks V, Dzeja P, Schlattner U, Vendelin M, Terzic A, Wallimann T. Cardiac system bioenergetics: metabolic basis of FrankStarling law. J Physiol 2006;571:25373. [35] Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands the phosphocreatine circuit for cellular energy homeostasis. Biochem J 1992;281:2140. [36] Kaasik A, Veksler V, Boehm E, Novotova M, Minajeva A, VenturaClapier R. Energetic crosstalk between organelles: architectural integration of energy production and utilization. Circ Res 2001;89:1539. [37] Kaasik A, Veksler V, Boehm E, Novotova M, Ventura-Clapier R. From energy store to energy channeling: a study in creatine kinase deficient fast skeletal muscle. FASEB J 2003;17:70810. [38] Saks VA, Kaambre T, Sikk P, Eimre M, Orlova E, Paju K, et al. Intracellular energetic units in red muscle cells. Biochem J 2001;356:64357. [39] Kelly DP, Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 2004;18:35768.

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on March 25, 2013

R. Ventura-Clapier et al. / Cardiovascular Research 73 (2007) 1018 [62] Gielen S, Adams V, Niebauer J, Schuler G, Hambrecht R. Aging and heart failure-similar syndromes of exercise intolerance? Implications for exercise-based interventions. Heart Fail Monit 2005;4:1306. [63] Moore RL. Cellular adaptations of the heart muscle to exercise training. Ann Med 1998;30:4653. [64] Stuewe SR, Gwirtz PA, Agarwal N, Mallet RT. Exercise training enhances glycolytic and oxidative enzymes in canine ventricular myocardium. J Mol Cell Cardiol 2000;32:90313. [65] Coleman R, Weiss A, Finkelbrand S, Silbermann M. Age and exercise-related changes in myocardial mitochondria in mice. Acta Histochem 1988;83:8190. [66] Murakami T, Shimomura Y, Fujitsuka N, Sugiyama S. Differential adaptation to endurance training between heart and gastrocnemius muscle mitochondria in rats. Biochem Mol Biol Int 1995;36: 28590. [67] Kayar SR, Conley KE, Claassen H, Hoppeler H. Capillarity and mitochondrial distribution in rat myocardium following exercise training. J Exp Biol 1986;120:18999. [68] Rosa EF, Silva AC, Ihara SS, Mora OA, Aboulafia J, Nouailhetas VL. Habitual exercise program protects murine intestinal, skeletal, and cardiac muscles against aging. J Appl Physiol 2005;99:156975. [69] Terblanche SE, Gohil K, Packer L, Henderson S, Brooks GA. The effects of endurance training and exhaustive exercise on mitochondrial enzymes in tissues of the rat (Rattus norvegicus). Comp Biochem Physiol A Mol Integr Physiol 2001;128:88996. [70] Iemitsu M, Miyauchi T, Maeda S, Sakai S, Fujii N, Miyazaki H, et al. Cardiac hypertrophy by hypertension and exercise training exhibits different gene expression of enzymes in energy metabolism. Hypertens Res 2003;26:82937. [71] Stuewe SR, Gwirtz PA, Mallet RT. Exercise training increases creatine kinase capacity in canine myocardium. Med Sci Sports Exerc 2001;33:928. [72] Howald H, Hoppeler H, Claassen H, Mathieu O, Straub R. Influences of endurance training on the ultrastructural composition of the different muscle fiber types in humans. Pflugers Arch 1985;403:36976. [73] Zoll J, Sanchez H, N'Guessan B, Ribera F, Lampert E, Bigard X, et al. Physical activity changes the regulation of mitochondrial respiration in human skeletal muscle. J Physiol 2002;543:191200. [74] Zoll J, Koulmann N, Bahi L, Ventura-Clapier R, Bigard AX. Quantitative and qualitative adaptation of skeletal muscle mitochondria to increased physical activity. J Cell Physiol 2003;194:18693. [75] Garcia-Roves PM, Huss J, Holloszy JO. Role of calcineurin in exercise-induced mitochondrial biogenesis. Am J Physiol Endocrinol Metab 2006;290:E11729. [76] Zoll J, N'Guessan B, Ribera F, Lampert E, Fortin D, Veksler V, et al. Preserved response of mitochondrial function to short-term endurance training in skeletal muscle of heart transplant recipients. J Am Coll Cardiol 2003;42:12632. [77] Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, Rosenberg PB, et al. Exercise stimulates Pgc-1alpha transcription in skeletal muscle through activation of the p38 MAPK pathway. J Biol Chem 2005;280: 1958793. [78] Wu H, Kanatous SB, Thurmond FA, Gallardo T, Isotani E, BasselDuby R, et al. Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 2002;296:34952. [79] Frosig C, Jorgensen SB, Hardie DG, Richter EA, Wojtaszewski JF. 5-AMP-activated protein kinase activity and protein expression are regulated by endurance training in human skeletal muscle. Am J Physiol Endocrinol Metab 2004;286:E4117. [80] Norrbom J, Sundberg CJ, Ameln H, Kraus WE, Jansson E, Gustafsson T. PGC-1alpha mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol 2004;96:18994. [81] Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy JO. Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol 2000;88:221926. [82] Terada S, Goto M, Kato M, Kawanaka K, Shimokawa T, Tabata I. Effects of low-intensity prolonged exercise on PGC-1 mRNA

17

[83] [84]

[85]

[86]

[87]

[88]

[89]

[90]

[91]

[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

expression in rat epitrochlearis muscle. Biochem Biophys Res Comm 2002;296:3504. Semenza GL. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda) 2004;19:17682. Ameln H, Gustafsson T, Sundberg CJ, Okamoto K, Jansson E, Poellinger L, et al. Physiological activation of hypoxia inducible factor-1 in human skeletal muscle. FASEB J 2005;19:100911. Birot OJ, Peinnequin A, Simler N, van Cuyck Gandre H, Hamel R, Bigard XA. Vascular endothelial growth factor expression in heart of rats exposed to hypobaric hypoxia: differential response between mRNA and protein. J Cell Physiol 2004;200:10715. McElroy CL, Gissen SA, Fishbein MC. Exercise-induced reduction in myocardial infarct size after coronary artery occlusion in the rat. Circulation 1978;57:95862. Freimann S, Scheinowitz M, Yekutieli D, Feinberg MS, Eldar M, Kessler-Icekson G. Prior exercise training improves the outcome of acute myocardial infarction in the rat. Heart structure, function, and gene expression. J Am Coll Cardiol 2005;45:9318. Ascensao A, Ferreira R, Magalhaes J. Exercise-induced cardioprotection biochemical, morphological and functional evidence in whole tissue and isolated mitochondria. Int J Cardiol Jul 21 2006 [Electronic publication ahead of print]. Wisloff U, Loennechen JP, Currie S, Smith GL, Ellingsen O. Aerobic exercise reduces cardiomyocyte hypertrophy and increases contractility, Ca2+ sensitivity and SERCA-2 in rat after myocardial infarction. Cardiovasc Res 2002;54:16274. Wang J, Yi GH, Knecht M, Cai BL, Poposkis S, Packer M, et al. Physical training alters the pathogenesis of pacing-induced heart failure through endothelium-mediated mechanisms in awake dogs. Circulation 1997;96:268392. Belardinelli R, Georgiou D, Cianci G, Berman N, Ginzton L, Purcaro A. Exercise training improves left ventricular diastolic filling in patients with dilated cardiomyopathy. Clinical and prognostic implications. Circulation 1995;91:277584. Giannuzzi P, Temporelli PL, Corra U, Tavazzi L. Antiremodeling effect of long-term exercise training in patients with stable chronic heart failure: results of the Exercise in Left Ventricular Dysfunction and Chronic Heart Failure (ELVD-CHF) trial. Circulation 2003;108:5549. Braith RW, Welsch MA, Feigenbaum MS, Kluess HA, Pepine CJ. Neuroendocrine activation in heart failure is modified by endurance exercise training. J Am Coll Cardiol 1999;34:11705. Conraads VM, Beckers P, Bosmans J, De Clerck LS, Stevens WJ, Vrints CJ, et al. Combined endurance/resistance training reduces plasma TNF-alpha receptor levels in patients with chronic heart failure and coronary artery disease. Eur Heart J 2002;23:185460. Adamopoulos S, Parissis J, Karatzas D, Kroupis C, Georgiadis M, Karavolias G, et al. Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure. J Am Coll Cardiol 2002;39:65363. De Sousa E, Lechene P, Fortin D, N'Guessan B, Belmadani S, Bigard X, et al. Cardiac and skeletal muscle energy metabolism in heart failure: beneficial effects of voluntary activity. Cardiovasc Res 2002;56:2608. Stolen KQ, Kemppainen J, Ukkonen H, Kalliokoski KK, Luotolahti M, Lehikoinen P, et al. Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy. J Am Coll Cardiol 2003;41:4607. Taylor RS, Brown A, Ebrahim S, Jolliffe J, Noorani H, Rees K, et al. Exercise-based rehabilitation for patients with coronary heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med 2004;116:68292. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al. ACC/AHA guidelines for the management of patients with STelevation myocardial infarction-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation 2004;110:588636.

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on March 25, 2013

18

R. Ventura-Clapier et al. / Cardiovascular Research 73 (2007) 1018 [112] Hambrecht R, Niebauer J, Fiehn E, Kalberer B, Offner B, Hauer K, et al. Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles. J Am Coll Cardiol 1995;25:123949. [113] Hambrecht R, Fiehn E, Yu JT, Niebauer J, Weigl C, Hilbrich L, et al. Effects of endurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic heart failure. J Am Coll Cardiol 1997;29:106773. [114] Santoro C, Cosmas A, Forman D, Morghan A, Bairos L, Levesque S, et al. Exercise training alters skeletal muscle mitochondrial morphometry in heart failure patients. J Cardiovasc Risk 2002;9:37781. [115] Menshikova EV, Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH. Effects of exercise on mitochondrial content and function in aging human skeletal muscle. J Gerontol A Biol Sci Med Sci 2006;61:53440. [116] Hambrecht R, Adams V, Gielen S, Linke A, Mbius-Winkler S, Yu J, et al. Exercise intolerance in patients with chronic heart failure and increased expression of inducible nitric oxide synthase in the skeletal muscle. J Am Coll Cardiol 1999;33:1749. [117] Tsutsui H, Ide T, Hayashidani S, Suematsu N, Shiomi T, Wen J, et al. Enhanced generation of reactive oxygen species in the limb skeletal muscles from a murine infarct model of heart failure. Circulation 2001;104:13446. [118] Gielen S, Adams V, Mobius-Winkler S, Linke A, Erbs S, Yu J, et al. Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure. J Am Coll Cardiol 2003;42: 861968. [119] Adams V, Linke A, Krankel N, Erbs S, Gielen S, Mobius-Winkler S, et al. Impact of regular physical activity on the NAD(P)H oxidase and angiotensin receptor system in patients with coronary artery disease. Circulation 2005;111:55562. [120] Linke A, Adams V, Schulze PC, Erbs S, Gielen S, Fiehn E, et al. Antioxidative effects of exercise training in patients with chronic heart failure: increase in radical scavenger enzyme activity in skeletal muscle. Circulation 2005;111:176370. [121] Stewart KJ. Physical activity and aging. Ann N YAcad Sci 2005;1055: 193206.

[100] Scheinowitz M, Harpaz D. Safety of cardiac rehabilitation in a medically supervised, community-based program. Cardiology 2005;103: 1137. [101] Adamopoulos S, Coats AJ, Brunotte F, Arnolda L, Meyer T, Thompson CH, et al. Physical training improves skeletal muscle metabolism in patients with chronic heart failure. J Am Coll Cardiol 1993;21:11016. [102] Minotti JR, Johnson EC, Hudson TL, Zuroske G, Murata G, Fukushima E, et al. Skeletal muscle response to exercise training in congestive heart failure. J Clin Invest 1990;86:7518. [103] Ohtsubo M, Yonezawa K, Nishijima H, Okita K, Hanada A, Kohya T, et al. Metabolic abnormality of calf skeletal muscle is improved by localised muscle training without changes in blood flow in chronic heart failure. Heart 1997;78:43743. [104] Stratton JR, Kemp GJ, Daly RC, Yacoub M, Rajagopalan B. Effects of cardiac transplantation on bioenergetic abnormalities of skeletal muscle in congestive heart failure. Circulation 1994;89:162431. [105] Sullivan MJ, Higginbotham MB, Cobb FR. Exercise training in patients with severe left ventricular dysfunction. Hemodynamic and metabolic effects. Circulation 1988;78:50615. [106] Duscha BD, Kraus WE, Keteyian SJ, Sullivan MJ, Green HJ, Schahat FH, et al. Capillary density of skeletal muscle. A contributing mechanism for exercise intolerance in class IIIII chronic heart failure independent of other peripheral alterations. J Am Coll Cardiol 1999;33: 195663. [107] Scarpelli M, Belardinelli R, Tulli D, Provinciali L. Quantitative analysis of changes occurring in muscle vastus lateralis in patients with heart failure after low-intensity training. Anal Quant Cytol Histol 1999;21:37480. [108] Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996;93: 2104. [109] Varin R, Mulder P, Richard V, Tamion F, Devaux C, Henry J-P, et al. Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure. Circulation 1999;99: 29517. [110] Ennezat PV, Malendowicz SL, Testa M, Colombo PC, Cohen-Solal A, Evans T, et al. Physical training in patients with chronic heart failure enhances the expression of genes encoding antioxidative enzymes. J Am Coll Cardiol 2001;38:1948. [111] Kojda G, Hambrecht R. Molecular mechanisms of vascular adaptations to exercise. Physical activity as an effective antioxidant therapy? Cardiovasc Res 2005;67:18797.

Downloaded from http://cardiovascres.oxfordjournals.org/ by guest on March 25, 2013