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Exp Physiol 99.4 (2014) pp 616–620
Symposium Report
Skeletal myopathy in heart failure: effects of aerobic exercise training P. C. Brum1,2 , A. V. Bacurau1 , T. F. Cunha1 , L. R. G. Bechara1 and J. B. N. Moreira2 1
Experimental Physiology
2
School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway
New Findings r What is the topic of this review? This symposium report addresses the effects of aerobic exercise training on skeletal muscle myopathy induced by heart failure (HF), with emphasis on the mechanisms involved in muscle atrophy. r What advances does it highlight? It highlights the therapeutic effect of aerobic exercise training to combat skeletal myopathy in HF. Our results demonstrated that aerobic exercise training re-established normal redox balance and prevented increased protein degradation by the ubiquitin–proteasome system, thereby preserving skeletal muscle mass in experimental models of HF. Our findings contribute to a better understanding of the mechanisms involved in skeletal myopathy in HF and the effects of training.
Reduced aerobic capacity, as measured by maximal oxygen uptake, is a hallmark in cardiovascular diseases and strongly predicts poor prognosis and higher mortality rates in heart failure patients. While exercise capacity is poorly correlated with cardiac function in this population, skeletal muscle abnormalities present a striking association with maximal oxygen uptake. This fact draws substantial attention to the clinical relevance of targeting skeletal myopathy in heart failure. Considering that skeletal muscle is highly responsive to aerobic exercise training, we addressed the benefits of aerobic exercise training to combat skeletal myopathy in heart failure, focusing on the mechanisms by which aerobic exercise training counteracts skeletal muscle atrophy. (Received 18 October 2013; accepted after revision 19 November 2013; first published online 22 November 2013) Corresponding author P. C. Brum: Escola de Educac¸a˜o F´ısica e Esporte, Universidade de S˜ao Paulo, Av. Professor Mello Moraes, 65 – S˜ao Paulo, SP 05508-900, Brazil. Email: [email protected]
Intrinsic alterations of skeletal muscle (referred from now on as skeletal myopathy) are the main determinants of limited exercise capacity in heart failure (HF) patients, and current literature presents such alterations as an important matter for the pathophysiology of HF (Massie et al. 1996; Middlekauff, 2010; Brum et al. 2011; Zizola & Schulze, 2013). Skeletal myopathy affects large and small muscles involved in posture, locomotion and respiration. In
HF patients and experimental models, several features of skeletal myopathy have been described, such as capillary rarefaction, a switch from type I (oxidative) to type II (glycolytic) fibres, impaired metabolism and excitation–contraction coupling, and skeletal muscle atrophy (Sullivan et al. 1990; Drexler et al. 1992). Importantly, skeletal muscle atrophy was depicted as an independent predictor of mortality in HF patients (Anker et al. 1997); therefore, therapeutic strategies that are able to delay the onset or minimize the consequences of skeletal myopathy in HF are of clinical relevance.
DOI: 10.1113/expphysiol.2013.076844
C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
Introduction
Exp Physiol 99.4 (2014) pp 616–620
Aerobic exercise training counteracts skeletal myopathy
Among the non-pharmacological interventions in HF, aerobic exercise training (AET) is the therapeutic approach with sufficient clinical evidence for counteracting skeletal muscle myopathy in HF (von Haehling et al. 2013), and the physiological and molecular mechanisms underlying its benefits are currently under intense investigation. In this symposium report, we discuss the effects of AET on the main features of skeletal myopathy, with a focus on the mechanisms by which AET counteracts skeletal muscle atrophy.
Impact of aerobic exercise training on features of skeletal myopathy
In order to understand better the mechanisms behind the benefits of AET on HF-induced skeletal myopathy, we used a genetic model of sympathetic hyperactivity-induced HF in mice lacking α2a /α2c -adrenergic receptors. These mice display chronically elevated sympathetic tone associated with cardiac dysfunction by 4 months of age and severe HF at 7 months of age (Brum et al. 2002; Rolim et al. 2007; Ferreira et al. 2011). Additionally, these mice present several features of skeletal myopathy, such as muscle dysfunction, capillary rarefaction, impaired aerobic metabolism, atrophy and exercise intolerance (Bacurau et al. 2009). Of interest, moderate-intensity AET (60% of maximal workload achieved in a graded treadmill running test, 1 h per day, 5 days per week for 8 weeks) improved exercise tolerance and muscle function, which was accompanied by greater abundance of proteins involved in sarcoplasmic reticulum calcium release and re-uptake in skeletal muscle (Bueno et al. 2010; Cunha et al. 2012). Importantly, AET also prevented impaired aerobic metabolism and muscle loss in our HF model (Bacurau et al. 2009). Muscle loss is a consequence of reduced protein synthesis and boosted protein degradation, the latter mainly associated with an overactivation of the ubiquitin–proteasome system (UPS; Glass, 2003). Considering that the UPS is the main proteolytic system responsible for disposal of damaged proteins (Attaix et al. 2008), we studied the effects of AET on the UPS in our HF mice model. We observed UPS overactivation associated with an upregulation of atrogin-1 mRNA levels and increased chymotrypsin-like proteasome activity, and AET re-established UPS activation to normal levels (Cunha et al. 2012). Interestingly, we later confirmed the clinical relevance of our findings by showing that AET also reduced chymotrypsin-like proteasome activity in muscle biopsies from HF patients (Cunha et al. 2012). The data we obtained in these first studies, together with updated literature regarding the regulation of protein catabolism (Gielen et al. 2012; Schiaffino et al. 2013; von C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
617
Haehling et al. 2013), led us to search for the mechanisms triggering UPS overactivation. In this context, oxidative stress directly modulates proteasome activity (Aiken et al. 2011); therefore, it emerged as a promising target in HF-induced skeletal myopathy (Barker & Traber, 2007). Increased oxidative stress in HF results from an imbalance between pro- and antioxidant activities. Antioxidant enzymes (e.g. superoxide dismutase, catalase and glutathione peroxidase) show reduced expression and impaired activity in skeletal muscle of HF patients, when compared with healthy individuals (Linke et al. 2005). In contrast, increased production of reactive oxygen species from mitochondria and other sources might play an important role in HF-induced skeletal myopathy. In this sense, our ongoing studies in an animal model of HF induced by myocardial infarction in rats (12 weeks after coronary artery ligation) suggest that NADPH oxidase, an important reactive oxygen species-generating source, is overactivated in skeletal muscle. Such overactivity presents a positive correlation with proteasome activity (L. Bechara, J. Moreira, P. Jannig, V. Voltarelli, P. Dourado, A. Vasconcelos, C. Scavone, P. Ramires and P. Brum, unpublished observations), which indicates that NADPH oxidase-generated reactive oxygen species induced proteasome activation, possibly by oxidation of proteasome substrates. We have recently demonstrated that AET restored redox balance in skeletal muscle in a rat model of HF, which was associated with reduced proteasome activity, improved skeletal muscle mass and restored superoxide dismutase activity (Moreira et al. 2013). Altogether, these responses might be related to the reduced NADPH activity observed in our ongoing study (L. Bechara, J. Moreira, P. Jannig, V. Voltarelli, P. Dourado, A. Vasconcelos, C. Scavone, P. Ramires and P. Brum, unpublished observations). Figure 1 summarizes our findings regarding the benefits of AET on skeletal muscle in HF. Even though the benefits of AET for HF patients have been reported for decades, the optimal training protocol is still heavily debated. Moderate-intensity AET [50–70% of maximal oxygen uptake (V˙ O2 max )] is an effective therapy (Roveda et al. 2003; Fraga et al. 2007); however, recent investigations have suggested that high-intensity protocols promote superior improvements of V˙ O2 max in HF patients (Wisløff et al. 2007; Moholdt et al. 2012). Considering these findings, we hypothesized that high-intensity AET would also promote superior benefits in skeletal muscle of infarcted rats. Thus, we compared the effects of high-intensity (running intervals of 4 min at 85–90% V˙ O2 max and 3 min at 60% V˙ O2 max at 15% inclination, 5 days per week for 8 weeks) and moderate-intensity AET protocols (60% V˙ O2 max at 15% inclination, 1 h per day, 5 days per week for 8 weeks) on skeletal muscle of myocardial-infarcted rats (12 weeks after coronary artery ligation). Surprisingly, our data
618
P. C. Brum and others
showed that despite superior effects of high-intensity AET on exercise capacity, skeletal muscle adaptations were remarkably similar between protocols (Moreira et al. 2013) with regard to muscle mass, metabolic capacity and proteasome activation. These findings, although against our hypothesis, call for evaluation of novel training regimens (other combinations of intensity, duration and frequency) that could optimize the effects of AET in HF. Finally, despite the indisputable benefits of AET, one can advocate that physical activity may acutely increase the risk of myocardial infarction and sudden cardiac death in HF patients, primarily due to increased cardiac demand above the capacity of the heart and excessive neurohumoral activation. It is important to highlight that the moderate-intensity AET is recommended for HF therapy in clinically stable patients and under optimized medication (European Society of Cardiology, 2001). However, the risk associated with AET is an important concern and has recently been addressed by small and
Exp Physiol 99.4 (2014) pp 616–620
large studies, as well as in scientific statements from major cardiac health associations (Thompson et al. 2007; Rognmo et al. 2012). Such studies show that the incidence of adverse cardiac events during aerobic exercise is one occurrence per 50–150,000 h of summed exercise time (including the total training time of all HF patients studied), concluding that the risk of major cardiac events is low, which suggests that the benefits of AET for HF patients outweigh the risks.
Concluding remarks
Nearly 30 years after the first study that demonstrated skeletal muscle abnormalities in HF, knowledge in this field has evolved immensely. Heart failure-induced skeletal myopathy grew from an unrecognized matter to a predictor of prognosis. At a similar pace, AET evolved from condemned practice to therapy for HF. Although
Figure 1. Effects of aerobic exercise training on heart failure-induced skeletal myopathy Increased generation of reactive oxygen species, together with worsened antioxidant defense, leads to increased protein degradation and reduced protein synthesis in the skeletal muscle (illustrated by open arrows). Aerobic exercise training counteracts the mechanisms responsible for skeletal muscle atrophy in heart failure (illustrated by filled arrows). Abbreviations: Akt, protein kinase B; atrogin-1/MAFbx, muscle atrophy F-box protein; IGF-I, insulin-like growth factor-1; MuRF-1, muscle RING-finger protein-1; ROS, reactive oxygen species; and UPS, ubiquitin–proteasome system.
C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
Exp Physiol 99.4 (2014) pp 616–620
Aerobic exercise training counteracts skeletal myopathy
such developments now benefit HF patients, there is still a long way to go. Firstly, most clinical trials that involve training protocols include specific HF patients, commonly those with an ischaemic aetiology. Therefore, little is known about the effects of AET on skeletal muscle of other HF populations, such as in HF with a preserved ejection fraction or after cardiac transplantation. Thus, further investigations in other HF populations are encouraged, because these patients also suffer from impaired functional capacity and could benefit from AET. Secondly, the combination of AET and medication for HF provides benefits in addition to those of either intervention alone (Vanzelli et al. 2013); therefore, it is an open field for promising studies. Finally, technological advances now provide powerful and still underestimated tools with which to approach molecular targets in HF. Unbiased approaches, such as RNA sequencing and proteomic detection of post-translational modifications, should be explored further because they may lead to discovery of novel targets for treatment of skeletal myopathy in HF. References Aiken CT, Kaake RM, Wang X & Huang L (2011). Oxidative stress-mediated regulation of proteasome complexes. Mol Cell Proteomics 10, 1–11. Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-Peploe KM, Harrington D, Kox WJ, Poole-Wilson PA & Coats AJ (1997). Wasting as independent risk factor for mortality in chronic heart failure. Lancet 349, 1050–1053. Attaix D, Combaret L, B´echet D & Taillandier D (2008). Role of the ubiquitin-proteasome pathway in muscle atrophy in cachexia. Curr Opin Support Palliat Care 2, 262–266. Bacurau AV, Jardim MA, Ferreira JC, Bechara LR, Bueno CR Jr, Alba-Loureiro TC, Negrao CE, Casarini DE, Curi R, Ramires PR, Moriscot AS & Brum PC (2009). Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: role of exercise training. J Appl Physiol 106, 1631–1640. Barker T & Traber MG (2007). From animals to humans: evidence linking oxidative stress as a causative factor in muscle atrophy. J Physiol 583, 421–422. Brum PC, Bacurau AV, Medeiros A, Ferreira JC, Vanzelli AS & Negrao CE (2011). Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle function. Braz J Med Biol Res 44, 827–835. Brum PC, Kosek J, Patterson A, Bernstein D & Kobilka B (2002). Abnormal cardiac function associated with sympathetic nervous system hyperactivity in mice. Am J Physiol Heart Circ Physiol 283, H1838–H1845. Bueno CR Jr, Ferreira JC, Pereira MG, Bacurau AV & Brum PC (2010). Aerobic exercise training improves skeletal muscle function and Ca2+ handling-related protein expression in sympathetic hyperactivity-induced heart failure. J Appl Physiol 109, 702–709.
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Cunha TF, Bacurau AV, Moreira JB, Paix˜ao NA, Campos JC, Ferreira JC, Leal ML, Negr˜ao CE, Moriscot AS, Wisløff U & Brum PC (2012). Exercise training prevents oxidative stress and ubiquitin-proteasome system overactivity and reverse skeletal muscle atrophy in heart failure. PLoS One 7, e41701. Drexler H, Riede U, M¨unzel T, K¨onig H, Funke E & Just H (1992). Alterations of skeletal muscle in chronic heart failure. Circulation 85, 1751–1759. European Society of Cardiology (2001). Recommendations for exercise training in chronic heart failure patients. Eur Heart J 22, 125–135. Ferreira JC, Moreira JB, Campos JC, Pereira MG, Mattos KC, Coelho MA & Brum PC (2011). Angiotensin receptor blockade improves the net balance of cardiac Ca2+ handling-related proteins in sympathetic hyperactivity-induced heart failure. Life Sci 88, 578–585. Fraga R, Franco FG, Roveda F, de Matos LN, Braga AM, Rondon MU, Rotta DR, Brum PC, Barretto AC, Middlekauff HR & Negr˜ao CE (2007). Exercise training reduces sympathetic nerve activity in heart failure patients treated with carvedilol. Eur J Heart Fail 9, 630–636. Gielen S, Sandri M, Kozarez I, Kratzsch J, Teupser D, Thiery J, Erbs S, Mangner N, Lenk K, Hambrecht R, Schuler G & Adams V (2012). Exercise training attenuates MuRF-1 expression in the skeletal muscle of patients with chronic heart failure independent of age: the randomized Leipzig Exercise Intervention in Chronic Heart Failure and Aging catabolism study. Circulation 125, 2716–2727. Glass DJ (2003). Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat Cell Biol 5, 87–90. Linke A, Adams V, Schulze PC, Erbs S, Gielen S, Fiehn E, M¨obius-Winkler S, Schubert A, Schuler G & Hambrecht R (2005). Antioxidative effects of exercise training in patients with chronic heart failure: increase in radical scavenger enzyme activity in skeletal muscle. Circulation 111, 1763–1770. Massie BM, Simonini A, Sahgal P, Wells L & Dudley GA (1996). Relation of systemic and local muscle exercise capacity to skeletal muscle characteristics in men with congestive heart failure. J Am Coll Cardiol 27, 140– 145. Middlekauff HR (2010). Making the case for skeletal myopathy as the major limitation of exercise capacity in heart failure. Circ Heart Fail 3, 537–546. Moholdt T, Aamot IL, Granøien I, Gjerde L, Myklebust G, Walderhaug L, Brattbakk L, Hole T, Graven T, Stølen TO, Amundsen BH, Mølmen-Hansen HE, Støylen A, Wisløff U & Slørdahl SA (2012). Aerobic interval training increases peak oxygen uptake more than usual care exercise training in myocardial infarction patients: a randomized controlled study. Clin Rehabil 26, 33–44. Moreira JB, Bechara LR, Bozi LH, Jannig PR, Monteiro AW, Dourado PM, Wisløff U & Brum PC (2013). High- versus moderate-intensity aerobic exercise training effects on skeletal muscle of infarcted rats. J Appl Physiol 114, 1029–1041.
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Rognmo Ø, Moholdt T, Bakken H, Hole T, Mølstad P, Myhr NE, Grimsmo J & Wisløff U (2012). Cardiovascular risk of high- versus moderate-intensity aerobic exercise in coronary heart disease patients. Circulation 126, 1436–1440. Rolim NP, Medeiros A, Rosa KT, Mattos KC, Irigoyen MC, Krieger EM, Krieger JE, Negr˜ao CE & Brum PC (2007). Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure. Physiol Genomics 29, 246–252. Roveda F, Middlekauff HR, Rondon MU, Reis SF, Souza M, Nastari L, Barretto AC, Krieger EM & Negr˜ao CE (2003). The effects of exercise training on sympathetic neural activation in advanced heart failure: a randomized controlled trial. J Am Coll Cardiol 42, 854–860. Schiaffino S, Dyar KA, Ciciliot S, Blaauw B & Sandri M (2013). Mechanisms regulating skeletal muscle growth and atrophy. FEBS J 280, 4294–4314. Sullivan MJ, Green HJ & Cobb FR (1990). Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. Circulation 81, 518–527. Thompson PD, Franklin BA, Balady GJ, Blair SN, Corrado D, Estes NA 3rd, Fulton JE, Gordon NF, Haskell WL, Link MS, Maron BJ, Mittleman MA, Pelliccia A, Wenger NK, Willich SN, Costa F; American Heart Association Council on Nutrition, Physical Activity, and Metabolism; American Heart Association Council on Clinical Cardiology; & American College of Sports Medicine (2007). Exercise and acute cardiovascular events placing the risks into perspective: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism and the Council on Clinical Cardiology. Circulation 115, 2358–2368.
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Vanzelli AS, Medeiros A, Rolim N, Bartholomeu JB, Cunha TF, Bechara LG, Gomes ER, Mattos KC, Sirvente R, Salemi V, Mady C, Negrao CE, Guatimosim S & Brum PC (2013). Integrative effect of carvedilol and aerobic exercise training therapies on improving cardiac contractility and remodeling in heart failure mice. PLoS One 8, e62452. von Haehling S, Steinbeck L, Doehner W, Springer J & Anker SD (2013). Muscle wasting in heart failure: an overview. Int J Biochem Cell Biol 45, 2257–2265. Wisløff U, Støylen A, Loennechen JP, Bruvold M, Rognmo Ø, Haram PM, Tjønna AE, Helgerud J, Slørdahl SA, Lee SJ, Videm V, Bye A, Smith GL, Najjar SM, Ellingsen Ø & Skjaerpe T (2007). Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation 115, 3086–3094. Zizola C & Schulze PC (2013). Metabolic and structural impairment of skeletal muscle in heart failure. Heart Fail Rev 18, 623–630.
Additional Information Competing interests None declared. Funding PCB holds grants from FAPESP (#2010/50048-1), Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de N´ıvel Superior (CAPES 6967-12-4) and Conselho Nacional de Pesquisa e Desenvolvimento (CNPq, #302201/2011-44).
C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
Exp Physiol 99.4 (2014) pp 616–620
Symposium Report
Skeletal myopathy in heart failure: effects of aerobic exercise training P. C. Brum1,2 , A. V. Bacurau1 , T. F. Cunha1 , L. R. G. Bechara1 and J. B. N. Moreira2 1
Experimental Physiology
2
School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway
New Findings r What is the topic of this review? This symposium report addresses the effects of aerobic exercise training on skeletal muscle myopathy induced by heart failure (HF), with emphasis on the mechanisms involved in muscle atrophy. r What advances does it highlight? It highlights the therapeutic effect of aerobic exercise training to combat skeletal myopathy in HF. Our results demonstrated that aerobic exercise training re-established normal redox balance and prevented increased protein degradation by the ubiquitin–proteasome system, thereby preserving skeletal muscle mass in experimental models of HF. Our findings contribute to a better understanding of the mechanisms involved in skeletal myopathy in HF and the effects of training.
Reduced aerobic capacity, as measured by maximal oxygen uptake, is a hallmark in cardiovascular diseases and strongly predicts poor prognosis and higher mortality rates in heart failure patients. While exercise capacity is poorly correlated with cardiac function in this population, skeletal muscle abnormalities present a striking association with maximal oxygen uptake. This fact draws substantial attention to the clinical relevance of targeting skeletal myopathy in heart failure. Considering that skeletal muscle is highly responsive to aerobic exercise training, we addressed the benefits of aerobic exercise training to combat skeletal myopathy in heart failure, focusing on the mechanisms by which aerobic exercise training counteracts skeletal muscle atrophy. (Received 18 October 2013; accepted after revision 19 November 2013; first published online 22 November 2013) Corresponding author P. C. Brum: Escola de Educac¸a˜o F´ısica e Esporte, Universidade de S˜ao Paulo, Av. Professor Mello Moraes, 65 – S˜ao Paulo, SP 05508-900, Brazil. Email: [email protected]
Intrinsic alterations of skeletal muscle (referred from now on as skeletal myopathy) are the main determinants of limited exercise capacity in heart failure (HF) patients, and current literature presents such alterations as an important matter for the pathophysiology of HF (Massie et al. 1996; Middlekauff, 2010; Brum et al. 2011; Zizola & Schulze, 2013). Skeletal myopathy affects large and small muscles involved in posture, locomotion and respiration. In
HF patients and experimental models, several features of skeletal myopathy have been described, such as capillary rarefaction, a switch from type I (oxidative) to type II (glycolytic) fibres, impaired metabolism and excitation–contraction coupling, and skeletal muscle atrophy (Sullivan et al. 1990; Drexler et al. 1992). Importantly, skeletal muscle atrophy was depicted as an independent predictor of mortality in HF patients (Anker et al. 1997); therefore, therapeutic strategies that are able to delay the onset or minimize the consequences of skeletal myopathy in HF are of clinical relevance.
DOI: 10.1113/expphysiol.2013.076844
C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
Introduction
Exp Physiol 99.4 (2014) pp 616–620
Aerobic exercise training counteracts skeletal myopathy
Among the non-pharmacological interventions in HF, aerobic exercise training (AET) is the therapeutic approach with sufficient clinical evidence for counteracting skeletal muscle myopathy in HF (von Haehling et al. 2013), and the physiological and molecular mechanisms underlying its benefits are currently under intense investigation. In this symposium report, we discuss the effects of AET on the main features of skeletal myopathy, with a focus on the mechanisms by which AET counteracts skeletal muscle atrophy.
Impact of aerobic exercise training on features of skeletal myopathy
In order to understand better the mechanisms behind the benefits of AET on HF-induced skeletal myopathy, we used a genetic model of sympathetic hyperactivity-induced HF in mice lacking α2a /α2c -adrenergic receptors. These mice display chronically elevated sympathetic tone associated with cardiac dysfunction by 4 months of age and severe HF at 7 months of age (Brum et al. 2002; Rolim et al. 2007; Ferreira et al. 2011). Additionally, these mice present several features of skeletal myopathy, such as muscle dysfunction, capillary rarefaction, impaired aerobic metabolism, atrophy and exercise intolerance (Bacurau et al. 2009). Of interest, moderate-intensity AET (60% of maximal workload achieved in a graded treadmill running test, 1 h per day, 5 days per week for 8 weeks) improved exercise tolerance and muscle function, which was accompanied by greater abundance of proteins involved in sarcoplasmic reticulum calcium release and re-uptake in skeletal muscle (Bueno et al. 2010; Cunha et al. 2012). Importantly, AET also prevented impaired aerobic metabolism and muscle loss in our HF model (Bacurau et al. 2009). Muscle loss is a consequence of reduced protein synthesis and boosted protein degradation, the latter mainly associated with an overactivation of the ubiquitin–proteasome system (UPS; Glass, 2003). Considering that the UPS is the main proteolytic system responsible for disposal of damaged proteins (Attaix et al. 2008), we studied the effects of AET on the UPS in our HF mice model. We observed UPS overactivation associated with an upregulation of atrogin-1 mRNA levels and increased chymotrypsin-like proteasome activity, and AET re-established UPS activation to normal levels (Cunha et al. 2012). Interestingly, we later confirmed the clinical relevance of our findings by showing that AET also reduced chymotrypsin-like proteasome activity in muscle biopsies from HF patients (Cunha et al. 2012). The data we obtained in these first studies, together with updated literature regarding the regulation of protein catabolism (Gielen et al. 2012; Schiaffino et al. 2013; von C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
617
Haehling et al. 2013), led us to search for the mechanisms triggering UPS overactivation. In this context, oxidative stress directly modulates proteasome activity (Aiken et al. 2011); therefore, it emerged as a promising target in HF-induced skeletal myopathy (Barker & Traber, 2007). Increased oxidative stress in HF results from an imbalance between pro- and antioxidant activities. Antioxidant enzymes (e.g. superoxide dismutase, catalase and glutathione peroxidase) show reduced expression and impaired activity in skeletal muscle of HF patients, when compared with healthy individuals (Linke et al. 2005). In contrast, increased production of reactive oxygen species from mitochondria and other sources might play an important role in HF-induced skeletal myopathy. In this sense, our ongoing studies in an animal model of HF induced by myocardial infarction in rats (12 weeks after coronary artery ligation) suggest that NADPH oxidase, an important reactive oxygen species-generating source, is overactivated in skeletal muscle. Such overactivity presents a positive correlation with proteasome activity (L. Bechara, J. Moreira, P. Jannig, V. Voltarelli, P. Dourado, A. Vasconcelos, C. Scavone, P. Ramires and P. Brum, unpublished observations), which indicates that NADPH oxidase-generated reactive oxygen species induced proteasome activation, possibly by oxidation of proteasome substrates. We have recently demonstrated that AET restored redox balance in skeletal muscle in a rat model of HF, which was associated with reduced proteasome activity, improved skeletal muscle mass and restored superoxide dismutase activity (Moreira et al. 2013). Altogether, these responses might be related to the reduced NADPH activity observed in our ongoing study (L. Bechara, J. Moreira, P. Jannig, V. Voltarelli, P. Dourado, A. Vasconcelos, C. Scavone, P. Ramires and P. Brum, unpublished observations). Figure 1 summarizes our findings regarding the benefits of AET on skeletal muscle in HF. Even though the benefits of AET for HF patients have been reported for decades, the optimal training protocol is still heavily debated. Moderate-intensity AET [50–70% of maximal oxygen uptake (V˙ O2 max )] is an effective therapy (Roveda et al. 2003; Fraga et al. 2007); however, recent investigations have suggested that high-intensity protocols promote superior improvements of V˙ O2 max in HF patients (Wisløff et al. 2007; Moholdt et al. 2012). Considering these findings, we hypothesized that high-intensity AET would also promote superior benefits in skeletal muscle of infarcted rats. Thus, we compared the effects of high-intensity (running intervals of 4 min at 85–90% V˙ O2 max and 3 min at 60% V˙ O2 max at 15% inclination, 5 days per week for 8 weeks) and moderate-intensity AET protocols (60% V˙ O2 max at 15% inclination, 1 h per day, 5 days per week for 8 weeks) on skeletal muscle of myocardial-infarcted rats (12 weeks after coronary artery ligation). Surprisingly, our data
618
P. C. Brum and others
showed that despite superior effects of high-intensity AET on exercise capacity, skeletal muscle adaptations were remarkably similar between protocols (Moreira et al. 2013) with regard to muscle mass, metabolic capacity and proteasome activation. These findings, although against our hypothesis, call for evaluation of novel training regimens (other combinations of intensity, duration and frequency) that could optimize the effects of AET in HF. Finally, despite the indisputable benefits of AET, one can advocate that physical activity may acutely increase the risk of myocardial infarction and sudden cardiac death in HF patients, primarily due to increased cardiac demand above the capacity of the heart and excessive neurohumoral activation. It is important to highlight that the moderate-intensity AET is recommended for HF therapy in clinically stable patients and under optimized medication (European Society of Cardiology, 2001). However, the risk associated with AET is an important concern and has recently been addressed by small and
Exp Physiol 99.4 (2014) pp 616–620
large studies, as well as in scientific statements from major cardiac health associations (Thompson et al. 2007; Rognmo et al. 2012). Such studies show that the incidence of adverse cardiac events during aerobic exercise is one occurrence per 50–150,000 h of summed exercise time (including the total training time of all HF patients studied), concluding that the risk of major cardiac events is low, which suggests that the benefits of AET for HF patients outweigh the risks.
Concluding remarks
Nearly 30 years after the first study that demonstrated skeletal muscle abnormalities in HF, knowledge in this field has evolved immensely. Heart failure-induced skeletal myopathy grew from an unrecognized matter to a predictor of prognosis. At a similar pace, AET evolved from condemned practice to therapy for HF. Although
Figure 1. Effects of aerobic exercise training on heart failure-induced skeletal myopathy Increased generation of reactive oxygen species, together with worsened antioxidant defense, leads to increased protein degradation and reduced protein synthesis in the skeletal muscle (illustrated by open arrows). Aerobic exercise training counteracts the mechanisms responsible for skeletal muscle atrophy in heart failure (illustrated by filled arrows). Abbreviations: Akt, protein kinase B; atrogin-1/MAFbx, muscle atrophy F-box protein; IGF-I, insulin-like growth factor-1; MuRF-1, muscle RING-finger protein-1; ROS, reactive oxygen species; and UPS, ubiquitin–proteasome system.
C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
Exp Physiol 99.4 (2014) pp 616–620
Aerobic exercise training counteracts skeletal myopathy
such developments now benefit HF patients, there is still a long way to go. Firstly, most clinical trials that involve training protocols include specific HF patients, commonly those with an ischaemic aetiology. Therefore, little is known about the effects of AET on skeletal muscle of other HF populations, such as in HF with a preserved ejection fraction or after cardiac transplantation. Thus, further investigations in other HF populations are encouraged, because these patients also suffer from impaired functional capacity and could benefit from AET. Secondly, the combination of AET and medication for HF provides benefits in addition to those of either intervention alone (Vanzelli et al. 2013); therefore, it is an open field for promising studies. Finally, technological advances now provide powerful and still underestimated tools with which to approach molecular targets in HF. Unbiased approaches, such as RNA sequencing and proteomic detection of post-translational modifications, should be explored further because they may lead to discovery of novel targets for treatment of skeletal myopathy in HF. References Aiken CT, Kaake RM, Wang X & Huang L (2011). Oxidative stress-mediated regulation of proteasome complexes. Mol Cell Proteomics 10, 1–11. Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-Peploe KM, Harrington D, Kox WJ, Poole-Wilson PA & Coats AJ (1997). Wasting as independent risk factor for mortality in chronic heart failure. Lancet 349, 1050–1053. Attaix D, Combaret L, B´echet D & Taillandier D (2008). Role of the ubiquitin-proteasome pathway in muscle atrophy in cachexia. Curr Opin Support Palliat Care 2, 262–266. Bacurau AV, Jardim MA, Ferreira JC, Bechara LR, Bueno CR Jr, Alba-Loureiro TC, Negrao CE, Casarini DE, Curi R, Ramires PR, Moriscot AS & Brum PC (2009). Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: role of exercise training. J Appl Physiol 106, 1631–1640. Barker T & Traber MG (2007). From animals to humans: evidence linking oxidative stress as a causative factor in muscle atrophy. J Physiol 583, 421–422. Brum PC, Bacurau AV, Medeiros A, Ferreira JC, Vanzelli AS & Negrao CE (2011). Aerobic exercise training in heart failure: impact on sympathetic hyperactivity and cardiac and skeletal muscle function. Braz J Med Biol Res 44, 827–835. Brum PC, Kosek J, Patterson A, Bernstein D & Kobilka B (2002). Abnormal cardiac function associated with sympathetic nervous system hyperactivity in mice. Am J Physiol Heart Circ Physiol 283, H1838–H1845. Bueno CR Jr, Ferreira JC, Pereira MG, Bacurau AV & Brum PC (2010). Aerobic exercise training improves skeletal muscle function and Ca2+ handling-related protein expression in sympathetic hyperactivity-induced heart failure. J Appl Physiol 109, 702–709.
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Additional Information Competing interests None declared. Funding PCB holds grants from FAPESP (#2010/50048-1), Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de N´ıvel Superior (CAPES 6967-12-4) and Conselho Nacional de Pesquisa e Desenvolvimento (CNPq, #302201/2011-44).
C 2013 The Authors. Experimental Physiology C 2013 The Physiological Society
