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Exercise as a Therapeutic Strategy for Sarcopenia in Heart Failure: Insights into Underlying Mechanisms

Institute of Sports & Arts Convergence (ISAC), Inha University, Incheon 22212, Korea
Department of Cardiovascular Diseases, Mayo Clinic, Rochester MN 55905, USA
Program in Biomedical Science & Engineering, Department of Kinesiology, Department of Biomedical Science, Inha University, Incheon 22212, Korea
Department of Pharmacology and Medicinal Toxicology Research Center, Inha University School of Medicine, Incheon 22212, Korea
Author to whom correspondence should be addressed.
Cells 2020, 9(10), 2284;
Submission received: 14 September 2020 / Revised: 6 October 2020 / Accepted: 10 October 2020 / Published: 13 October 2020
(This article belongs to the Section Cellular Aging)


Sarcopenia, a syndrome commonly seen in elderly populations, is often characterized by a gradual loss of skeletal muscle, leading to the decline of muscle strength and physical performance. Growing evidence suggests that the prevalence of sarcopenia increases in patients with heart failure (HF), which is a dominant pathogenesis in the aging heart. HF causes diverse metabolic complications that may result in sarcopenia. Therefore, sarcopenia may act as a strong predictor of frailty, disability, and mortality associated with HF. Currently, standard treatments for slowing muscle loss in patients with HF are not available. Therefore, here, we review the pathophysiological mechanisms underlying sarcopenia in HF as well as current knowledge regarding the beneficial effects of exercise on sarcopenia in HF and related mechanisms, including hormonal changes, myostatin, oxidative stress, inflammation, apoptosis, autophagy, the ubiquitin-proteasome system, and insulin resistance.

1. Introduction

Heart failure (HF) is an age-related geriatric health issue, defined as reduced cardiac output due to myocardial dysfunction. Over 5.8 million people in the US and over 23 million people worldwide suffer from this syndrome [1]. The prevalence of HF increases sharply in patients aged ≥65 years, and the disease is strongly associated with a number of pathophysiological complications, including pulmonary hypertension, renal disease, vascular dysfunction, and stroke [2,3]. Additionally, patients with HF often demonstrate a reduced exercise capacity that restricts daily activity and mobility [4]. There are several causes of exercise intolerance in HF patients, including systemic impairment of blood perfusion, blood flow, oxygen supply, and diffusivity of blood to skeletal muscle tissues [4]. Such chronic impairments of the cardiovascular system, along with limited physical activity, may cause quantitative and qualitative loss of skeletal muscle and accelerate the onset of sarcopenia [5].
Sarcopenia is an age-related geriatric syndrome that is characterized by qualitative and quantitative loss of skeletal muscle [6]. The prevalence of sarcopenia gradually increases with age, with ~30% of older adults, aged 59–86 years, being affected by this syndrome [6]. Growing evidence suggests that sarcopenia is commonly associated with HF as a comorbidity that synergistically influences a reduction in physiological function and physical mobility [7,8]. Moreover, the prevalence of sarcopenia in HF patients is approximately 20% higher than that in the healthy elderly population [9]. Sarcopenia is considered a salient health issue associated with HF and a factor that plays an important role in the maintenance of mobility and quality of life [7]. However, given the lack of standard treatment options, attenuating the progression of sarcopenia in HF poses a serious challenge. Accordingly, this review will discuss sarcopenia-related pathophysiology in HF and the therapeutic effect of exercise as a potential treatment strategy for attenuating sarcopenia progression associated with HF.

2. Potential Mechanisms of Sarcopenia in Heart Failure

Due to the general physiological degeneration that accompanies advance in age, gradual loss of muscle is commonly seen in older adults, even in the absence of sarcopenia. However, this pathophysiological phenomenon appears to be facilitated by HF [9]. Haykowsky et al. [10] reported that older patients with HF who presented with preserved ejection fractions showed significantly lower percentages of total lean muscle mass and leg muscle mass relative to those in healthy age-matched controls. Additionally, a decrease in the fat-free mass index, which reflects muscle mass, appeared to be associated with an increased risk for negative cardiac health outcomes in patients with HF [10,11]. Thus, muscle loss combined with HF may accelerate pathophysiological changes and reduce mobility in elderly patients with HF.
Sarcopenia is clinically defined by the European Working Group on Sarcopenia in older People using the following criteria: a low appendicular lean mass (AML) adjusted for height (AML/height2 <7.0 kg/m2 for men and <5.5 kg/m2 for women), low muscle strength (handgrip strength <27 kg for men and <16 kg for women), and/or poor physical function (gait speed ≤0.8 m/s) [6]. Although the above-stated clinical evaluation appears to focus on quantitative muscle loss, the pathophysiology of sarcopenia involves metabolic changes, particularly accelerated catabolism [12]. Accordingly, there is growing interest in the qualitative loss of muscle, the broad physiological changes resulting from which include altered levels of anabolic hormones, myostatin, oxidative stress, inflammation, apoptosis, autophagy, ubiquitin-proteasome system activity, and insulin resistance [12,13,14]. These changes lead to an imbalance between muscle protein synthesis and degradation, which, in turn, results in the wasting of skeletal muscle, leading to cardiometabolic and functional abnormalities in patients with HF.

2.1. Hormonal Changes

Decreased anabolic hormone levels have been investigated for association with skeletal muscle wasting. Age-related decreases in anabolic hormones, including growth hormones (GHs), insulin-like growth factor-1 (IGF-1), and testosterone, contribute to muscle loss by disrupting muscle metabolism [15,16,17]. Reduced GH and IGF-1 levels in HF are associated with impaired cardiac performance and lower exercise tolerance, which possibly contribute to muscle loss, and individuals with HF often demonstrate serum GH and IGF-1 levels that are lower than those of healthy age-matched controls [16]. Moreover, a randomized controlled study indicated that long-term GH replacement therapy improved the cardiac function of GH-deficient patients with chronic HF, as evidenced by enhanced peak oxygen consumption (peak VO2) values, left ventricular ejection fractions, and left ventricular end-systolic volumes [16]. Recently, an animal study conducted by Brioche et al. [18] demonstrated that administering GH alleviated sarcopenia, as shown by improvements in muscle protein synthesis and mitochondrial biogenesis. These findings suggest that decreased levels of GH and IGF-1 are associated with sarcopenia and HF.
Testosterone is the primary male sex anabolic hormone. Testosterone levels in older healthy people are a subject of considerable debate. A number of cross-sectional studies have reported that testosterone levels decrease with advancing age and that age-related decrease in testosterone levels in older adults is associated with a corresponding decrease in muscle mass and muscle strength [19]. Storer et al. [20] reported that older men who underwent a 3-year-long testosterone treatment showed improved muscle performance and physical function, including stairclimbing power and muscle mass, compared with older men in the placebo group. Testosterone deficiency is often observed in HF patients. It has been shown that low level of testosterone in HF is associated with a worse prognosis and increased mortality [21,22]. Further, low testosterone levels are associated with reduced peak VO2 in men with HF [23]. Thus, decreasing testosterone levels may contribute to skeletal muscle atrophy and dysfunction in HF.

2.2. Myostatin

Myostatin, a member of the transforming growth factor- β superfamily, is released mainly by skeletal muscle and, to a lesser extent, by the heart and adipose tissue [24]. Muscle growth, which is mediated by the downregulation of the Akt pathway and upregulation of the ubiquitin-proteasome system, is inversely regulated by myostatin [25]. The serum myostatin levels of HF patients were elevated compared with those of age-matched healthy controls [26]. Lenk et al. [27] reported that, in HF patients, myostatin mRNA and protein levels in skeletal muscle were augmented compared with healthy subjects. These findings suggested that myostatin may play a role in HF-related muscle wasting.

2.3. Oxidative Stress

Oxidative stress occurs due to imbalances between the production of reactive oxygen species (ROS) and antioxidant defenses. ROS are mainly produced by mitochondria, and excessive production of ROS contributes to reduced mitochondrial function and oxidative capacity [28]. Upregulated mitochondrial apoptosis signaling induced by oxidative damage may accelerate the atrophying of skeletal muscle in HF patients [29]. In addition, exercise intolerance associated with HF may be increased due to oxidative damage related to endothelial dysfunction [30]. Thus, appropriate regulation of oxidative stress may exert positive effects against muscle atrophy in HF.
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which comprises seven isoforms (i.e., NOX1-5, Duox1, and Duox2), is a source of ROS production [31]. This enzymatic complex appears to be elevated in patients with HF [32]. A previous study demonstrated that elevation of myocardial NADPH oxidase activity in HF is associated with the modulation of redox-sensitive signaling pathways, such as those involving mitogen-activated protein (MAP) kinases (ERK1/2, ERK5, p38, MAPK) [33]. Further, NADPH oxidase overactivity, following increased ROS production, is also associated with nuclear factor kappa B (NF-κB) signaling and the ubiquitin-proteasome system in skeletal muscle, both of which may participate in the pathogenesis of sarcopenia [34].

2.4. Inflammation

The serum concentrations of pro-inflammatory markers, such as interleukin-6 (IL-6), C-reactive protein, and tumor necrosis factor (TNF), are known to be elevated in HF patients [35,36]. Increased inflammation is associated with disease severity and adverse prognosis [37]. Levine et al. [35] reported that HF-related increases in serum TNF-α levels are associated with skeletal muscle wasting. Additionally, studies have suggested that an increase in pro-inflammatory cytokines during skeletal muscle wasting is indicative of the role played by these cytokines in the development of sarcopenia, which, in turn, demonstrates the involvement of these cytokines in muscle loss in HF patients [36,38]. In vivo data have been supported by in vitro studies involving muscle cells, which indicated that treatment with TNF-α inhibited myoblast differentiation and limited the regenerative response of satellite cells to muscle damage by inducing NF-κB [39]. Moreover, TNF-α/NF-κB signaling elevates ROS production via mitochondrial electron transport chain, resulting in stimulation of muscle protein degradation [40]. Therefore, chronic low-level systemic inflammation may be an important contributing factor in HF-related muscle catabolism.

2.5. Apoptosis

Myonuclear apoptosis, which is characterized by the absence of myonuclei and condensation of sarcoplasm, contributes to fiber atrophy rather than cell death, resulting in skeletal muscle atrophy [41]. Activation of the apoptotic signaling pathway leads to protein degradation via the ubiquitin-proteasome system [42]. Adams et al. [43] reported that myonuclear apoptosis, which is frequently found in HF patients compared with age-matched healthy control subjects, was linked to exercise intolerance.

2.6. Autophagy

Autophagy is an intracellular degradation process that removes misfolded proteins and damaged organelles [44]. Activation of the autophagic pathway in skeletal muscle plays a crucial role in maintaining protein homeostasis via several signaling pathways, including phosphatidylinositol-3-kinase (PI3K), myostatin, proteasome, and autophagy-lysosome pathways [44]. Any imbalance between these multiple signaling pathways during aging results in loss of muscle mass and function. Recent findings have reported that impaired autophagy in skeletal muscle is seen in HF animal models, which may contribute to skeletal muscle damage and degeneration [45,46,47,48]. Thus, autophagy signaling must be properly regulated to maintain skeletal muscle quality and quantity in HF patients.

2.7. Ubiquitin-Proteasome System

Increased protein degradation is recognized as one of the mechanisms underlying muscle loss in HF patients. The ubiquitin-proteasome system is known to regulate intracellular protein degradation in skeletal muscle cells. This degradation process is mediated by the activation of ubiquitin ligases (E3), such as atrogin-1 and muscle RING-finger protein-1 (MuRF-1), which polyubiquitinate proteins in order to mark them for degradation by the 26S proteasome [49]. A study reported that elevation of atrogin-1 and MuRF-1 levels is associated with muscle atrophy and promotes the pathological progression of sarcopenia [49]. Interestingly, the levels of E3 ligases in the diaphragm and quadriceps of an animal with chronic HF model were found to be elevated [50], suggesting that activation of the ubiquitin-proteasome system contributes to cardiac and peripheral muscle dysfunction in HF patients.

2.8. Insulin Resistance

During aging, a decrease in muscle mass combined with an increase in intramuscular fat content interferes with insulin-mediated glucose usage, causing insulin resistance [51]. Such metabolic abnormalities associated with skeletal muscle are also related to HF [52,53]. A clinical study showed that quadriceps muscle strength in both patients with HF and healthy controls was positively correlated with the insulin sensitivity index [52,53]. These findings suggest that insulin resistance is pathologically linked to skeletal muscle loss. Mechanistically, insulin resistance impairs insulin/IGF-1 signaling, which regulates phosphatidylinositol-3-kinases/Akt signaling and attenuates protein regeneration [54]. Promotion of muscle catabolism and impairment of protein synthesis and muscle wasting by these activities indicate an association between insulin resistance and HF-related skeletal muscle wasting.

3. Exercise Intolerance and Sarcopenia in HF

Exercise intolerance, a major symptom of HF, is often utilized to predict disease severity and mortality. To quantify exercise capacity, peak VO2 is measured during a cardiopulmonary exercise test. This test is commonly accepted as the gold-standard for such assessments [55]. A decrease in peak VO2 in HF may be largely due to complications in the central region, including reduced carbon monoxide (CO), impaired respiratory gas exchange, and insufficient blood flow [56]. In addition, systemic oxygen delivery to locomotor muscles is significantly reduced during exercise because of impaired endothelium-dependent vasodilation [57], muscle capillarization [58], systemic inflammation, oxygen unloading [59], and oxidative stress [60]. These cardiovascular impairments mainly limit exercise capacity in HF. However, emerging evidence supports the postulate that muscle waste/sarcopenia contributes to impaired exercise capacity in HF [61], based on the link between sarcopenia and multiple pathophysiological changes taking place in skeletal muscle, which lead to locomotor muscle dysfunction during exercise.
To the best of our knowledge, studies that are currently investigating the direct impact of skeletal muscle wasting on exercise capacity in HF are either very few or non-existent. However, previous studies have found that exercise capacity is related to skeletal muscle mass and that reduced exercise capacity in older cohorts is associated with age-related decline in muscle mass [62]. Longitudinal studies using muscle biopsies have indicated that the capillary-to-fiber ratio in the skeletal muscles of older adults was significantly lower than that in the skeletal muscles of younger adults, demonstrating the association between exercise intolerance and limited oxygen supply [51]. Lower skeletal muscle capillarization was also found to be associated with a reduction in the exercise capacity of older adults, which was again found to be due to reduced oxygen supply [63]. Haykowsky et al. [10] demonstrated that the peak VO2 level for a given lean body mass was lower in HF patients than in healthy controls, implying that skeletal muscle abnormalities may contribute to exercise intolerance in HF patients. Recently, Weiss et al. [64] reported that HF patients with exercise intolerance and high fatigability exhibited significantly faster rates of exercise-induced decline in skeletal muscle high-energy phosphate and reduced maximal oxidative capacity than HF with low fatigability. These findings indicate that skeletal muscle metabolism may contribute to exercise intolerance in HF, suggesting an avenue for developing a strategy to improve exercise capacity.

4. Effects of Exercise on HF-Related Sarcopenia

Currently, there is no standard treatment for loss of muscle mass and function in HF patients. However, growing evidence suggests that lifestyle-modifiable factors, particularly regular exercise training, may help improve the muscular function and fitness of HF patients. The beneficial effects of exercise on the cardiovascular system have been reported frequently [65,66,67]. Since potential mechanisms underlying sarcopenia and HF appear to be shared, exercise training may simultaneously improve cardiac and skeletal muscle functions associated with HF-related sarcopenia, although the processes associated with such potential improvements remain unclear. A conceptual overview of the potential effects of exercise on HF-related sarcopenia is shown in Figure 1.

4.1. Physical Activity

Epidemiologic studies have demonstrated that appropriate amounts of physical activity may enable the preservation of muscle-related functions, including gait, speed, balance, and daily activities, in addition to reducing the risk of age-related diseases, such as sarcopenia and cardiovascular diseases [68,69,70]. Additionally, the Framingham Study, which involved 1142 older adults, demonstrated that individuals with higher physical activity displayed a 15–56% lower risk for HF [71], whereas a cross-sectional study by Ribeiro Santos et al. [72] found that less active older adults engaged in occupational and locomotion domains showed a higher risk of sarcopenia. Overall, although the relationship between HF-related sarcopenia and physical activity remains insufficiently studied, existing evidence suggests that adequate physical activity may prevent HF-related muscle loss.

4.2. Exercise Training

Exercise training is a well-known strategy that improves maximal oxygen consumption (VO2max) as well as muscle mass [73]. Although the impact of exercise training on HF patients is not fully understood, it is clear that exercise training enables muscle mass to be effectively maintained and reduces muscle abnormalities in HF. Notably, exercise training increases the mass and activity of skeletal muscle mitochondria, thereby enhancing exercise tolerance in HF. Numerous human and rodent studies have demonstrated the beneficial effects of exercise training on skeletal muscles in HF (Table 1 and Table 2).

4.2.1. Aerobic Exercise Training

HF-induced muscle abnormalities that contribute to skeletal muscle atrophy result from an imbalance between protein synthesis and degradation, which is a function of reduced anabolic gene expression and increased catabolic gene expression. On the contrary, clinical studies revealed that aerobic exercise training (AET) enhanced peak VO2, increased anabolic gene expression (i.e., IGF-1), reduced catabolic gene expression (i.e., MuRF-1, myostatin, and TNF- α ), and improved the oxidative capacity of skeletal muscle [27,74,75,76,77,78]. Similar results were observed in animal models. For example, AET upregulated IGF-1 levels through activated Akt and ERK1/2 signaling while reducing forkhead box O3 (FoxO3) mRNA levels in the skeletal muscle of myocardial infarction model [84,86]. An animal study by Bacurau et al. [80] demonstrated that 8 weeks of AET prevented muscle loss by activating Akt and mammalian target of rapamycin (mTOR) and subsequently increasing the phosphorylation of p70-S6 kinase 1 (p70S6K). Although the exact mechanisms underlying the AET-mediated activation of protein synthesis in human HF-induced muscle atrophy are not clearly understood, it is assumed that AET stimulates protein synthesis via IGF-1 and the related signaling pathways such as Akt/mTOR and Akt/FoxO3.
Moreover, AET may exert beneficial effects by reducing the expression of catabolic genes such as myostatin [27]. Deletion of the myostatin gene in heart tissues prevented skeletal muscle atrophy in animal HF models [87]. Lenk et al. [81] showed that 4 weeks of AET resulted in significant reduction in myostatin expression levels in both the skeletal muscle and myocardium in an animal model of HF. The decrease in myostatin expression levels in skeletal muscle depends on the p38 MAPK-dependent pathway, which involves NF-κB [81]. However, in contrast to changes in skeletal muscle, no significant differences were observed between serum myostatin levels following AET [27,88]. Although myostatin is expressed in both local tissues (i.e., skeletal muscle, heart, and adipose tissue) and systemic pools [89], AET may modulate myostatin levels in the skeletal muscle of HF patients via localized action.
Histological analysis of skeletal muscle from patients with HF have shown the changes of muscle fiber type from type Ι oxidative fibers to type Ⅱ glycolytic fibers, which leads to skeletal muscle mitochondrial dysfunction [90]. The findings of many studies indicate that mitochondrial dysfunction in skeletal muscle contributes to exercise intolerance in HF as estimated by peak VO2 and may therefore be considered as a potential therapeutic target for this condition. Molina et al. [91] examined the content, dynamics, proteins, and oxidative capacity of skeletal muscle mitochondria using a vastus lateralis skeletal muscle biopsy from an HF patient. The levels of mitochondrial fusion factors, mitofusin 2 (Mfn2) and porin, as well as citrate synthase activity, were lower in HF patients than those in age-matched healthy control subjects [91]. However, mitochondrial dysfunction may be partially normalized by exercise training in HF [83,92]. Our group showed that acute AET-induced upregulation of PGC-1 α levels regulated the signaling pathway modulating mitochondrial biogenesis and protected muscles from oxidative stress, proteolysis, and inflammation [93]. Similar findings were reported by Souza et al. [82] in an animal model of HF. Ten weeks of AET suppressed the deterioration of muscle loss, and maintained the PGC-1 α levels in the skeletal muscle. Furthermore, AET-induced anti-oxidative effects may be associated with redox-sensitive proteins, such as NADPH oxidase. Using animal HF models, Cunha et al. [76,79] demonstrated that 8 weeks of AET suppressed the progression of HF pathology as well as skeletal muscle atrophy. In this study, AET regulated proteolysis signaling by reducing the protein levels of Atrogin-1/muscle atrophy F-box (MAFbx) and E3α. AET also modulated the redox balance in the membrane-enriched fraction of plantaris by downregulating Nox2 and p47phox protein levels as well as NADPH oxidase hyperactivity. These findings suggested that AET may partially reverse certain features of skeletal muscle abnormalities, such as mitochondrial function, in HF patients.

4.2.2. Resistance Exercise Training

Some studies have reported that although resistance training (RT) leads to improved muscle strength and function, AET provides greater benefits by improving cardiorespiratory fitness [85,94,95,96]. Accordingly, Gomes et al. [85] compared the effects of aerobic and resistance exercise on the physical capacity and skeletal muscle oxidative stress in HF rats. The results of this study indicated that AET and RT increased the aerobic capacity and strength gain of HF rats respectively, regardless of changes caused by cardiac remodeling. Thus, RT can be expected to play a crucial role in improving muscle strength and function in HF patients. For example, Esposito et al. [78] examined the effects of 8 weeks of knee extensor exercise training on skeletal muscle function in HF patients. Compared with the baseline, RT induced a 1.5-fold increase in 50% of maximum work rate along with muscle capillary density, fiber cross-section area, and percentage area of type I fiber [78]. Cai et al. [84] reported that 4 weeks of RT inhibited muscle atrophy by downregulating the mRNA levels of MuRF-1 and atrogin-1, decreased ROS, and upregulated the IGF-1/Akt/ERK signaling pathway in soleus muscle. These data indicate that the regulation of protein synthesis-related genes in skeletal muscle may be modulated in response to RT in HF.

4.2.3. Combined Exercise Training

Current guidelines recommend regular physical activity for HF patients to alleviate cardiac and muscular dysfunction [3]. As far as exercise types are concerned, aerobic exercise has been suggested as the primary mode due to beneficial effects exerted on anabolic hormones, antioxidant status, and inflammatory markers, as well as on muscle and cardiovascular function. Since resistance exercise is considered relatively unsafe for HF patients, the beneficial effects of exercise have mostly been attributed to aerobic exercise [94]. Jakovljevic et al. [97] studied the effects of both aerobic and resistance exercise on HF patients and concluded that both increased cardiac pumping capabilities and physical functional capacities. Moreover, they showed that while peak VO2 improvements were more closely associated with aerobic exercise, muscle mass was best maintained via RT [97]. All findings considered, aerobic exercise combined with RT appears to be effective in preventing muscle loss associated with HF.
All European nations and South America guidelines recommend both AET and RT for improving the muscle mass and function of HF patients [98]. Thus, a training procedure that involves a combination of two types of exercise training strategies may be most beneficial for improving physical function in HF [99]. Accordingly, using vastus lateralis muscle biopsy samples from older adults, Irving et al. [100] showed that oxidative capacity and expression of mitochondrial proteins (i.e., Mitochondrial Oxidative Phosphorylation (OXPHOS) protein and citrate synthase) and transcription factors (i.e., PGC-1α, Sirtuin 3 (SIRT3), and mitochondrial transcription factor A (TFAM)) after 8 weeks of combined training were superior to those after either AET or RT alone. These findings suggest that exercise intervention, especially via combined exercise training, may attenuate abnormalities in muscle quantity and quality, thereby minimizing deleterious peripheral conditions, such as muscle loss and endothelial dysfunction, in HF patients. However, more standardized clinical trials are needed in the future to explore optimal exercise prescriptions that may be used to improve cardiac and skeletal muscle function.

5. Conclusions

Patients with HF exhibit a loss of cardiovascular function and skeletal muscle quantity and quality due to sarcopenia, which can lead to poor prognosis. Although the mechanisms underlying the direct interaction between HF and sarcopenia remain unclear, those underlying skeletal muscle wasting in HF patients appear to be associated with anabolic hormones, myostatin, oxidative stress, inflammation, apoptosis, autophagy, the ubiquitin-proteasome system, and insulin resistance. Currently, standard methods that may be used to treat sarcopenia in HF patients have not been established. However, exercise training represents a non-pharmacological method that shows potential for attenuating skeletal muscle wasting in these patients. This review attempted to highlight potential mechanisms via which exercise plays a role in decreasing muscle loss in patients with HF. Further studies are needed to provide additional molecular and clinical evidences concerning effective exercise protocols, particularly in terms of type, intensity, and volume of exercise required.

Author Contributions

J.C. and D.-H.P. contributed to the conception and design of the present review. J.C., Y.C., P.S., S.-H.L., S.K., J.-W.H., M.-H.N., E.-J.C., E.C., D.-H.P., J.-H.K., and H.-B.K. conducted critical discussion. J.C. and D.-H.P. wrote the manuscript. All authors have read and agreed to the published version of the manuscript.


This work was supported by the Ministry of Education of the Republic of Korea and National Research Foundation of Korea (NRF-2019S1A5C2A03082727).

Conflicts of Interest

The authors declare no conflict of interest.


  1. Roger, V.L. Epidemiology of Heart Failure. Circ. Res. 2013, 113, 646–659. [Google Scholar] [CrossRef]
  2. Braunwald, E. Heart Failure. JACC Heart Fail. 2013, 1, 1–20. [Google Scholar] [CrossRef]
  3. Ponikowski, P.; Voors, A.A.; Anker, S.D.; Bueno, H.; Cleland, J.G.F.; Coats, A.J.S.; Falk, V.; González-Juanatey, J.R.; Harjola, V.-P.; Jankowska, E.A.; et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 2016, 37, 2129–2200. [Google Scholar] [CrossRef]
  4. Tucker, W.J.; Haykowsky, M.J.; Seo, Y.; Stehling, E.; Forman, D.E. Impaired Exercise Tolerance in Heart Failure: Role of Skeletal Muscle Morphology and Function. Curr. Heart Fail. Rep. 2018, 15, 323–331. [Google Scholar] [CrossRef]
  5. Bekfani, T.; Pellicori, P.; Morris, D.A.; Ebner, N.; Valentova, M.; Steinbeck, L.; Wachter, R.; Elsner, S.; Sliziuk, V.; Schefold, J.C.; et al. Sarcopenia in patients with heart failure with preserved ejection fraction: Impact on muscle strength, exercise capacity and quality of life. Int. J. Cardiol. 2016, 222, 41–46. [Google Scholar] [CrossRef] [Green Version]
  6. Cruz-Jentoft, A.; Bahat, G.; Bauer, J.; Boirie, Y.; Bruyère, O.; Cederholm, T.; Cooper, C.; Landi, F.; Rolland, Y.; Sayer, A.A.; et al. Sarcopenia: Revised European consensus on definition and diagnosis. Age Ageing 2018, 48, 16–31. [Google Scholar] [CrossRef] [Green Version]
  7. Brunjes, D.L.; Kennel, P.J.; Schulze, P.C. Exercise capacity, physical activity, and morbidity. Heart Fail. Rev. 2017, 22, 133–139. [Google Scholar] [CrossRef] [Green Version]
  8. Emami, A.; Saitoh, M.; Valentova, M.; Sandek, A.; Evertz, R.; Ebner, N.; Loncar, G.; Springer, J.; Doehner, W.; Lainscak, M.; et al. Comparison of sarcopenia and cachexia in men with chronic heart failure: Results from the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF). Eur. J. Heart Fail. 2018, 20, 1580–1587. [Google Scholar] [CrossRef] [Green Version]
  9. Fülster, S.; Tacke, M.; Sandek, A.; Ebner, N.; Tschöpe, C.; Doehner, W.; Anker, S.D.; Von Haehling, S. Muscle wasting in patients with chronic heart failure: Results from the studies investigating co-morbidities aggravating heart failure (SICA-HF). Eur. Heart J. 2012, 34, 512–519. [Google Scholar] [CrossRef] [Green Version]
  10. Haykowsky, M.J.; Brubaker, P.H.; Morgan, T.M.; Kritchevsky, S.B.; Eggebeen, J.; Kitzman, D.W. Impaired Aerobic Capacity and Physical Functional Performance in Older Heart Failure Patients with Preserved Ejection Fraction: Role of Lean Body Mass. J. Gerontol. Ser. A 2013, 68, 968–975. [Google Scholar] [CrossRef] [Green Version]
  11. Narumi, T.; Watanabe, T.; Kadowaki, S.; Takahashi, T.; Yokoyama, M.; Kinoshita, D.; Honda, Y.; Funayama, A.; Nishiyama, S.; Takahashi, H.; et al. Sarcopenia evaluated by fat-free mass index is an important prognostic factor in patients with chronic heart failure. Eur. J. Intern. Med. 2015, 26, 118–122. [Google Scholar] [CrossRef]
  12. Springer, J.; Springer, J.-I.; Anker, S.D. Muscle wasting and sarcopenia in heart failure and beyond: Update 2017. ESC Heart Fail. 2017, 4, 492–498. [Google Scholar] [CrossRef]
  13. Yoo, S.-Z.; No, M.-H.; Heo, J.-W.; Park, D.-H.; Kang, J.-H.; Kim, S.H.; Kwak, H.-B. Role of exercise in age-related sarcopenia. J. Exerc. Rehabil. 2018, 14, 551–558. [Google Scholar] [CrossRef]
  14. Collamati, A.; Marzetti, E.; Calvani, R.; Tosato, M.; D’Angelo, E.; Sisto, A.N.; Landi, F. Sarcopenia in heart failure: Mechanisms and therapeutic strategies. J. Geriatr. Cardiol. 2016, 13, 615–624. [Google Scholar]
  15. Saccà, L. Growth hormone: A newcomer in cardiovascular medicine. Cardiovasc. Res. 1997, 36, 3–9. [Google Scholar] [CrossRef] [Green Version]
  16. Cittadini, A.; Marra, A.M.; Arcopinto, M.; Bobbio, E.; Salzano, A.; Sirico, D.; Napoli, R.; Colao, A.; Longobardi, S.; Baliga, R.R.; et al. Growth Hormone Replacement Delays the Progression of Chronic Heart Failure Combined with Growth Hormone Deficiency: An Extension of a Randomized Controlled Single-Blind Study. JACC Heart Fail. 2013, 1, 325–330. [Google Scholar] [CrossRef]
  17. Rezus, E.; Burlui, M.A.; Cardoneanu, A.; Rezus, C.; Codreanu, C.; Pârvu, M.; Rusu-Zota, G.; Tamba, B.I. Inactivity and Skeletal Muscle Metabolism: A Vicious Cycle in Old Age. Int. J. Mol. Sci. 2020, 21, 592. [Google Scholar] [CrossRef] [Green Version]
  18. Brioche, T.; Kireev, R.A.; Cuesta, S.; Gratas-Delamarche, A.; Tresguerres, J.A.; Gómez-Cabrera, M.C.; Viña, J. Growth Hormone Replacement Therapy Prevents Sarcopenia by a Dual Mechanism: Improvement of Protein Balance and of Antioxidant Defenses. J. Gerontol. Ser. A 2013, 69, 1186–1198. [Google Scholar] [CrossRef] [Green Version]
  19. Saad, F.; Röhrig, G.; Von Haehling, S.; Traish, A. Testosterone Deficiency and Testosterone Treatment in Older Men. Gerontology 2016, 63, 144–156. [Google Scholar] [CrossRef]
  20. Storer, T.W.; Basaria, S.; Traustadottir, T.; Harman, S.M.; Pencina, K.; Li, Z.; Travison, T.G.; Miciek, R.; Tsitouras, P.; Hally, K.; et al. Effects of Testosterone Supplementation for 3-Years on Muscle Performance and Physical Function in Older Men. J. Clin. Endocrinol. Metab. 2016, 102, 583–593. [Google Scholar] [CrossRef] [Green Version]
  21. Wehr, E.; Pilz, S.; Boehm, B.O.; März, W.; Grammer, T.; Obermayer-Pietsch, B. Low free testosterone is associated with heart failure mortality in older men referred for coronary angiography. Eur. J. Heart Fail. 2011, 13, 482–488. [Google Scholar] [CrossRef] [Green Version]
  22. Jankowska, E.A.; Biel, B.; Majda, J.; Szklarska, A.; Lopuszanska, M.; Medras, M.; Anker, S.D.; Banasiak, W.; Poole-Wilson, P.A.; Ponikowski, P. Anabolic Deficiency in Men with Chronic Heart Failure. Circulation 2006, 114, 1829–1837. [Google Scholar] [CrossRef] [Green Version]
  23. Jankowska, E.A.; Filippatos, G.; Ponikowska, B.; Borodulin-Nadzieja, L.; Anker, S.D.; Banasiak, W.; Poole-Wilson, P.A.; Ponikowski, P. Reduction in Circulating Testosterone Relates to Exercise Capacity in Men with Chronic Heart Failure. J. Card. Fail. 2009, 15, 442–450. [Google Scholar] [CrossRef]
  24. McPherron, A.C.; Lawler, A.M.; Lee, S.-J. Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member. Nature 1997, 387, 83–90. [Google Scholar] [CrossRef]
  25. Mendias, C.L.; Kayupov, E.; Bradley, J.R.; Brooks, S.V.; Claflin, D.R. Decreased specific force and power production of muscle fibers from myostatin-deficient mice are associated with a suppression of protein degradation. J. Appl. Physiol. 2011, 111, 185–191. [Google Scholar] [CrossRef] [Green Version]
  26. Gruson, D.; Ahn, S.A.; Ketelslegers, J.-M.; Rousseau, M.F. Increased plasma myostatin in heart failure. Eur. J. Heart Fail. 2011, 13, 734–736. [Google Scholar] [CrossRef]
  27. Lenk, K.; Erbs, S.; Höllriegel, R.; Beck, E.; Linke, A.; Gielen, S.; Winkler, S.M.; Sandri, M.; Hambrecht, R.; Schuler, G.; et al. Exercise training leads to a reduction of elevated myostatin levels in patients with chronic heart failure. Eur. J. Prev. Cardiol. 2011, 19, 404–411. [Google Scholar] [CrossRef]
  28. Kiyuna, L.A.; E Albuquerque, R.P.; Chen, C.-H.; Mochly-Rosen, D.; Ferreira, J.C.B. Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities. Free. Radic. Biol. Med. 2018, 129, 155–168. [Google Scholar] [CrossRef] [PubMed]
  29. Libera, L.; Zennaro, R.; Sandri, M.; Ambrosio, G.B.; Vescovo, G. Apoptosis and atrophy in rat slow skeletal muscles in chronic heart failure. Am. J. Physiol. Content 1999, 277, C982–C986. [Google Scholar] [CrossRef]
  30. Shirakawa, R.; Yokota, T.; Nakajima, T.; Takada, S.; Yamane, M.; Furihata, T.; Maekawa, S.; Nambu, H.; Katayama, T.; Fukushima, A.; et al. Mitochondrial reactive oxygen species generation in blood cells is associated with disease severity and exercise intolerance in heart failure patients. Sci. Rep. 2019, 9, 14709. [Google Scholar] [CrossRef]
  31. Dröge, W. Redox regulation in anabolic and catabolic processes. Curr. Opin. Clin. Nutr. Metab. Care 2006, 9, 190–195. [Google Scholar] [CrossRef]
  32. Heymes, C.; Bendall, J.K.; Ratajczak, P.; Cave, A.C.; Samuel, J.-L.; Hasenfuss, G.; Shah, A.M. Increased myocardial NADPH oxidase activity in human heart failure. J. Am. Coll. Cardiol. 2003, 41, 2164–2171. [Google Scholar] [CrossRef] [Green Version]
  33. Li, J.-M.; Gall, N.P.; Grieve, D.J.; Chen, M.; Shah, A.M. Activation of NADPH Oxidase During Progression of Cardiac Hypertrophy to Failure. Hypertension 2002, 40, 477–484. [Google Scholar] [CrossRef] [Green Version]
  34. Bechara, L.R.; Moreira, J.B.; Jannig, P.R.; Voltarelli, V.A.; Dourado, P.M.; Vasconcelos, A.R.; Scavone, C.; Ramires, P.R.; Brum, P.C. NADPH oxidase hyperactivity induces plantaris atrophy in heart failure rats. Int. J. Cardiol. 2014, 175, 499–507. [Google Scholar] [CrossRef]
  35. Levine, B.; Kalman, J.; Mayer, L.; Fillit, H.M.; Packer, M. Elevated Circulating Levels of Tumor Necrosis Factor in Severe Chronic Heart Failure. N. Engl. J. Med. 1990, 323, 236–241. [Google Scholar] [CrossRef]
  36. Seiler, M.; Bowen, T.S.; Rolim, N.; Dieterlen, M.-T.; Werner, S.; Hoshi, T.; Fischer, T.; Mangner, N.; Linke, A.; Schuler, G.; et al. Skeletal Muscle Alterations Are Exacerbated in Heart Failure with Reduced Compared with Preserved Ejection Fraction: Mediated by circulating cytokines? Circ. Heart Fail. 2016, 9, e003027. [Google Scholar] [CrossRef] [Green Version]
  37. Briasoulis, A.; Androulakis, E.; Christophides, T.; Tousoulis, D. The role of inflammation and cell death in the pathogenesis, progression and treatment of heart failure. Heart Fail. Rev. 2016, 21, 169–176. [Google Scholar] [CrossRef]
  38. Schaap, L.A.; Pluijm, S.M.; Deeg, D.J.; Visser, M. Inflammatory Markers and Loss of Muscle Mass (Sarcopenia) and Strength. Am. J. Med. 2006, 119, 526.e9–526.e17. [Google Scholar] [CrossRef]
  39. Guttridge, D.C.; Mayo, M.W.; Madrid, L.V.; Wang, C.-Y.; Baldwin, A.S., Jr. NF-κB-Induced Loss of MyoD Messenger RNA: Possible Role in Muscle Decay and Cachexia. Science 2000, 289, 2363–2366. [Google Scholar] [CrossRef] [Green Version]
  40. Thaloor, D.; Miller, K.J.; Gephart, J.; Mitchell, P.O.; Pavlath, G.K. Systemic administration of the NF-κB inhibitor curcumin stimulates muscle regeneration after traumatic injury. Am. J. Physiol. 1999, 277, C320–C329. [Google Scholar] [CrossRef]
  41. Cheema, N.; Herbst, A.; McKenzie, D.; Aiken, J.M. Apoptosis and necrosis mediate skeletal muscle fiber loss in age-induced mitochondrial enzymatic abnormalities. Aging Cell 2015, 14, 1085–1093. [Google Scholar] [CrossRef] [PubMed]
  42. Du, J.; Wang, X.; Miereles, C.; Bailey, J.L.; Debigare, R.; Zheng, B.; Price, S.R.; Mitch, W.E. Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. J. Clin. Investig. 2004, 113, 115–123. [Google Scholar] [CrossRef] [PubMed]
  43. Adams, V.; Jiang, H.; Yu, J.; Möbius-Winkler, S.; Fiehn, E.; Linke, A.; Weigl, C.; Schuler, G.; Hambrecht, R. Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance. J. Am. Coll. Cardiol. 1999, 33, 959–965. [Google Scholar] [CrossRef] [Green Version]
  44. Fan, J.; Kou, X.; Jia, S.; Yang, X.; Yang, Y.; Chen, N. Autophagy as a Potential Target for Sarcopenia. J. Cell. Physiol. 2015, 231, 1450–1459. [Google Scholar] [CrossRef]
  45. De Meyer, G.R.Y.; De Keulenaer, G.W.; Martinet, W. Role of autophagy in heart failure associated with aging. Heart Fail. Rev. 2010, 15, 423–430. [Google Scholar] [CrossRef]
  46. Jannig, P.R.; Moreira, J.B.N.; Bechara, L.R.G.; Bozi, L.H.M.; Bacurau, A.V.; Monteiro, A.W.A.; Dourado, P.M.; Wisløff, U.; Brum, P.C. Autophagy Signaling in Skeletal Muscle of Infarcted Rats. PLoS ONE 2014, 9, e85820. [Google Scholar] [CrossRef] [Green Version]
  47. Fujita, N.; Fujino, H.; Sakamoto, H.; Takegaki, J.; Deie, M. Time course of ubiquitin-proteasome and macroautophagy-lysosome pathways in skeletal muscle in rats with heart failure. Biomed. Res. 2015, 36, 383–392. [Google Scholar] [CrossRef] [Green Version]
  48. Bowen, T.S.; Herz, C.; Rolim, N.P.; Berre, A.-M.O.; Halle, M.; Kricke, A.; Linke, A.; Da Silva, G.J.; Wisloff, U.; Adams, V. Effects of Endurance Training on Detrimental Structural, Cellular, and Functional Alterations in Skeletal Muscles of Heart Failure with Preserved Ejection Fraction. J. Card. Fail. 2018, 24, 603–613. [Google Scholar] [CrossRef] [Green Version]
  49. Gumucio, J.P.; Mendias, C.L. Atrogin-1, MuRF-1, and sarcopenia. Endocrine 2012, 43, 12–21. [Google Scholar] [CrossRef]
  50. Mangner, N.; Weikert, B.; Bowen, T.S.; Sandri, M.; Höllriegel, R.; Erbs, S.; Hambrecht, R.; Schuler, G.; Linke, A.; Gielen, S.; et al. Skeletal muscle alterations in chronic heart failure: Differential effects on quadriceps and diaphragm. J. Cachexia Sarcopenia Muscle 2015, 6, 381–390. [Google Scholar] [CrossRef]
  51. Srikanthan, P.; Hevener, A.L.; Karlamangla, A.S. Sarcopenia Exacerbates Obesity-Associated Insulin Resistance and Dysglycemia: Findings from the National Health and Nutrition Examination Survey III. PLoS ONE 2010, 5, e10805. [Google Scholar] [CrossRef] [PubMed]
  52. Doehner, W.; Gathercole, D.; Cicoira, M.; Krack, A.; Coats, A.J.; Camici, P.G.; Anker, S.D. Reduced glucose transporter GLUT4 in skeletal muscle predicts insulin resistance in non-diabetic chronic heart failure patients independently of body composition. Int. J. Cardiol. 2010, 138, 19–24. [Google Scholar] [CrossRef] [PubMed]
  53. Doehner, W.; Von Haehling, S.; Anker, S.D. Protective overweight in cardiovascular disease: Moving from ‘paradox’ to ‘paradigm’. Eur. Heart J. 2015, 36, 2729–2732. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Sandri, M.; Barberi, L.; Bijlsma, A.Y.; Blaauw, B.; Dyar, K.A.; Milan, G.; Mammucari, C.; Meskers, C.G.M.; Pallafacchina, G.; Paoli, A.; et al. Signalling pathways regulating muscle mass in ageing skeletal muscle. The role of the IGF1-Akt-mTOR-FoxO pathway. Biogerontology 2013, 14, 303–323. [Google Scholar] [CrossRef]
  55. Marburger, C.; Brubaker, P.; Pollock, W.; Morgan, T.; Kitzman, D. Reproducibility of cardiopulmonary exercise testing in elderly patients with congestive heart failure. Am. J. Cardiol. 1998, 82, 905–909. [Google Scholar] [CrossRef]
  56. Bensimhon, D.R.; Leifer, E.S.; Ellis, S.J.; Fleg, J.L.; Keteyian, S.J.; Piña, I.L.; Kitzman, D.W.; McKelvie, R.S.; Kraus, W.E.; Forman, D.E.; et al. Reproducibility of Peak Oxygen Uptake and Other Cardiopulmonary Exercise Testing Parameters in Patients with Heart Failure (from the Heart Failure and A Controlled Trial Investigating Outcomes of exercise traiNing). Am. J. Cardiol. 2008, 102, 712–717. [Google Scholar] [CrossRef] [Green Version]
  57. Toda, N.; Okamura, T. Obesity impairs vasodilatation and blood flow increase mediated by endothelial nitric oxide: An overview. J. Clin. Pharmacol. 2013, 53, 1228–1239. [Google Scholar] [CrossRef]
  58. Niemeijer, V.M.; Snijders, T.; Verdijk, L.B.; Van Kranenburg, J.; Groen, B.B.L.; Holwerda, A.M.; Spee, R.F.; Wijn, P.F.F.; Van Loon, L.J.C.; Kemps, H.M.C. Skeletal muscle fiber characteristics in patients with chronic heart failure: Impact of disease severity and relation with muscle oxygenation during exercise. J. Appl. Physiol. 2018, 125, 1266–1276. [Google Scholar] [CrossRef]
  59. Kisaka, T.; Stringer, W.W.; Koike, A.; Agostoni, P.; Wasserman, K. Mechanisms That Modulate Peripheral Oxygen Delivery during Exercise in Heart Failure. Ann. Am. Thorac. Soc. 2017, 14, S40–S47. [Google Scholar] [CrossRef]
  60. Rullman, E.; Melin, M.; Mandić, M.; Gonon, A.; Fernandez-Gonzalo, R.; Gustafsson, T. Circulatory factors associated with function and prognosis in patients with severe heart failure. Clin. Res. Cardiol. 2019, 109, 655–672. [Google Scholar] [CrossRef] [Green Version]
  61. Anker, S.D.; Ponikowski, P.; Varney, S.; Chua, T.P.; Clark, A.L.; Webb-Peploe, K.M.; Harrington, D.; Kox, W.J.; A Poole-Wilson, P.; Coats, A.J. Wasting as independent risk factor for mortality in chronic heart failure. Lancet 1997, 349, 1050–1053. [Google Scholar] [CrossRef]
  62. Proctor, D.N.; Le, K.U.; Ridout, S.J. Age and regional specificity of peak limb vascular conductance in men. J. Appl. Physiol. 2005, 98, 193–202. [Google Scholar] [CrossRef] [PubMed]
  63. Prior, S.J.; Ryan, A.S.; Blumenthal, J.B.; Watson, J.M.; Katzel, L.I.; Goldberg, A.P. Sarcopenia Is Associated with Lower Skeletal Muscle Capillarization and Exercise Capacity in Older Adults. J. Gerontol. Ser. A Biol. Sci. Med Sci. 2016, 71, 1096–1101. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Weiss, K.; Schär, M.; Panjrath, G.S.; Zhang, Y.; Sharma, K.; Bottomley, P.A.; Golozar, A.; Steinberg, A.; Gerstenblith, G.; Russell, S.D.; et al. Fatigability, Exercise Intolerance, and Abnormal Skeletal Muscle Energetics in Heart Failure. Circ. Heart Fail. 2017, 10. [Google Scholar] [CrossRef] [PubMed]
  65. Romero, S.A.; Minson, C.T.; Halliwill, J.R. The cardiovascular system after exercise. J. Appl. Physiol. 2017, 122, 925–932. [Google Scholar] [CrossRef]
  66. Adams, V.; Linke, A. Impact of exercise training on cardiovascular disease and risk. Biochim. Biophys. Acta Mol. Basis Dis. 2019, 1865, 728–734. [Google Scholar] [CrossRef]
  67. Sharman, J.E.; La Gerche, A.; Coombes, J.S. Exercise and Cardiovascular Risk in Patients with Hypertension. Am. J. Hypertens. 2014, 28, 147–158. [Google Scholar] [CrossRef] [Green Version]
  68. Pillard, F.; Laoudj-Chenivesse, D.; Carnac, G.; Mercier, J.; Rami, J.; Riviere, D.; Rolland, Y. Physical Activity and Sarcopenia. Clin. Geriatr. Med. 2011, 27, 449–470. [Google Scholar] [CrossRef]
  69. Wannamethee, S.G.; Shaper, A.G. Physical Activity in the Prevention of Cardiovascular Disease. Sports Med. 2001, 31, 101–114. [Google Scholar] [CrossRef]
  70. Arbab-Zadeh, A.; Dijk, E.; Prasad, A.; Fu, Q.; Torres, P.; Zhang, R.; Thomas, J.D.; Palmer, D.; Levine, B.D. Effect of Aging and Physical Activity on Left Ventricular Compliance. Circulation 2004, 110, 1799–1805. [Google Scholar] [CrossRef] [Green Version]
  71. Kraigher-Krainer, E.; Lyass, A.; Massaro, J.M.; Lee, U.S.; Ho, J.E.; Levy, D.; Kannel, W.B.; Vasan, R.S. Association of physical activity and heart failure with preserved vs. reduced ejection fraction in the elderly: The Framingham Heart Study. Eur. J. Heart Fail. 2013, 15, 742–746. [Google Scholar] [CrossRef] [Green Version]
  72. Santos, V.R.; Correa, B.D.; Pereira, C.G.D.S.; Gobbo, L.A. Physical Activity Decreases the Risk of Sarcopenia and Sarcopenic Obesity in Older Adults with the Incidence of Clinical Factors: 24-Month Prospective Study. Exp. Aging Res. 2020, 46, 166–177. [Google Scholar] [CrossRef] [PubMed]
  73. Helgerud, J.; Høydal, K.; Wang, E.; Karlsen, T.; Berg, P.; Bjerkaas, M.; Simonsen, T.; Helgesen, C.; Hjorth, N.; Bach, R.; et al. Aerobic High-Intensity Intervals Improve VO2max More than Moderate Training. Med. Sci. Sports Exerc. 2007, 39, 665–671. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Lelyavina, T.A.; Galenko, V.L.; Ivanova, O.A.; Komarova, M.Y.; Ignatieva, E.V.; Bortsova, M.A.; Yukina, G.Y.; Khromova, N.V.; Sitnikova, M.Y.; Kostareva, A.; et al. Clinical Response to Personalized Exercise Therapy in Heart Failure Patients with Reduced Ejection Fraction Is Accompanied by Skeletal Muscle Histological Alterations. Int. J. Mol. Sci. 2019, 20, 5514. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Gielen, S.; Sandri, M.; Kozarez, I.; Kratzsch, J.; Teupser, D.; Thiery, J.; Erbs, S.; Mangner, N.; Lenk, K.; Hambrecht, R.; et al. 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 2012, 125, 2716–2727. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Cunha, T.F.; Bacurau, A.V.N.; Moreira, J.B.N.; Paixão, N.A.; Campos, J.C.; Ferreira, J.C.B.; Leal, M.L.; Negrão, C.E.; Moriscot, A.S.; Wisløff, U.; et al. Exercise Training Prevents Oxidative Stress and Ubiquitin-Proteasome System Overactivity and Reverse Skeletal Muscle Atrophy in Heart Failure. PLoS ONE 2012, 7, e41701. [Google Scholar] [CrossRef]
  77. Williams, A.D.; Carey, M.F.; Selig, S.; Hayes, A.; Krum, H.; Patterson, J.; Toia, D.; Hare, D.L. Circuit Resistance Training in Chronic Heart Failure Improves Skeletal Muscle Mitochondrial ATP Production Rate—A Randomized Controlled Trial. J. Card. Fail. 2007, 13, 79–85. [Google Scholar] [CrossRef]
  78. Esposito, F.; Mathieu-Costello, O.; Wagner, P.D.; Richardson, R.S. Acute and chronic exercise in patients with heart failure with reduced ejection fraction: Evidence of structural and functional plasticity and intact angiogenic signalling in skeletal muscle. J. Physiol. 2018, 596, 5149–5161. [Google Scholar] [CrossRef]
  79. Cunha, T.F.; Bechara, L.R.G.; Bacurau, A.V.N.; Jannig, P.R.; Voltarelli, V.A.; Dourado, P.M.; Vasconcelos, A.R.; Scavone, C.; Ferreira, J.C.B.; Brum, P.C. Exercise training decreases NADPH oxidase activity and restores skeletal muscle mass in heart failure rats. J. Appl. Physiol. 2017, 122, 817–827. [Google Scholar] [CrossRef] [Green Version]
  80. Bacurau, A.V.; Jannig, P.R.; De Moraes, W.M.; Cunha, T.F.; Medeiros, A.; Barberi, L.; Coelho, M.A.; Bacurau, R.F.; Ugrinowitsch, C.; Musarò, A.; et al. Akt/mTOR pathway contributes to skeletal muscle anti-atrophic effect of aerobic exercise training in heart failure mice. Int. J. Cardiol. 2016, 214, 137–147. [Google Scholar] [CrossRef]
  81. Lenk, K.; Schur, R.; Linke, A.; Erbs, S.; Matsumoto, Y.; Adams, V.; Schuler, G. Impact of exercise training on myostatin expression in the myocardium and skeletal muscle in a chronic heart failure model. Eur. J. Heart Fail. 2009, 11, 342–348. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Souza, R.W.A.; Piedade, W.P.; Soares, L.C.; Souza, P.A.T.; Aguiar, A.F.; Vechetti-Júnior, I.J.; Campos, D.H.S.; Fernandes, A.A.H.; Okoshi, K.; Carvalho, R.F.; et al. Aerobic Exercise Training Prevents Heart Failure-Induced Skeletal Muscle Atrophy by Anti-Catabolic, but Not Anabolic Actions. PLoS ONE 2014, 9, e110020. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Moreira, J.B.N.; Bechara, L.R.G.; Bozi, L.H.M.; Jannig, P.R.; Monteiro, A.W.A.; Dourado, P.M.; Wisløff, U.; Brum, P.C. High- versus moderate-intensity aerobic exercise training effects on skeletal muscle of infarcted rats. J. Appl. Physiol. 2013, 114, 1029–1041. [Google Scholar] [CrossRef] [Green Version]
  84. Cai, M.; Wang, Q.; Liu, Z.; Jia, D.; Feng, R.; Tian, Z. Effects of different types of exercise on skeletal muscle atrophy, antioxidant capacity and growth factors expression following myocardial infarction. Life Sci. 2018, 213, 40–49. [Google Scholar] [CrossRef] [PubMed]
  85. Gomes, M.J.; Pagan, L.U.; Lima, A.R.R.; Reyes, D.R.A.; Martinez, P.F.; Damatto, F.C.; Pontes, T.H.D.; Rodrigues, E.A.; Souza, L.M.; Tosta, I.F.; et al. Effects of aerobic and resistance exercise on cardiac remodelling and skeletal muscle oxidative stress of infarcted rats. J. Cell. Mol. Med. 2020, 24, 5352–5362. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Kavazis, A.N.; Smuder, A.J.; Powers, S.K. Effects of short-term endurance exercise training on acute doxorubicin-induced FoxO transcription in cardiac and skeletal muscle. J. Appl. Physiol. 2014, 117, 223–230. [Google Scholar] [CrossRef] [Green Version]
  87. Heineke, J.; Auger-Messier, M.; Xu, J.; Sargent, M.; York, A.; Welle, S.; Molkentin, J.D. Genetic Deletion of Myostatin from the Heart Prevents Skeletal Muscle Atrophy in Heart Failure. Circulation 2010, 121, 419–425. [Google Scholar] [CrossRef]
  88. Hofmann, M.; Schober-Halper, B.; Oesen, S.; Franzke, B.; Tschan, H.; Bachl, N.; Strasser, E.-M.; Quittan, M.; Wagner, K.-H.; Wessner, B. Effects of elastic band resistance training and nutritional supplementation on muscle quality and circulating muscle growth and degradation factors of institutionalized elderly women: The Vienna Active Ageing Study (VAAS). Eur. J. Appl. Physiol. 2016, 116, 885–897. [Google Scholar] [CrossRef] [Green Version]
  89. Breitbart, A.; Auger-Messier, M.; Molkentin, J.D.; Heineke, J. Myostatin from the heart: Local and systemic actions in cardiac failure and muscle wasting. Am. J. Physiol. Circ. Physiol. 2011, 300, H1973–H1982. [Google Scholar] [CrossRef]
  90. Haykowsky, M.J.; Kouba, E.J.; Brubaker, P.H.; Nicklas, B.J.; Eggebeen, J.; Kitzman, D.W. Skeletal Muscle Composition and Its Relation to Exercise Intolerance in Older Patients with Heart Failure and Preserved Ejection Fraction. Am. J. Cardiol. 2014, 113, 1211–1216. [Google Scholar] [CrossRef] [Green Version]
  91. Molina, A.J.A.; Bharadwaj, M.S.; Van Horn, C.; Nicklas, B.J.; Lyles, M.F.; Eggebeen, J.; Haykowsky, M.J.; Brubaker, P.H.; Kitzman, D.W. Skeletal Muscle Mitochondrial Content, Oxidative Capacity, and Mfn2 Expression Are Reduced in Older Patients with Heart Failure and Preserved Ejection Fraction and Are Related to Exercise Intolerance. JACC Heart Fail. 2016, 4, 636–645. [Google Scholar] [CrossRef] [PubMed]
  92. Heo, J.-W.; Yoo, S.-Z.; No, M.-H.; Park, D.-H.; Kang, J.-H.; Kim, T.-W.; Kim, C.-J.; Seo, D.-Y.; Han, J.; Yoon, J.-H.; et al. Exercise Training Attenuates Obesity-Induced Skeletal Muscle Remodeling and Mitochondria-Mediated Apoptosis in the Skeletal Muscle. Int. J. Environ. Res. Public Health 2018, 15, 2301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Yoo, S.-Z.; No, M.-H.; Heo, J.-W.; Park, D.-H.; Kang, J.-H.; Kim, J.-H.; Seo, D.Y.; Han, J.; Jung, S.-J.; Kwak, H.-B. Effects of Acute Exercise on Mitochondrial Function, Dynamics, and Mitophagy in Rat Cardiac and Skeletal Muscles. Int. Neurourol. J. 2019, 23, S22–S31. [Google Scholar] [CrossRef] [PubMed]
  94. Mandic, S.; Myers, J.; Selig, S.E.; Levinger, I. Resistance Versus Aerobic Exercise Training in Chronic Heart Failure. Curr. Heart Fail. Rep. 2011, 9, 57–64. [Google Scholar] [CrossRef] [PubMed]
  95. Giuliano, C.; Karahalios, A.; Neil, C.; Allen, J.D.; Levinger, I. The effects of resistance training on muscle strength, quality of life and aerobic capacity in patients with chronic heart failure—A meta-analysis. Int. J. Cardiol. 2017, 227, 413–423. [Google Scholar] [CrossRef] [PubMed]
  96. Suzuki, T.; Palus, S.; Springer, J. Skeletal muscle wasting in chronic heart failure. ESC Heart Fail. 2018, 5, 1099–1107. [Google Scholar] [CrossRef]
  97. Jakovljevic, D.G.; Donovan, G.; Nunan, D.; McDonagh, S.; Trenell, M.I.; Grocott-Mason, R.; Brodie, D.A. The effect of aerobic versus resistance exercise training on peak cardiac power output and physical functional capacity in patients with chronic heart failure. Int. J. Cardiol. 2010, 145, 526–528. [Google Scholar] [CrossRef] [PubMed]
  98. Bjarnason-Wehrens, B.; Mayer-Berger, W.; Meister, E.; Baum, K.; Hambrecht, R.; Gielen, S. Recommendations for resistance exercise in cardiac rehabilitation. Recommendations of the German Federation for Cardiovascular Prevention and Rehabilitation. Eur. J. Cardiovasc. Prev. Rehabil. 2004, 11, 352–361. [Google Scholar] [CrossRef] [PubMed]
  99. Wang, Z.; Peng, X.; Li, K.; Wu, C.-J. Effects of combined aerobic and resistance training in patients with heart failure: A meta-analysis of randomized, controlled trials. Nurs. Health Sci. 2019, 21, 148–156. [Google Scholar] [CrossRef] [PubMed]
  100. Irving, B.A.; Lanza, I.R.; Henderson, G.C.; Rao, R.R.; Spiegelman, B.M.; Nair, K.S. Combined Training Enhances Skeletal Muscle Mitochondrial Oxidative Capacity Independent of Age. J. Clin. Endocrinol. Metab. 2015, 100, 1654–1663. [Google Scholar] [CrossRef] [Green Version]
Figure 1. Schematic overview of the potential beneficial effects of exercise on heart failure-related sarcopenia.
Figure 1. Schematic overview of the potential beneficial effects of exercise on heart failure-related sarcopenia.
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Table 1. Beneficial effects of exercise training in patients with heart failure.
Table 1. Beneficial effects of exercise training in patients with heart failure.
AuthorsStudy DesignSubjectsExercise TypeBeneficial Effects of Exercise
Lenk et al. [27]RCTChronic HF patientsType: aerobic exercise (bicycle ergometer)
Duration: 12 weeks
Frequency: daily
Time: 20–30 min/day
In skeletal muscle
⇓ Catabolic gene expression (Myostatin)
In serum
⇔ Myostatin level
Lelyavina et al. [74]RCTHF patientsType: aerobic exercise (walking)
Duration: 12 weeks
Frequency: 4–5 times/week
⇑ Peak VO2 (mL/kg/min)
⇑ Left ventricular ejection fraction (%)
⇑ Exercise tolerance
In skeletal muscle
⇓ Fiber diameter, endomysium thickness
Gielen et al. [75]RCTChronic HF patientsType: aerobic exercise (bicycle ergometer)
Duration: 4 weeks
Frequency: 4 times/week
Time: 20 min/day
⇑ Peak VO2 (mL/kg/min)
In vastus lateralis muscle biopsies
⇓ Catabolic gene expression (MuRF-1)
⇑ Anabolic gene expression (IGF-1)
⇓ Inflammatory gene expression (TNF- α )
Cunha et al. [76]RCTHF patientsType: aerobic exercise (walking)
Duration: 12 weeks
Frequency: 3 times/week
Time: 50 min/week
⇑ Peak VO2 (mL/kg/min)
In skeletal muscle
⇓ Proteasome activity
William et al. [77]RCTChronic HF patientsType: resistance training (upper and lower body)
Duration: 11 weeks
Frequency: 3 session/week
⇑ Peak VO2 (mL/kg/min)
⇑ Lactate threshold (W)
⇑ Peak lactate (mmol/L)
⇑ Capillary density
In skeletal muscle
⇑ Oxidative capacity (CS, HAD enzyme activity)
⇑ MAPR (mmol ATP/min/kg)
Esposito et al. [78]RCTHF patients with reduced ejection fractionType: resistance training (knee extensor exercise)
Duration: 8 weeks
Frequency: 3 times/week
In skeletal muscle
⇑ Type 1 fiber
⇑ Mitochondria volume
RCT, randomized controlled trial; HF, heart failure; MuRF-1, muscle RING-finger protein-1; IGF-1, insulin-like growth factor-1; TNF-α, tumor necrosis factor-α; CS, citrate synthase; HAD, beta-hydroxyacyl CoA-dehydrogenase; MAPR, mitochondrial ATP production rate; VEGF, vascular endothelial growth factor; ⇑, upregulation; ⇓, downregulation; ⇔, no significant changes.
Table 2. Beneficial effects of exercise training in animal model with heart failure.
Table 2. Beneficial effects of exercise training in animal model with heart failure.
AuthorsSubjectsExercise TypeBeneficial Effects of Exercise
Cunha et al. [76]α2A2CARKO miceType: Treadmill running
Duration: 8 weeks
Intensity: moderate intensity
Frequency: 5 days/week
⇑ Exercise performance
In plantaris muscle
⇑ Cross area of muscle
Atrogin-1/MAFbx and E3α mRNA levels
Cunha et al. [79]LAD-ligation ratType: Treadmill running
Duration: 8 weeks
Intensity: Moderate intensity
Frequency: 5 days/week
⇑ Exercise performance
⇑ Type 1 fiber percentage
⇓ Serum TNFα
In plantaris muscle
NOX2, p47phox and NADPH oxidase
NF-kB and p38 MAPK
Bacurau et al. [80]α2A2CARKO miceType: Treadmill running Duration: 8 weeks
Intensity: Moderate intensity
Frequency: 5 days/week
⇑ Exercise performance
⇑ Soleus atrophy
In soleus muscle
IGF-1/Akt/mTOR signaling,
⇓ Proteasome activity (p4E-BP1/4E-BP1, p-p70S6K/p70S6K)
Lenk et al. [81]LAD-ligation ratType: Treadmill running
Duration: 4 weeks
Intensity: 30 m/min
Frequency: 5 days/week
In gastrocnemius muscle
⇓ Myostatin expression
In muscle cell
⇑ Myostatin via TNFα/p38MAPK/NFkB signaling pathway
Souza et al. [82]Aortic stenosis surgery ratType: Treadmill running
Duration: 10 weeks
Intensity: 15 m/min
Frequency: 5 days/week
⇑ Serum IGF-1
In soleus and plantaris muscle
⇑ Cross area of muscle
⇑ CS activity
Moreira et al. [83]LAD-ligation ratType: Treadmill running
Duration: 8 weeks
Intensity: moderate intensity (60% VO2max vs. 85% VO2max)
Frequency: 5 days/week
⇑ Exercise performance
In soleus muscle
⇑ CS activity
⇑ Glycogen content
Atrogin-1, MuRF1 mRNA
In plantaris muscle
⇑ CS activity
⇑ Glycogen content
⇑ Hexokinase
Atrogin-1 mRNA
Cai et al. [84]Myocardial infarction surgery ratType: Resistance exercise (Ladder climbing)
Duration: 3 sessions/day, 4 weeks
Intensity: moderate intensity
Frequency: 5 days/week
In soleus muscle
Atrogin-1 and MuRF-1
Gomes et al. [85]LAD-ligation ratType: Treadmill running vs. resistance exercise (ladder climbing)
Duration: 12 weeks
Intensity: moderate intensity
Frequency: 3 days/week
Treadmill running
⇑ Maximum exercise capacity
Ladder climbing
⇑ Maximum carrying load
In gastrocnemius muscle
⇓ Lipid hydroperoxide
⇑ Glutathione peroxidase activity
⇑ Superoxide dismutase activity
ROS, reactive oxygen species; α2A/α2CARKO, α2A- and α2C-adrenergic receptors knock out mice; LAD-ligation rat, left anterior descending artery-ligation rat; TNF-α, tumor necrosis factor-α; NF-kB, nuclear factor-κB; MAPK, mitogen-activated protein kinases; IGF-1, insulin like growth factor-1; mTOR, mammalian target of rapamycin; NOX2, NADPH oxidase 2; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; FOXO1, Forkhead Box O1; PDK1, 3-phosphoinositide-dependent protein kinase-1; MuRF-1, muscle RING-finger protein-1; CS, citrate synthase; ERK, extracellular signal-regulated protein kinase; ⇑, upregulation; ⇓, downregulation; ⇔, no significant changes.

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MDPI and ACS Style

Cho, J.; Choi, Y.; Sajgalik, P.; No, M.-H.; Lee, S.-H.; Kim, S.; Heo, J.-W.; Cho, E.-J.; Chang, E.; Kang, J.-H.; et al. Exercise as a Therapeutic Strategy for Sarcopenia in Heart Failure: Insights into Underlying Mechanisms. Cells 2020, 9, 2284.

AMA Style

Cho J, Choi Y, Sajgalik P, No M-H, Lee S-H, Kim S, Heo J-W, Cho E-J, Chang E, Kang J-H, et al. Exercise as a Therapeutic Strategy for Sarcopenia in Heart Failure: Insights into Underlying Mechanisms. Cells. 2020; 9(10):2284.

Chicago/Turabian Style

Cho, Jinkyung, Youngju Choi, Pavol Sajgalik, Mi-Hyun No, Sang-Hyun Lee, Sujin Kim, Jun-Won Heo, Eun-Jeong Cho, Eunwook Chang, Ju-Hee Kang, and et al. 2020. "Exercise as a Therapeutic Strategy for Sarcopenia in Heart Failure: Insights into Underlying Mechanisms" Cells 9, no. 10: 2284.

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