Skeletal myopathy has been identified as a major comorbidity of heart failure (HF) affecting up to 20% of ambulatory patients leading to shortness of breath, early fatigue, and exercise intolerance. Neurohumoral blockade, through the inhibition of renin angiotensin aldosterone system (RAS) and
Heart failure (HF) is a significant cause of morbidity and mortality associated with high health care costs [
Cardiac cachexia is a serious complication of HF with a prevalence of 16–42% [
Chronic muscle underperfusion and/or metabolic disturbance in HF lead to an overactivation of muscle afferents, such as mechano-metaboreceptors [
The understanding of HF as a neurohumoral disorder instead of a hemodynamic disease (throughout most of the 20th century) has driven changes in the mandatory pharmacological therapy of HF. In this sense, inhibition of the RAS and
It is widely recognized that aerobic exercise training (AET) is an efficient nonpharmacologic therapy for HF that improves quality of life and exercise tolerance; the latter associated with remarkable attenuation of skeletal myopathy. In fact, AET counteracts systemic and local inflammation, neurohumoral exacerbation, and increased oxidative stress, which contribute to skeletal myopathy in HF [
Since both pharmacological and nonpharmacological therapies have a direct and/or indirect impact on skeletal myopathy, this review aims to provide an overview of these therapeutic approaches in counteracting skeletal myopathy in HF.
Sustained sympathetic hyperactivity and RAS activation are commonly associated with the pathogenesis of HF [
In this section, we will discuss the impact of
Sympathetic hyperactivity is a hallmark of HF associated with poor prognosis being an independent predictor of mortality [
In skeletal muscle, the sympathetic activity is mediated by
The
Even though the acute and chronic effects of sympathetic activation in skeletal muscle are well known, the role played by sympathetic overactivation in skeletal muscle associated with chronic diseases, such as HF, needs to be better clarified. In this sense, direct acute effects of
Effects of
Considering the hypertrophic effects of chronic
Studies have shown that
The inhibition of RAS has been demonstrated as an effective pharmacological therapy in HF. The beneficial effects of RAS inhibition in HF include improved clinical status and quality of life and survival paralleled by reduction in neurohumoral activation and hospitalization [
Angiotensin II (Ang II), the main effector molecule of the RAS (canonical axis), is processed by angiotensin converting enzyme (ACE) from inactive angiotensin I, which is responsible for vasoconstriction, proliferation, and proinflammatory effects [
Several studies have demonstrated a detrimental role of Ang II in skeletal muscle, either independently or combined with the systemic RAS activation [
Besides its effects on muscle tissue, Ang II inhibits skeletal muscle stem (satellite) cell proliferation, leading to reduced muscle regenerative capacity [
In addition to Ang II direct effects on skeletal muscle and muscle satellite cells, indirect effects of Ang II regulating circulating hormones, cytokines, and metabolic effectors besides ROS formation also affect muscle wasting. The AMP-activated protein kinase (AMPK) is a key regulator of energy status acting as a metabolic energy sensor modulating glucose and lipid metabolism. Ang II blocks AMPK activity and reduces muscle mass [
Considering that Ang II plays a role in weight body loss and muscle wasting in HF [
Another important effector of canonical RAS axis activation is the aldosterone, which is also involved in muscle atrophy in HF [
It is important to highlight the complexity of RAS on skeletal muscle mass regulation, since there is a paradoxical “protective arm” in RAS system. While the most deleterious effects of Ang II-induced muscle wasting are mediated via AT1 receptors, AT2 receptor triggers beneficial effects on muscle regeneration in both
A noncanonical protective axis of RAS involves the peptide Ang-(1–7). Ang-(1–7) is synthesized directly from Ang II or indirectly from Ang I by an ACE homolog enzyme (ACE2), which in turn binds into the Mas receptor [
Taken together, pharmacological therapy with inhibitors of RAS (canonical axis) has demonstrated some positive outcomes in skeletal myopathy of HF patients, such as a partial attenuation in exercise intolerance and muscle wasting. The relative contribution of direct
Direct and indirect effects of Ang II on skeletal muscle mass. The direct effects of angiotensin II (Ang II) in skeletal muscle include increases ROS production via AT1 receptor and NADPH oxidase activation, which results in activation of UPS and protein degradation. The indirect effects of systemic Ang II are mediated by increased ROS induced caspase-3 besides enhanced TNF-
AET has been recognized as an efficient and safe preventive and therapeutic strategy for cardiovascular diseases [
Skeletal myopathy leads to several muscle metabolic changes in human and animal HF [
AET has been considered an effective strategy in modulating muscle metabolic changes induced by HF. In fact, AET increases peak VO2 and exercise tolerance, which is related to energy production and utilization efficacy. Regarding substrate supply, AET increases muscle phosphocreatine availability and resynthesis [
Another important change induced by HF is a significant impaired muscle contractility associated with changes in Ca2+ handling, which will further affect muscle strength and resistance to fatigue. In this sense, HF in rats decreases skeletal muscle sarcoplasmic Ca2+ levels associated with reduced rate of sarcoplasmic reticulum Ca2+ release [
AET improves skeletal muscle Ca2+ handling. We have previously demonstrated that AET improves the net balance of Ca2+ handling proteins in HF mice involved in sarcoplasmic Ca2+ release and reuptake in
Taken together, data from the literature provide evidence for AET as a strategy of paramount importance to prevent muscle metabolic and contractile dysfunction in HF.
Skeletal muscle loss is considered an independent predictor of morbidity and mortality in HF patients [
Regarding neurohumoral overactivation, AET reduces muscle sympathetic nerve activity, which is associated with an improved clinical outcome [
AET reduces circulating catecholamine levels in both HF patients and animal models [
RAS hyperactivity is also involved in skeletal myopathy in HF primarily by activation of Ang II, increasing ROS generation, protein degradation, and apoptosis as aforementioned in Section
Neurohumoral overactivation is also associated with increased circulating/muscle proinflammatory cytokine concentrations and muscle redox imbalance, which are directly involved in muscle catabolism. In fact, increased circulating TNF-
Increased TNF-
UPS is considered the main proteolytic system responsible for disposal of damaged proteins in skeletal muscle [
Besides protein degradation, protein synthesis also plays an essential role in maintaining muscle mass [
Altogether, these results suggest that AET reestablishes skeletal muscle homeostasis attenuating muscle wasting. This is crucial since muscle wasting in HF is related to a poor prognosis and reduced quality of life [
This seems to be AET effects on skeletal muscle in HF as can be seen in Figure
Effects of aerobic exercise training in counteracting heart failure-induced skeletal myopathy. Neurohumoral hyperactivity and reduced blood perfusion associated with heart failure contribute to skeletal myopathy, which is characterized by muscle prooxidant and inflammatory state associated with muscle contractile dysfunction and atrophy, exercise intolerance, and reduced quality of life. These responses are associated with impaired Ca2+ handling, reduced protein synthesis paralleled by increased proteolysis. Note that aerobic exercise training counteracts most of the features involved in skeletal myopathy (illustrated by filled arrows and
Over the last few decades, the therapeutic approach most commonly used in HF has been the neurohumoral blockade, which is currently mandatory [
RAS has also been inhibited to minimize the neurohumoral overactivation and improve cardiac function in HF. Moreover, ACE inhibitors have been associated with beneficial effects on skeletal muscle, such as improved muscle glucose uptake and mitochondrial function and a modulation of IGF-I, which is related to skeletal muscle trophicity [
AET has been considered the most effective strategy to counteract skeletal myopathy in HF. As aforementioned, AET improves several aspects involved in skeletal muscle function regulation, such as substrate supply availability, oxidative enzyme activities, and mitochondrial content (metabolism) [
Similarities and differences between aerobic exercise training and neurohumoral blockade in heart failure-induced skeletal myopathy. Skeletal myopathy in heart failure plays a major role in exercise intolerance. Neurohumoral hyperactivity is associated with the pathogenesis of heart failure and also affects skeletal muscle by increasing inflammatory response and oxidative stress and decreasing muscle perfusion. In this perspective, neurohumoral blockade has an important indirect effect on attenuating skeletal myopathy by improving cardiac function and reducing neurohumoral hyperactivity (thick solid lines and ⊥). The efficacy of direct effects of
In conclusion, an association between pharmacological treatment and AET is currently the most efficient strategy to treat the cardiac dysfunction and skeletal myopathy, improving exercise tolerance and quality of life in HF. It is expected for the future that an association between more selective/specific drugs and AET optimizes the treatment, increasing the responsiveness and outcomes.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Patricia C. Brum holds grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, no. 2010/50048-1 and no. 2014/25957-9) and Conselho Nacional de Pesquisa e Desenvolvimento (CNPq, no. 302201/2011-4).