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Alterations in Skeletal Muscle in Heart Failure
The syndrome of heart failure (HF) is characterized by adaptations in numerous physiologic systems that contribute to disease symptomology and progression. The cardinal symptom of HF, exercise intolerance, which manifests as dyspnea and skeletal muscle fatigue, has long been attributed to cardiac insufficiency. However, research over the past three decades has conclusively demonstrated a role for adaptations in the skeletal musculature in these symptoms. The overall goal of this chapter is to summarize the skeletal muscle adaptations to HF identified in clinical studies and model systems. When possible, we extend the description of these adaptations to the cellular and molecular levels. We present this evidence with a focus on describing how skeletal muscle adaptations contribute to diminished skeletal muscle and whole body physiological functional capacity, which, in turn, would contribute to exercise intolerance.
Skeletal Muscle Adaptations in Heart Failure
Dyspnea and fatigue, resulting in diminished exercise tolerance, are among the main factors contributing to decreased social and physical functioning and quality of life of HF patients. There has long been evidence that measures of cardiac function, such as ejection fraction and cardiac output, only poorly correlate with a patient’s capacity to exercise, suggesting the involvement of factors other than cardiac insufficiency. Furthermore, many studies of the effects of exercise in patients with HF have failed to demonstrate improvements in cardiac output, stroke volume, or ejection fraction, despite showing gains in exercise capacity and peak oxygen uptake (VO 2 ). The lack of a close correlation between central hemodynamics and exercise tolerance has led to investigations into alterations in peripheral skeletal muscle. As will be discussed later, the view that alterations in skeletal muscle metabolism, structure, mass, and function play a rate-limiting role in the functional capacity in patients with HF is now broadly accepted. Fig. 16.1 provides a broad hypothetical framework for how factors related to the syndrome of HF (disease-related effectors) diminish skeletal muscle functional capacity (functional phenotypes) and promote exercise intolerance (fatigue and dyspnea) via their effects on skeletal muscle structure and function (skeletal muscle adaptations). To date, most studies have evaluated skeletal muscle adaptations in patients with HF with reduced ejection fraction (HFrEF). As knowledge has grown regarding the syndrome of HF with preserved ejection fraction (HFpEF), work has begun to accumulate on the skeletal muscle phenotype in these patients ( see also Chapters 11 and 39 ). Although still limited in number, studies show comparable changes in skeletal muscle metabolism, structure, and function in patients with HFpEF as seen in patients with HFrEF. Nonetheless, the majority of work has focused on patients with HFrEF, and we will refer to those studies throughout the text as simply “HF,” unless adaptations are specified as being evaluated in HFpEF patients.
The myopathy associated with HF affects both cardiac and skeletal muscle and encompasses alterations in structure and function. Regarding skeletal muscle, the classical model of the myopathy of HF includes a loss of muscle size, strength, and oxidative capacity. More specifically, HF patients experience skeletal muscle atrophy secondary to muscle fiber atrophy, and this loss of muscle quantity may account for a large proportion of the reduction in peak VO 2 . Patients also experience muscle weakness, which is due in part to muscle atrophy, but there are also unique effects of the disease to reduce intrinsic skeletal muscle contractile function. Finally, patients exhibit abnormal skeletal muscle metabolism, with a shift toward glycolytic pathways, changes in mitochondrial function and structure, and decreased oxidative enzyme activity. This is due in part to a shift from fatigue-resistant, oxidative type I fibers toward oxidative, type II fibers. Altogether, these abnormalities in skeletal muscle structure, function, and cell viability are intimately linked to each other and contribute to the abnormal exercise response, enhanced fatigability, and progressive symptom complex of patients with HF.
Skeletal Muscle Atrophy
HF patients develop generalized muscle atrophy. Calf muscle volume, assessed by magnetic resonance imaging, revealed reduced muscle volume in patients with HF and significant water and/or fat infiltration. Muscle atrophy develops in patients with severe HF compared with age- and gender-matched controls. However, some studies report normal muscle mass in patients with HF. This disparity may relate to the patients studied, because muscle atrophy may develop secondary to weight loss or inactivity in a subset of the HF population. However, HF patients generally experience some degree of muscle atrophy during the course of the disease.
The mechanisms that mediate skeletal muscle wasting and atrophy have been studied in patients with HF and animal models of cardiac dysfunction. Muscle atrophy occurs during periods of negative muscle protein imbalance, which are due to decreased protein synthesis, increased protein degradation, or both . There is controversy on the impact of clinical status and disease exacerbations on muscle atrophy in HF. The majority of studies have shown no defects in either muscle protein synthesis or breakdown in clinically stable HF patients. It is possible that muscle atrophy initiation and progression is directly linked to episodes of disease exacerbation and hospitalization, which are accompanied by bed rest, malnutrition, and other factors that may incite atrophy. Unfortunately, no studies have examined patients during acute disease exacerbation to test this postulate or determine what metabolic defects might account for muscle atrophy, although one study has evaluated patients shortly after hospitalization and found evidence for enhance muscle protein breakdown.
Skeletal muscle atrophy contributes to exercise intolerance in HF patients. Strong correlations have been found between muscle mass and peak VO 2 . Moreover, in contrast to nondiseased individuals, in patients with severe HF, the addition of upper arm exercise significantly increases peak VO 2 , suggesting the importance of skeletal muscle mass in determining peak VO 2 in patients with HF. Thus there is ample evidence supporting a role for muscle atrophy in promoting exercise intolerance. We will now consider the mechanisms underlying this loss of skeletal muscle.
Skeletal Muscle Protein Synthesis and Reduced Anabolic Hormones/Effectors
Skeletal muscle protein synthesis is controlled by mechanoresponsive pathways and paracrine growth factor signaling loops, such as the local insulin-like growth factor-1 (IGF-1) system, but also responds to systemic stimuli, including growth hormone (GH), systemic IGF-1, anabolic steroids, and others. The GH/IGF-1 axis plays a key role in skeletal muscle growth and differentiation. Low systemic IGF-1 levels have been associated with a reduced leg muscle cross-sectional area (CSA) and total muscle strength in HF patients. Catabolic syndromes, such as chronic inflammation, sepsis, or cancer, show an altered state of the GH/IGF-1 axis, most probably due to a peripheral IGF-1 deficiency because of an impaired IGF-1 response to GH but also abnormal intrahepatic responses to GH. This has been attributed, in part, to increased serum levels and the local expression of proinflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α).
In humans with advanced HF and animal models of ischemic cardiomyopathy, reduced local expression of IGF-1 was detected in skeletal muscle compared with controls, accompanied by an increased expression of the IGF-1 receptor in the presence of normal serum levels of IGF-1. The serum concentration of the proinflammatory cytokines IL-1β and IL-6 were not found to be significantly changed, whereas TNF-α showed a trend toward higher levels in HF. Notably, the local expression of both IL-1β and TNF-α is increased in chronic HF and can be reduced by aerobic exercise training. Furthermore, a decreased single muscle fiber CSA in HF has been linked to local expression of IL-1β and impaired expression levels of expression of IGF-1 in skeletal muscle. These results suggest that, despite normal serum levels of IGF-1 and proinflammatory cytokines, the local expression of IGF-I is substantially reduced in HF, indicating a reduction in local anabolic stimuli. Because decreased IGF-1 levels and a reduced muscle fiber CSA correlate with increased levels of IL-1β, these results point toward a cytokine-mediated local catabolic process that is mediated, in part, through reductions in anabolic hormone expression.
Local expression of IGF-1 in skeletal muscle is mainly regulated by two different mechanisms. The first is GH receptor–dependent, a mechanism which, at least in part, is impaired in HF-induced weight loss due to a peripheral GH resistance. In addition, skeletal muscle IGF-1 expression is modulated in response to alterations in muscle use, and the expression of IGF-1 increases significantly in response to work-overload and passive stretch. In contrast, TNF-α and other cytokines may decrease skeletal muscle expression of IGF-1.
In addition to its classical role to enhance protein synthesis, IGF-1 has antiapoptotic effects in various tissues, protecting against cytokine-mediated apoptosis. These findings suggest that IGF-1 may regulate cell survival by modulating both proapoptotic and antiapoptotic stimuli. Thus the increased rate of skeletal muscle apoptosis in HF may be explained by a decline in local IGF-1 expression. This is suggested by preclinical models, where stimulation of IGF-1 production via GH administration reduces atrophy via reductions in apoptosis.
In male HF patients, deficiencies in circulating total testosterone, dehydroepiandrosterone (DHEA), and IGF-1 are common and correlate with a poor prognosis. Testosterone maintains skeletal muscle mass by increasing fractional muscle protein synthesis. In addition, testosterone appears to stimulate IGF-1 expression, but the exact molecular pathways are incompletely understood. At supraphysiologic doses, testosterone appears to act through androgen receptor–independent mechanisms. In HF patients, serum levels of free testosterone and DHEA are decreased, and this decrease correlates with HF severity. Perhaps most importantly, replacement of testosterone improves exercise capacity, muscle strength, and metabolic function.
Finally, insulin resistance is a hallmark of advanced HF. This metabolic abnormality is more pronounced during acute decompensated HF and improves upon cardiac recompensation. Moreover, improved cardiac output through left ventricular assist device placement results in reduced insulin resistance and improved glucose homeostasis in advanced HF. The effects of insulin to promote skeletal muscle anabolism occur during the daily cycle of feeding and fasting, where it serves to promote postprandial anabolism by reducing skeletal muscle protein breakdown. Studies have suggested that HF patients experience impaired suppression of insulin’s effects to reduce protein breakdown in response to meal-associated stimuli and that this impaired response was related to the circulating IL-6 level. Thus tissue insulin sensitivity, possibly secondary to immune activation, may contribute to skeletal muscle atrophy.
Skeletal Muscle Protein Breakdown and Increased Catabolic Hormones/Effectors
HF is a catabolic state, with increased levels of various catabolic hormones. Several authors have suggested a role for myostatin in muscle atrophy in patients with advanced HF. Myostatin is a local and circulating factor secreted from skeletal muscle with antianabolic and antihypertrophic actions. In fact, such a mechanism may be operable in patients, because circulating levels of myostatin, and other transforming growth factor (TGF) receptor ligands, such as activin, are increased in HF patients. Whatever might be the proximal hormonal/circulating effector, local skeletal muscle protein breakdown is mediated by several cellular systems that include lysosomal proteases, the adenosine triphosphate (ATP)–dependent ubiquitin-proteasome system, and the Ca 2+ -dependent calpain system ( Fig. 16.2 ). Specifically the ubiquitin–proteasome system has been implicated in the enhanced protein breakdown of atrophying skeletal muscle in a number of disease models, including chronic HF. Of particular interest is a group of ubiquitin-conjugating enzymes (E3-ligases) that target proteins for degradation by the proteasome. Through transcriptional screening, two E3-ligases, atrogin-1 (also called MFbx-1) and MURF-1 (muscle ring finger protein-1), have been identified to be highly induced in processes of muscular atrophy of different origin. Gomes and colleagues reported the identification and initial description of an increased expression of atrogin-1 (also called MAFbx-1), a muscle-specific E3-ligase, following starvation. Through a comparable analysis of genes regulated in atrophying muscle caused by different mechanisms, Bodine and colleagues identified the same gene (here called MAFbx-1) and, additionally, MURF-1, another E3-ligase. Through adenovirally mediated overexpression of these genes, their catabolic effects were demonstrated. Furthermore, animals with targeted deletion of MAFbx-1 or MURF-1 exhibit less muscular atrophy in response to denervation and hind limb suspension.
Increased atrogin-1 has been reported in other animal models of muscular atrophy induced by immobilization, denervation, hind limb suspension, starvation, and sepsis. The induction of atrogin-1 expression prior to muscle weight loss in starvation suggests that the activation of this gene is involved in the development and progression of muscle protein loss. In support of this possibility, overexpression of atrogin-1 in C 2 C 12 myotubes induced atrophy in vitro, whereas muscular atrophy following denervation was prevented in animals with targeted deletion of atrogin-1. Intriguingly, infusion of the proinflammatory cytokine IL-1β induces the expression of atrogin-1 42 and TNF-α increases the ubiquitin-conjugating capacity in myocytes, findings that again support the hypothesis of cytokines as putative mediators of muscular atrophy. Prior studies have shown transcriptional activation of E3 ligases in muscle of animals with left ventricular dysfunction and humans with advanced HF, whereas other reports did not show these changes. This might relate to the type of muscle injury and severity of HF. However, the exact mechanisms underlying the transcriptional activation of atrogin-1 by IL-1β remain to be elucidated.
Activation of the renin-angiotensin system results in vasoconstriction and elevated skeletal muscle concentration of angiotensin II (Ang II), which increases local oxidative stress, increases muscle proteolysis, and lowers skeletal muscle concentration of IGF-1. These mechanisms may accelerate protein degradation while decreasing protein synthesis. Loss of skeletal muscle mass contributes to muscle reflex alterations in HF. In normal subjects, muscle reflex activation helps to raise blood pressure and thereby maintain muscle perfusion during muscle acidosis. In HF, muscle reflex activation occurs at the onset of exercise, resulting in vasoconstriction and limited skeletal muscle perfusion.
Skeletal Muscle Contractile Dysfunction
Skeletal muscle contractile dysfunction has received relatively minimal attention as a precipitant of functional limitations in the clinical syndrome of HF. Despite this lack of attention, data suggest that HF is associated with marked reductions in skeletal muscle contractility. Skeletal muscle atrophy contributes to this diminished contractile function, but there is evidence for diminished function per unit muscle size (i.e., intrinsic contractile dysfunction). Studies under both static (isometric) and dynamic (isokinetic) conditions suggest intrinsic contractile deficits in HF patients on the order of 15% to 25%. This reduction is greater in cachectic versus noncachectic patients and is not corrected by cardiac transplantation, although ventricular assist device implantation has been shown to mitigate upper extremity weakness. Of note, studies show that these decrements in muscle function persist when patients are compared with controls who are matched for habitual physical activity level, arguing that decreased contractility is not a consequence of muscle disuse. Moreover, reduced contractility is not related to impairments in central motor drive or neural transmission. Thus there is compelling evidence that HF alters the intrinsic contractile properties of skeletal muscle and that the resulting muscle weakness contributes to exercise intolerance.
Myofilament Contractile Adaptations
Alterations in skeletal muscle contractile function in HF may relate to changes in myofilament protein expression, their function, or both. Regarding the former, adult human skeletal muscle is composed of three fiber types, characterized primarily by the type of myosin isoform expressed. Table 16.1 details the structural and functional features of these types of muscle fibers. In general, most skeletal muscles contain a mixture of these fiber types, with myosin heavy chain (MHC) I and IIA being predominant and with very few fibers that express only the fastest MHC isoform (MHC IIX). This differs from rodents, which express a fourth fiber type MHC IIB that is faster and less oxidative than all the other fiber types. There are other contractile proteins whose expression varies by fiber types, but the functional character of each fiber is largely dictated by the type of myosin expressed.
TABLE 16.1
Structural and Functional Features of Muscle Fibers
| Human Fiber Types | Low-Order Mammals | |||
|---|---|---|---|---|
| Fiber Type | Type I (Red) | Type IIA (Red) | Type IIX (White) | Type IIB (White) |
| Contraction time | Slow | Moderate fast | Fast | Very fast |
| Oxidative capacity | High | High | Intermediate | Low |
| Mitochondrial density | High | High | Medium | Low |
| Glycolytic capacity | Low | High | High | High |
| Resistance to fatigue | High | Fairly high | Intermediate | Low |
| Major storage fuel | Triglycerides | Creatine phosphate, glycogen | Creatine phosphate, glycogen | Creatine phosphate, glycogen |
| Capillary density | High | Intermediate | Low | Low |
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