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The Heart-Brain Connection in Patients with Duchenne Muscular Dystrophy

  • Claudia Bearzi
  • Roberto RizziEmail author
Living reference work entry

Abstract

Duchenne muscular dystrophy (DMD) is a progressive form of muscular dystrophy that occurs primarily in males and though in rare cases may affect females. It is caused by mutations in the DMD gene, which result in the completely lack of the related protein dystrophin (Dp427). Absence of Dp427 causes progressive weakening and degeneration of muscles. In addition, beyond skeletal muscle, these mutations alter the respiratory and heart performances, representing the leading causes of death in these patients. Furthermore, certain neuronal populations express Dp427, whose perturbation is correlated with several neural disorders in DMD patients. Recently, it has been hypothesized that dystrophin could play a fundamental role also in the axonal growth mediated by the nerve growth factor (NGF). Indeed, different studies have shown that in a dystrophic scenario, different neural populations exhibit reduced responsiveness to NGF stimulation, compared to controls. Parameters, such as number and length of neurites, growth cone advancement, and receptor ligand responsiveness (NGF/TrkA), are significantly reduced in neurons deriving from DMD patients or dystrophin-deficient (mdx) mice, a murine dystrophic model. Remarkably, the reduced sympathetic innervation affects even more distal districts, such as the heart, disturbing electrophysiology, beating, and contraction force. A deepen analysis of the relationship between the heart and brain in the context of DMD offers a new strategy for patient stratification and knowledge of the pathology that could open up new therapeutic scenarios.

Keywords

Heart Brain Innervation Duchenne muscular dystrophy Nerve growth factor Sympathetic nervous system Fibrosis Postganglionic adrenergic neurons 

Introduction

Cardiac innervation originates from the sympathetic nervous system (SNS), and it occurs in the late stages of embryogenesis. SNS is able to condition cardiac activity throughout life, modulating rhythm and contractility based on emotional and physical stresses. The sympathetic neurons (SNs) are capable to regulate the contractility, frequency, and electrical conductivity of the entire cardiac system, releasing specific neurotransmitters, such as norepinephrine (NE). On the other hand, cardiac cells are able to guide the innervation and guarantee the survival of the afferent neurons through the secretion of specific molecules. The main molecule that guides the distribution of sympathetic synapses is the nerve growth factor (NGF).

The topology of innervation is generated over a fine balance between chemoattracting and chemorepellent cardiac signals, which allow or repel penetration of the nerve endings within the myocardium. Some areas of the heart are differentially innervated, such as the subendocardial and subepicardial regions, because of the function that the SNS must exercise in that particular area. Although cardiac innervation density reflects in general the levels of NGF produced by the heart, some myocardial elements, such as the sinoatrial node, are more intensely innervated, in line with the specific physiologic role of the SNS in controlling heart rhythm in response to stimuli related to fight-or-flight response. The physiologic role of such innervation pattern is not fully understood, and its alteration is connected with impaired cardiac function, activity, and arrhythmias, leading to different pathologies. Indeed, many diseases present unconventional innervation, such as diabetes mellitus, heart failure, and several dystrophies, including Duchenne muscular dystrophy (DMD).

In individuals affected by DMD, despite muscle wasting, cardiomyocytes (CMs) degeneration and necrosis are the main causes of morbidity and death. Heart failure (HF) is generally preceded by disturbances in heart rate variability (HRV), and noninvasive measurement of the autonomic nervous system is an important instrument to envisage adverse cardiovascular events. As major observations in DMD patients, several studies reported a reduced parasympathetic activity and an augmented sympathetic predominance: indeed, regional differences in sympathetic discharge are linked to arrhythmias in both ischemic and structurally normal hearts of arrhythmic patients. This hypothesis is also supported by a reduced presence of neurons at superior cervical ganglia level and by an imbalance of many components linked to the NGF signal, in the same patients. The mechanism, by which regional heterogeneity of sympathetic discharge triggers arrhythmia, is related to the action potential (AP) dispersion, an electrophysiological state favoring ventricular arrhythmias. The increment in sympathetic tone may be the primary cause or may be a compensatory response (secondary cause) to cardiac dystrophy that further directs DMD patients toward HF. Moreover, there is a robust correlation between reduced HRV and myocardial fibrosis within the DMD population. These patterns manifest in DMD patients at early stage and become more evident as the disease severity and age increment. Because a primary role for autonomic imbalance in DMD is not well sustained, deeper studies are necessary to completely define this possibility.

In this chapter, the relationship between the heart and brain in DMD scenario will be analyzed both morphologically and physiologically, deconstructing the state of the art and focusing on interactions that could promote alternative hypotheses for the treatment of the disease.

Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is triggered by mutations of the gene encoding for the dystrophin enzyme, found on the short arm of the X chromosome in the Xp21 region [18], and manifests mostly in males. Although most boys with DMD inherit the abnormal gene from their mothers, some may develop the diseases as the result of a spontaneous mutation of the dystrophin gene that occurs randomly for unknown reasons (de novo or sporadic cases). Some females, who inherit a single copy of the DMD gene, may display some of the symptoms related to the disease, such as weakness of certain muscles, especially those of the arms, legs, and back. Carrier females, who acquire DMD symptoms, are at risk for developing heart abnormalities, which may present as exercise intolerance or shortness of breath, and, if left untreated, heart abnormalities can cause life-threatening complications.

DMD represents the most common lethal genetic disorder and cause progressive muscle degeneration. This pathology is provoked by a mutation of the DMD gene, which regulates the assembly of a protein, called dystrophin (Dp427), that is found in association with the inner side of the membrane of skeletal and cardiac muscle cells.

DMD is the most common childhood onset form of muscular dystrophy and affects males almost exclusively. The prevalence is estimated to be 1 in every 3500 live male births. Age of onset is usually 3–5 years old [18], and it is usually recognized between 3 and 6 years of age.

Duchenne disease is characterized by the progressive loss of voluntary movement of the lower limbs and subsequently of the upper ones, caused by the increase of the fibrotic tissue and, in the late stages, by significant intensification of adipose tissue in the muscle compartment. The disease is progressive, and most affected individuals require a wheelchair by the teenage years. The long-term effects imply cardiac or respiratory malfunction, analogically to the skeletal muscle, which fails to accumulate the cytoskeletal protein dystrophin and subsequently lead to death [68].

DMD is an incurable disease, but the life can be made more comfortable by physiotherapy, surgery, and a positive supportive environment. Cares are focused to specific symptoms present in each individual. Boys affected by DMD require multidisciplinary care, including clinical and functional assessment, pharmacological agents, physical exercises, prevention of anticipated complications, and genetic counselling. Surgery may be suggested in some patients to handle contractures or scoliosis. Supports could be utilized to prevent the development of contractures. The use of mechanical aids, such as braces and wheelchairs, may become required to aid walking (ambulation).

End-stage heart failure (HF) is increasingly becoming the main cause of death in DMD patients; consequently, current therapy options include inhibitors of the renin-angiotensin system, which are used as first-line therapy, along with corticosteroid treatment, COX-inhibiting nitric oxide donors, and beta-blockers. Mechanical cardiac support with left ventricular assist devices (LVAD) is a possible treatment, as these patients usually are not recommended for cardiac transplants, due to progressive myopathy and limited functional capacity. However, the insufficient availability of LVAD devices and the lack of prospective studies with large follow-up periods, for evaluating their use in DMD, are a concern.

Finally, several therapeutic approaches to cure DMD are being investigated, which can be divided into two groups: therapies focused to restore dystrophin expression and those that point to compensate for the lack of dystrophin. Therapies that restore dystrophin expression include read-through therapy, exon skipping, vector-mediated gene therapy, and cell therapy. Among these approaches, the most advanced are the read-through and exon skipping therapies [64].

Dystrophin and the Heart

The dystrophin protein is associated with a large complex of proteins and glycoproteins, known as the dystrophin-glycoprotein complex (DGC). Dystrophin is thought to play an important role in maintaining the membrane (sarcolemma) of skeletal and cardiac muscle cells, and its main function is to connect the cytoskeleton of myocytes with the extracellular matrix (ECM).

The clinical features of DMD include skeletal myopathy and respiratory and cardiac dysfunctions, which are the most common cause of death.

In DMD patients, a high resting heart rate (HR) is present at early stages [31, 58]. Surprisingly, this dysfunction occurs before the onset of changes in the ejection fraction (EF), and this high resting frequency can be considered an abnormal form of heart rate variability (HRV), which could correlate with autonomic dysfunction. HRV is a parameter of autonomic cardiac activity and is connected with various morbidity and mortality, resulting in acute myocardial infarction, congenital heart disease, diabetic neuropathy, and congestive HF, while in DMD, only recently, has been demonstrated the necessity to consider it for the patients’ stratification [4, 38, 53, 67].

Currently, two theories have been promoted to explain the mechanisms underlying DMD cardiomyopathy: (i) the loss of myocyte structural integrity, following the absence of dystrophin, leads to a deterioration under hemodynamic stress together with an impairment of ventricular function; and (ii) the cause could be the interruption in the regulatory function and, consequently, in the secondary signaling pathways, triggered by the absence of dystrophin [31].

The lack of dystrophin in cardiomyocytes (CMs) sensitizes the cells to stressful stimuli, such as chemical, mechanical, neurohormonal, or inflammatory insults, inducing apoptosis and a severe cardiac remodeling. Thus, many researchers have hypothesized that autonomic dysfunction in DMD can be traced back to excessive remodeling and to abnormal conduction, given by the extent of the fibrotic cardiac areas, characteristic of the disease.

Duchenne Muscular Dystrophy and Myocardium

Patients affected by DMD, initially, have structurally normal hearts. Successively, CMs death initiates an inflammatory cascade, during which macrophages (MP) migrate to clear the damaged cells and debris. After MP recruitment, fibroblasts invade the damaged area developing scar tissue or fibrosis in the heart, considered as the earliest sign of myocardial involvement. Fibrotic tissue is very inflexible compared to the normal cardiac tissue and thus restricts the efficiency of myocardial contraction. The fibrosis starts in the left ventricular wall, from the epicardium, and advances into the endocardium and progressively extends throughout most of the outer half of the ventricular wall. This pattern of fibrosis is unique to dystrophinopathy. Gradually, the fibrotic region stretches, becomes thinner, loses contractility, and results in dilated cardiomyopathy leading to end-stage HF (Fig. 1). The dilation of the heart increases left ventricular volume, decreases systolic function, and often leads to mitral valve regurgitation, resulting in reduced cardiac output and hemodynamic decompensation. The cardiac phenotype in each DMD patient depends from the patient’s particular type of dystrophin gene mutation; however, the relationship between genotype and phenotype remains elusive. Recognition of HF symptoms in DMD patients can be difficult due to physical inactivity and other respiratory complaints that can hide the diagnosis. Currently, clinical guidelines recommend the initial cardiac screening at the time of diagnosis of DMD, every 2 years until 10 years of age and yearly thereafter [35].
Fig. 1

Flow diagram describing the natural progression of cardiovascular dysfunction in patients affected by DMD and lacking dystrophin. The process begins with cardiomyocyte (CMs) death, develops in dilated cardiomyopathy, and leads to cardiac end-stage failure. ECM, extracellular matrix; NGF, nerve growth factor; HRV, heart rate variability; LVAD, left ventricular assist device

Many DMD patients develop sinus tachycardia by the age of 5, and conduction changes by 10 years of age. Irregular conduction patterns, named fragmented QRS (fQRS), are characterized by the presence of an additional R-wave (R′) or notching in R-wave or S-wave or the occurrence of more than one R′ without a typical bundle branch block. These outlines indicate wall motion abnormalities and could be one of the first signs of myocardial change in the patients. Depolarization and repolarization abnormalities are gradually prominent in patients over 10 years of age. Shortened PR intervals are appreciated in about 50% of patients, and QT prolongation is rare but can also be present. Resting sinus tachycardia, loss of circadian rhythm, and reduced HRV, caused by increased sympathetic activity, can be detected by electrocardiogram (ECG). More important, arrhythmias could develop with an advanced fibrosis, including atrial fibrillation, atrioventricular block, ventricular tachycardia, and ventricular fibrillation [33, 73]. The presence and progress of fQRS may be a useful marker of cardiac involvement for detection and follow-up. Electrocardiographic evidence of repolarization abnormalities implicating the risks of cardiac dysrhythmias and sudden cardiac death is gradually prominent in patients with DMD over 10 years old.

HF, with multisystem organ involvement and inability to rehabilitate after cardiac transplantation, is a relative contraindication for heart transplantation, limiting the broad use of this therapy in the DMD population. Given the scarcity of organs for heart transplantation, the use of LVADs is demonstrated to be effective in treating patients with end-stage or advanced HF.

Changes in cardiac function, induced by DMD, determine a physiopathological scenario almost unique, whose effects are still to be properly clarified. Normally, cardiac remodeling and fibrosis are compensatory mechanisms consequent to cardiovascular events. Both processes are interrelated and critical, strictly determining the clinical outcome. However, they are also balanced under physiological conditions as they represent the attempt of the cardiac muscle to repair the tissue [56]. The DMD exacerbates this scenario, and fibrosis progressively substitutes all dead CMs, thus leading to cardiac failure and subsequently to death. In addition, patients affected by DMD have a very characteristic electrocardiographic pattern. Some subjects present a reduction in variability in response to sympathetic activation, correlated with a distinct tachycardia [75].

Scientists, from all over the world, have tried to give different explanations of the phenomenon. The cardiac remodeling correlates with reduced contractility, autonomic nervous system, and posture dysfunction that are the main outputs and could affect cardiac performance, but the solution of the problem, faced with a multifactorial approach, has not yet been revealed.

As mentioned, patients affected by DMD have characteristic ECG, showing tachycardia and substantial decreasing in HRV [50, 75]: common and characteristic features, such as sinus tachycardia (40%), mild alteration of repolarization, and reduced HRV (75%), are detected, while no abnormalities are found in arrhythmias. Tachycardia, altered states of repolarization, and HRV presuppose a reduced tone of the parasympathetic system and the predominance of sympathetic tone, already reported in the literature relative to DMD patients.

Electrocardiographic abnormalities have been ascribed to various mechanisms, including postural syndromes that intensify cardiac responses, iperactivation of endogenous compensating mechanisms, and a possible autonomic dysfunction. However, the pathogenesis of electrical and autonomic disorders in patients affected by DMD remains completely unveiled [16]. In most patients, the ECG shows an abnormal cardiac profile. In particular, shortening of atrioventricular conduction time seems to be a feature always present in the pathology. Indeed, some pathological features, such as persistent sinus tachycardia, appear in the subject before muscular degeneration [11, 54].

The heartbeat of DMD patients presents a higher baseline than the healthy subjects, approximately 20%, regardless of the registration condition or the rash manifestations of the disease [50, 75].

Although there is no clear evidence that the mechanism of autonomous regulation is responsible, many theories are promoting the hypothesis that in the pathological scenario of DMD, there is a decrease of the parasympathetic nervous system in favor of the sympathetic nervous system. Furthermore, the same researchers claim that this condition would be aggravated during the disease progression [12, 50, 74, 75]. The mechanisms of these changes in the ECG are not known, although there is a growing consensus that an abnormal autonomous regulation is responsible.

For this reason, the combination of chronic tachycardia, prolonged sympathetic activation, and impairment of baroreceptor reflex control is thought could be the triggering cause of HF in patients with DMD [65].

Dystrophin and the Brain

In 2005, a theory based on a possible autonomic dysfunction has been proposed as the cause of frequent cognitive impairment in DMD patients [13].

The smooth and cardiac muscles and the nervous system express truncated isoforms of dystrophin, unlike skeletal muscle. These isoforms, encoded by the same gene, are generated by alternative splicing or by a different action of the promoter [3, 47].

Data generated on mdx mouse, a DMD animal model, demonstrated that, in the superior cervical ganglia (SCG), dystrophin is localized at the postsynaptic apparatus of a number of intraganglionic synapses where, together with the transmembrane glycoprotein β-dystroglycan (β-DG), it stabilizes the nicotinic acetylcholine receptors, containing the α3 subunit (α3nAChR). In this mouse model, the number of synapses containing α3nAChR is significantly decreased [14], suggesting alterations in the fast intraganglionic synaptic transmission that it could cause the autonomic dysfunction described in patients affected by DMD.

One of the most fascinating theories claims that the damage produced in the heart could affect retrogradely the ganglion neurons [24]. Some characteristics and responses of neurons are regulated by the dynamics of the target organs, such as cell body size, dendritic arborization, synapse formation and plasticity, neurotransmitter secretion, and neuron apoptosis [1, 60]. Recently, dystrophin has been shown to be able to modulate the neuronal size, the dendritic arborization, the stabilization of the neurotransmitter receptor groups, the synaptogenesis, the synaptic plasticity, and the neuronal survival [7].

The analysis carried out at SCG level of adult mdx mice showed a 36% neuron reduction compared to the wild-type condition. The degeneration occurred between day 5 and 10, while, at earlier stages, the number of neurons was the same as the wild type. These findings highlight the possibility that degeneration and neuronal loss occur after birth due to the retrograde pathological modulation exerted by the target organ. However, immunofluorescence experiments, labelling tyrosine hydroxylase (T-OH), displayed a reduction of axonal defasciculation and/or terminal germination throughout the SCG target already at day 5, following changes in the dynamic link between the cortical actin cytoskeleton and ECM.

Signals that are conveyed from nerve terminals to remote cell bodies are crucial for neuronal survival. Tropomyosin-related tyrosine kinase receptors (Trks) are internalized from axon membranes and transported by dynein motors to cell bodies, in response to neurotrophin stimulation. Survival maintained by target-derived neurotrophins is abolished when internalization and dynein-based transport of Trks are disrupted [26].

Dystrophin is responsible for the cytoskeleton-ECM connection through the dystrophin-glycoprotein complex [48] and, in the absence/dysfunction condition, dramatically alters this linking. This could also trigger an aberrant axonal growth, caused by the impairment of ganglionic transmission, following the reduction of intraganglion α3nAChR [14]. Indeed, ganglionic neurons may also be retrogradely affected by the injuries induced in the heart, one of the SCG target organs, by the lack of dystrophin, which develops into the dilated cardiomyopathy, described in DMD patients and mdx mice. Neuron survival and differentiation, density of innervation, and collateral sprouting firmly depend on target-derived neurotrophic factors, such as NGF. Therefore, excessive neuron death in mdx mouse SCG may be triggered by an insufficient provision of these factors, attributable to their reduced synthesis by cardiac muscle cells damaged by the lack of dystrophin. This condition may also be linked to an impairment of Trks-activated retrograde signals due to degeneration of the actin cortical cytoskeleton degeneration, which can diminish axonal retrograde transmission. Dynein-dependent transport is necessary for retrograde survival signals triggered by Trks in sensory neurons, and the integrity of the cortical actin cytoskeleton is needed for the neurofilament transport based on dynein and myosin [32]. Neurotrophins, secreted by target tissues, bind and activate specific receptors, such as Trks, located on axon terminals of the innervating neurons and thereby initiate retrograde signals that culminate in neuronal survival. If this process requires transport of long-range signals, then defects in dynein function might cause cell death by interfering with neurotrophin-dependent survival.

The dystrophin-glycoprotein complex protects the cell membrane from the mechanical stress developed during contraction. The complex deficiency in DMD causes plasma membrane rupture, and the injured muscle cells show greater permeability to the macromolecules, affecting muscle physiology, contractile properties, and survival [3, 30]. Possible CMs functional alterations, resulting from plasma membrane impairment, may render them unreceptive for axon growing and provoke synapse removal and retraction of the sympathetic fiber. Furthermore, the same deficiency of dystrophin would influence the innervation by neurons that would not be capable to drive the axon in that hostile system [13]. Therefore, the altered physiology of SNs and corresponding muscle target cells, in the DMD scenario, may perform a combined action and trigger the autonomic impairment described in patients affected by DMD.

Sympathetic Innervation System

The autonomic nervous system (ANS) is the component of the peripheral nervous system that controls cardiac muscle contraction, visceral activities, and glandular functions of the body. Specifically, the ANS can regulate heart rate, blood pressure, rate of respiration, body temperature, sweating, gastrointestinal motility and secretion, and other visceral activities that maintain homeostasis. The ANS has two interacting systems: the sympathetic and parasympathetic systems. Sympathetic and parasympathetic neurons exert opposed effects on the heart. The sympathetic system prepares the body for energy spending, emergency, or stressful situations, such as “fight-or-flight” response, while the parasympathetic system is most active under restful conditions. The parasympathetic responds to the sympathetic system, after a stressful event, and reestablishes the body to a restful state. The SNS releases norepinephrine (NE), while the parasympathetic nervous system (PNS) releases acetylcholine (ACh). Sympathetic stimulation increases heart rate and myocardial contractility; therefore during exercise, emotional excitement, or under various pathological conditions, such as HF, the SNS is activated. During rest, sleep, or emotional tranquility, the PNS prevails and regulates the heart rate. Consequently, the ANS effect on the heart is the balance between the opposing actions of the SNS and PNS [23].

Thus, cardiac sympathetic innervation, releasing neurotransmitters, mostly NE, is the principal cardiac rhythm, force, and relaxation/conduction speed modulator, initiating at the late embryonic stage and prosecuting throughout the whole life [61]. On the other hand, the cardiac sympathetic system development, the networking between neurons and their myocardial targets, and the neuronal survival preservation are controlled by the paracrine effect of cardiac signaling molecules. Indeed, during postnatal development, the equilibrium between the action of chemoattracting neurotrophins, principally NGF, and neuro-chemorepellent factors allows the verve endings permeation into the cardiac walls [29]. The selective allocation of the neurons to different heart regions and the physiologic function of the innervation outline are not completely understood, and its variation is correlated to a reduced cardiac function/activity and arrhythmias [29]. Though cardiac sympathetic nerve density mirrors the NGF expression levels produced by the heart [34], some myocardial structures, such as sinoatrial node, are more densely innervated, coherently with the SNS function in the control of cardiac rhythm.

NGF and Sympathetic Cardiac Innervation

SN differentiation and viability are supported by NGF secretion from the target organs, as demonstrated by the complete loss of postganglionic neurons in mice ablated for NGF or its receptor, TrkA. Like other neurotrophins, NGF is expressed as a pre-pro protein of the alternative splicing isoforms A and B. NGF maturation occurs through cleavage of the pre-domain in the endoplasmic reticulum and the pro-domain in the Golgi apparatus, and N-linked glycosylation and sulfation gain the expression of mature NGF.

The major NGF source, used by mature SNs, originates in its target organs. In the murine cardiac system, the neurotrophin became detectable around the time of initial innervation by SNs (embryonic day l2) and augmented 14-fold in the following 2 days, to reach adult levels already at embryonic day l4. Successively, there is a reduction of NGF levels, and a second expression peak appears about a week after birth (postnatal day 8); afterward NGF expression decreases to that of the adult heart. The initial growth of postganglionic SNs during development reflects NGF expression, but the penetration of neurons into the myocardial walls occurs postnatally and the adult neuronal pattern appears only 3 weeks after birth (postnatal d21) [37].

Thus, NGF synthesis, in target organs, begins alongside with the onset of sympathetic innervation, and NGF responsiveness, in SNs of the SCG, also progresses parallel to or shortly after the target contact, since the earliest stage, at which a small population of NGF-responsive neurons could be identified, is day l4. Therefore, both, sufficient NGF synthesis and NGF responsiveness, seem not to occur before the establishment of the initial target contact by innervating neurons, indicating that NGF is not implicated in the initial direction of outgrowing sympathetic axons to their target organs and that SNs during development are provided with NGF via retrograde axonal transport from the target organs.

Different cardiac cell types express NGF both in physiological and in pathological conditions: in CMs and smooth muscle cells, NGF modulates the cardiac wall innervation and is regulated by extracellular factors, such as endothelin-1 [28]. Cardiac fibroblasts (CFs) possess a fundamental function in pathological circumstances, such as myocardial infarction, inducing NGF production and consequently higher innervation of the peri-infarcted tissues. MPs, which, in response to ischemic damage, penetrate the myocardium, express NGF [25].

NGF, once released by any of cellular sources, operates on the neurons by binding to specific membrane receptors. Two are the neurotrophin receptors expressed on SNs: TrkA, which is specific for the mature form of NGF and binds it with intermediate affinity, and p75NTR, which binds to different neurotrophins and pro-neurotrophins, such as pro-NGF, with low affinity. Co-expression of both receptors on neuronal membrane increases NGF affinity for the TrkA.

NGF variants (mature NGF and pro-NGF) possess opposed effects on neuronal viability that depend on their interaction with the receptors (TrkA and p75NTR) co-expressed on the same cell [51]. Mature NGF is released as a homodimer and binds to the high-affinity TrkA receptor, triggering its autophosphorylation, endocytosis, and retrograde transport to neuronal soma. These interactions sustain neuronal viability and differentiation by regulation of gene transcription for proteins involved in signaling, in intracellular trafficking, and in function of synapsis and cell survival [27]. Instead, removal of TrkA activation, following NGF deprivation, or p75NTR activation, by either other neurotrophins or pro-NGF, causes neuronal apoptosis [51].

The function of NGF, in the postnatal days, regards cardiac sympathetic innervation network, through the selection of neurons that will innervate the target organ, meaning that only neurons that successfully innervate the heart would receive sufficient neurotrophin and survive and the quantity of sympathetic nerves that the organ receives becomes proportional to the produced neurotrophin [52].

Co-expression of two neurotrophin receptors with opposite effects on cell viability permits selection by neuronal competition. Indeed, in vitro experiments, using neurons, revealed that NGF treatment increases the expression levels of TrkA and neurotrophins with the following effects: (i) the upregulation of TrkA receptors amplifies the duration of survival signaling in those neurons receiving high amounts of NGF; (ii) the NGF-stimulated neurons release the neurotrophin, which activates p75NTR, and oppose TrkA effects provoking apoptosis of the nearby neurons that receive lower NGF quantity [15]. Beside the effect that NGF exerts on SNs supporting cell survival, the NGF has also a pivotal role in guidance during development [20].

Neuronal survival and differentiation, axonal growth, and terminal branching have been studied mainly on mouse models, and it has been shown that NGF plays a fundamental role in all these processes through its link with the TrkA receptor [21]. As mentioned before, the pro-NGF/p75NTR promotes neuronal apoptosis, especially in limiting NGF-TrkA signaling conditions [21]. Therefore, an imbalance in the relationship between immature form and mature form of NGF could be the cause of the loss of the neurons of the ganglia of the cervical roots, which project toward the heart, altering the peripheral system.

In fact, some data generated in the DMD animal model have indicated a significant increase in the 32 kDa pro-NGF form in both day 5 and day 10. Considering the apoptotic effect of pro-NGF in some conditions [21], the contribution of the pro-NGF in the induction of apoptosis in neurons would emerge [13].

Furthermore, the decrease in TrkA and phospho-TrkA (pTrkA, the tyrosine phosphorylated residues of TrkA that interacts with proteins which have potential roles in signal transduction) in the same animal models also suggests an alteration in the receptor-mediated NGF signaling, which may influence the expression of molecules important for the correct axonal growth and defasciculation [22].

Sympathetic Innervation in Duchenne Muscular Dystrophy

Both, patients affected by DMD and mdx mice, display impairment of the autonomic nervous system confirmed by electrocardiographic analysis, but it is not clear yet if the dysfunction induces the sympathetic activity to increase or to decrease: indeed, the greater basal heart rate in DMD patients and mdx mice indicates that the sympathetic complex is favored respect to the parasympathetic nervous system. Instead, ECG recording upon inhibition of the PSN system by atropine treatment exhibited augmented heart rate in the wild type and not in the mdx mice, suggesting that impairment of cardiac sympathetic innervation occurs in dystrophic mice. This evidence is further reinforced by alterations of the components, implicated in NGF-mediated signaling and by the decreased number of SNs in SCG from mdx mice, when compared to controls [13, 42].

NGF Role in Duchenne Muscular Dystrophy

DMD subjects suffer several neural syndromes since selected neuronal populations express dystrophin. In contrast to the muscle scenario, where dystrophin expression reaches a plateau already in fetal life, in the brain it appears to be developmentally regulated, probably because of the need to modulate neurogenesis, neuronal migration and differentiation, neuronal size, and dendritic arborization [47]. Consequently, DMD patients and mdx mice show, during development, different degrees of cognitive and behavioral anomalies [55, 69]. Mdx mice display several structural and functional alterations in SCG, which innervates different muscular, such as the heart, and nonmuscular targets; further they present reduced muscular noradrenergic innervation and diminished axon defasciculation and terminal branching [13, 42]. The expression of NGF receptors (TrkA and p75NTR) is also altered, indicating a discrepancy in the NGF signaling cascade [42] and a diverse modulation expression of genes implicated in neuron survival and differentiation [40].

It has been, therefore, hypothesized that dystrophin could have a role in NGF-dependent axonal growth during development and adulthood [42, 43]. After axotomy, axon regeneration potential of SCG neurons was analyzed in mdx and wild-type mice: while noradrenergic innervation of mdx mouse submandibular gland, main source of NGF, was recovered similarly to wild type, iris innervation (muscular target) didn’t restore. Therefore, it was evaluated whether dystrophic SCG neurons were weakly responsive to NGF, particularly at low concentration. Following in vitro axotomy, the number of regenerated axons in mdx mouse neuron cultures was indeed diminished, compared to wild type, at the lower concentration of NGF. These results imply that neuronal damages in mdx mice are sufficient for dropping regeneration capabilities and that NGF concentration is a limiting factor in vitro and could be in vivo as well: when higher NGF concentration was used, the neuron regenerative performance in mdx mouse improved.

Further, it was noticed that neurite growth parameters and NGF/TrkA receptor signaling in differentiating neurons (not injured) were significantly reduced when cultured with low concentration of NGF, as well as with higher NGF concentrations. These data indicate a role for dystrophin in NGF-dependent cytoskeletal dynamics connected to growth cone advancement, possibly through indirect stabilization of TrkA receptors. Decreasing of TrkA/NGF signaling prevents growth cone regeneration and reduces cytoskeleton dynamics at the axon terminal. It has been theorized that, since in mdx mice, lower concentrations of NGF recall less TrkA receptors on the neuron membrane, there is a consequent decrease in intracellular signaling pathways, which could be due to the inefficient stabilization of the receptor on the cell surface, indirectly induced by lack of dystrophin. Interestingly, when NGF concentration increases, no differences were observed in terms of TrkA phosphorylation, supporting the hypothesis that the more NGF is present, the more efficiently TrkA receptors in dystrophic neurons are able to bind it. Although the dynamical characteristics to be considered are multiple and intermingled, the main idea is that dystrophic neurons are less sensitive to NGF compared to wild type.

This is very important to address the DMD pathology: muscle-innervating autonomic neuron impairment could convey to weakening axon recovery, neuron survival, and consequently augment dysfunctions. Finally, these data could provide the incentive for new research aimed at developing therapeutic strategies to reduce neural dysfunctions and autonomic failures in DMD patients.

Neuro-Cardiac Junction

The whole mammalian heart is innervated by SNs, which enter the heart from the epicardium and extend their processes throughout the myocardial interstitium, running parallel to capillary vessels. On the other hand, NGF, released by the myocardium, modulates the cardiac innervation by SNs after binding to its receptor (TrkA) and is required for neuronal survival. Therefore, it presents a bidirectional coupling between SNS and the heart. Sympathetic neurons are joined to the heart for neurotrophic stimulation necessary for neuronal viability. On the other hand, the heart requires to be connected to sympathetic neurons to receive NE stimulation for an efficient heart contraction, thus modulating the frequency of heart contraction (positive chronotropic effect), the conduction velocity (positive dromotropic effect), the contractility (positive inotropic effect), the relaxation (positive lusitropic effect), and the CM size [78]. To achieve such sophisticated functions, sympathetic ganglia incorporate both peripheral and central inputs and transmit information to the heart via motor neurons, directly interacting with target CMs. So far, the dynamics and mode of communication between these two cell types, which determine how neuronal information is adequately translated into the wide spectrum of cardiac responses, are still blurry.

Merging the anatomical and structural information, recently highlighted using imaging technologies, and the functional evidence in cellular systems, it can be promoted the existence of a specific “neuro-cardiac junction” (NCJ), where sympathetic neurotransmission occurs in a “quasisynaptic” way. The properties of such junctional-type communication meet with those of the physiological responses, generated by the cardiac SNS, and elucidate its capability to coordinate heart function with precision, specificity, and elevated temporal resolution.

Lately several investigators focus on the interactions in the mammalian heart between cardiac SNs and CMs. Similarly, to the specific neuromuscular contact sites of the neuromuscular junction (NMJ), many morphological and ultrastructural analyses revealed that sympathetic varicosities and CM membranes are in close contact [8].

In rodent hearts it was demonstrated by two-photon microscopy that not only all CMs are in contact with several varicosities from the same neuronal process but also that each CM establishes parallel contacts, possibly with processes from different neurons. The heart consists of a complex multicellular network, composed mostly of CMs, CFs, and endothelial cells and is held together by ECM and encapsulated in a dense mesh of neurons. All these cells express receptors for sympathetic neurotransmitters, and, because of the capillary innervation of the heart, each cell type is close to a neuronal process, indicating that cardiac SNs may control myocardial function in a cell-specific fashion [77].

The dense innervation of the myocardium and the direct interaction between SN and myocardial target cells suggest that neuro-cardiac coupling may occur at specific junctional sites.

The existence of a neuro-cardiac communication can be assumed considering the following concepts: (i) sympathetic neurotransmission has to take place powerfully upon maximal neuronal activation (“fight-or-flight” reaction); (ii) neuronal activation requires to initiate cardiac activation almost instantaneously, to quickly increment blood pressure, through frequency of heart contractions; (iii) the system has to guarantee that under stress the entire heart muscle undergoes changes in inotropy at the same time; and (iv) the system must be precise enough to operate almost on a beat-to-beat basis in the regulation of electrophysiology and trophic signaling. To coordinate all these tasks, it is necessary a signaling dynamics of intercellular communication that permit the system to work with wide effect range, precision, and specificity of responses to the diverse stimuli.

However, the NCJ hypothesis is not completely accepted, since specific molecular factors are not determined, and the obtained results are not conclusive [41, 79]. An effort was done to find molecular determinants focusing on proteins that normally participate in intercellular junctions, such as VCAM1 and α4p1 integrins [71]. Larsen and coworkers determined protein complexes present in neurons and CMs at cell-cell interface [39], as β-ARs, SAP97, AKAP79, cadherin, and β-catenins are confirmed in ex vivo studies as well [62]. Still the molecular machinery that links the two membranes together (synapses/junction structure) is not fully reassembled. Remarkably, based on in vitro experiments, even CFs could interact with sympathetic neurons, but the interactions are labile and transient in time, in contrast with stable connection endorsed with CMs [77].

Even if recent studies indicate that the contact site is enriched in presynaptic markers (synapsin I, synaptotagmin), in cell-to-cell adhesion molecules (cadherins, β-catenin), and in postsynaptic specializations of the CM membrane [62], this model has not been explained at the functional level. Moreover, the neurotransmitters, the intercellular signaling dynamics, and how the target cells respond to the intercellular communication have not been clarified.

Animal Models

Several mouse models have been developed to better understand the DMD basic biology. However, there has been a lack of animal models that recapitulate the severe phenotype of DMD disease and facilitate a test of therapeutic strategies.

The mdx mouse is the most employed model for studying DMD. This strain originated from a spontaneous mutation in the premature stop codon that terminated exon 23 of the dystrophin gene in the C57BL/10ScSnJ mouse [5]. Although this mutation leads to dystrophin function loss, there is a compensatory upregulation of another protein, named utrophin, which exhibits 80% homology and shares structural and functional motifs with dystrophin [2]. In mdx mice the upregulation of utrophin repairs plasma membrane integrity and muscle degeneration [19], while in human DMD muscle, the levels are not sufficient to prevent disease progression [44]. Consequently, the lack of dystrophin and compensatory upregulation of utrophin in the mdx mouse indicate that dysfunction of skeletal muscle characteristic of DMD is less severe. In contrast to the degeneration of skeletal muscle, which is rescued to some extent, this strain exhibits myocardial damage, even if it develops cardiomyopathy very late in its life. Starting from 3 months of age, mdx mice display altered metabolic processing associated with increased oxygen consumption, decreased cardiac efficiency, and increased cell membrane fragility [36]. At 6 months, mdx heart is hypertrophied compared to wild-type controls, suggesting cardiac dysfunction, and, from 9 months of age, fibrosis is evident histologically. 10-month-old mdx mice have poor contraction and slower rate beating than normal [57], and at 15 months, interstitial fibrosis is detectable in the endocardium, myocardium, and epicardium of the ventricular wall and septum [45]. Considering these characteristics, the mdx mouse model can provide helpful information on the pathophysiology of the DMD cardiomyopathy.

Many of the knowledge, we have gained over the last few years on DMD, stems from the in-depth study of mdx mouse model, although the recapitulation of the disease sometimes appears to be less aggressive. Some scientists have developed echocardiographic profiles of mdx mice to confirm the fact that many DMD patients die from HF. Mice also have significant tachycardia and reduced HRV, as already observed in DMD patients. In particular, the recorded heart rate is faster in mdx mice than the control mice approximately of 15%, while, the correct QT interval based on speed, the duration, and the PR interval are reduced.

Using atropine, a muscarinic receptor antagonist, it was observed that, in C57 mice, it significantly increases heart rate and reduces the PR interval, while in mdx it has a totally inverse effect [9]. Deepening the study with other pharmacological approaches to the blockade of the autonomous system, it was demonstrated an imbalance in the modulation of the autonomic nervous system of heart rate, with a decrease in parasympathetic activity and an increase in sympathetic activity in mdx mice. Furthermore, it has also been proven, by the same researchers, that autonomic dysfunction in mdx mice may be independent of decreased myocardial nitric neuron oxide synthase (nNOS), which is a component of the dystrophin complex [59]. It was demonstrated that the absence of dystrophin protein, in DMD and in mdx mouse, triggers a redistribution of nNOS from the plasma membrane to the cytosol in muscle cells. Aberrant nNOS activity in the cytosol can stimulate free radical oxidation, which is toxic to myofibers. These data are very important and can provide new bases for diagnosing, understanding, and treating DMD patients. Unfortunately, the mdx mouse is a mild model of DMD due to a minimal cardiac dysfunction, as they do not develop early-dilated cardiomyopathy as seen in DMD patients.

The most severe cardiomyopathy was found in mice also lacking utrophin, indicating that the homologous protein effectively compensated for the lack of dystrophin in mdx mice [24].

Currently, the mdx4cv/mTRG2 model with shortened telomeres seems to most faithfully recapitulate both cardiovascular and skeletal muscle features of the disease. It was shown that species-specific differences in telomere length account for diversities in the regenerative capacity of satellite cells from mdx animals compared to humans and revealed premature telomere shortening in CMs, which was an unknown characteristic of DMD [76].

HDAC Inhibitor Therapy for Duchenne Muscular Dystrophy

Recently, among the biological and molecular mechanisms involved in the adaptive response to a cardiac insult, the histone deacetylases (HDAC)-mediated epigenetic processes are receiving a special attention. HDACs are common enzymes regulating the histone deacetylation in the core histones (preferentially at the amino groups of lysine residues). From a physiological standpoint, HDACs are strictly correlated to the regulation of homeostatic gene expression of vascular and cardiac populations including stem cell commitment [17]. More importantly, abnormal acetylation of core histones, likely linked to environmental factors, is associated with major cardiovascular diseases [70]. After a cardiac insult, HDAC activity is enhanced, resulting in increased proliferation, migration, and apoptosis of adventitial fibroblasts, endothelial and smooth muscle cells, as well as MP activation and phenotype switching [72], suggesting the involvement of HDAC in driving the response to vascular injury and remodeling even through the early inflammatory phase. Hence, targeting HDACs would represent a powerful tool to design novel pharmacological approaches for cardiac disorders. Accordingly, a wide range of molecules, such as trichostatin A, suberoylanilide hydroxamic acid, or valproic acid, has been described to inhibit the activity of HDACs. Pan or selective HDAC inhibitors (HDACis) have been shown to have protective effects and, consequently, to preserve the cardiac function by exerting anti-inflammatory properties, reducing cardiac hypertrophy and remodeling, and modulating the fibrosis and even its potential reversion through definite molecular signaling pathways, mainly targeting oxidase states and/or specific kinases [6, 46].

Despite this, epigenetic therapeutic options available in the cardiovascular field are still limited, and the clinical implications of the use of the HDACis have still to be clearly elucidated, including issues related to their safety and long-term effects. Among these compounds, givinostat (GIV, ITF2357), a powerful pan HDACi, has recently gained considerable attention due to its varied applicability, safety, and efficacy in humans. Described in 2005 [66], GIV is currently employed in ongoing clinical trials for myeloproliferative diseases, as well as for several inflammation-based disorders, such as acute central nervous system injuries, rheumatoid and juvenile idiopathic arthritis, bowel diseases, and DMD [10, 63]. Recent studies suggest that GIV treatment implies a decrease of the TNF-α, IL-6, and IL-1, followed by a striking reduction of the inflammatory response in combination with pro-angiogenic effects [49].

To date, the effects of GIV in cardiac diseases have still to be verified, because the lacking of studies on this specific effect. DMD dispatches, reporting that cardiac dysfunction may parallel the skeletal muscle degeneration [10], suggest that GIV might indirectly and beneficially act on the cardiac muscle, defining this HDACi as a novel potential cardiac therapeutic target and tool.

Milan and coworkers highlighted a cardiac functional recovery concurrently to a reduced fibrosis in the cardiac tissue. It has been postulating that GIV may protect the heart tissue from an excessive remodeling by reverting the endothelial-to-mesenchymal transition (EndMT) process. Based on this, it can be speculated that GIV might represent an excellent candidate both to attenuate the cardiac failure in DMD patients and to treat heart diseases.

From a physiological standpoint, HDACs are strictly correlated with the regulation of homeostatic gene expression of vascular and cardiac cell populations. Targeting HDACs is a potentially powerful strategic target for the treatment of cardiac disorders.

Conclusion

Current care options and constant surveillance have permitted a significant amelioration in the life quality of DMD patients. However, the increased lifespan of DMD patients has revealed the developing cardiomyopathy as an essential health problem that has to be addressed. Because it could be too late for improving heart performance, the belief that heart medicines should begin when symptoms appear is now reconsidered. Indeed, currently treatments start before the evident symptoms with the idea to protect the heart from damage. It would be advantageous to have matched study protocols intended to achieve the reliability of the results in mdx mice and use other models as an additional source of information, as it was done for skeletal muscle studies. Despite the important understandings into the disease progression covered by these many mouse models, there are still few acceptable therapies. The longer life in DMD patients has been mostly due to improvements in cardiac and respiratory support, which only treat symptoms of the disease. Finally, strong and clear protocols can drive a direct comparison between various studies, and any outcomes can be more easily translated into changes in care regimens for patients affected by DMD.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institute for Genetic and Biomedical Research (IRGB), National Research Council of Italy (CNR)MilanItaly
  2. 2.Fondazione Giovanni Paolo IICampobassoItaly
  3. 3.Institute of Cell Biology and Neurobiology (IBCN), National Research Council of Italy (CNR)RomeItaly
  4. 4.Fondazione Istituto Nazionale di Genetica Molecolare (INGM) “Romeo ed Enrica Invernizzi”MilanItaly

Section editors and affiliations

  • Alessia Pascale
    • 1
  • Emilia d'Elia
    • 2
  1. 1.Department of Drug Sciences, Section of PharmacologyUniversity of PaviaPaviaItaly
  2. 2.Dipartimento CardiovascolareAzienda Ospedaliera Papa Giovanni XXIIIBergamoItaly

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