Cardiovascular Disease in Duchenne Muscular Dystrophy: Overview and Insight Into Novel Therapeutic Targets

Abstract

Duchenne muscular dystrophy (DMD) is a devastating disease affecting approximately 1 in every 3,500 male births worldwide. Multiple mutations in the dystrophin gene have been implicated as underlying causes of DMD. However, there remains no cure for patients with DMD, and cardiomyopathy has become the most common cause of death in the affected population. Extensive research is under way investigating molecular mechanisms that highlight potential therapeutic targets for the development of pharmacotherapy for DMD cardiomyopathy. In this paper, the authors perform a literature review reporting on recent ongoing efforts to identify novel therapeutic strategies to reduce, prevent, or reverse progression of cardiac dysfunction in DMD.

Keywords: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ApN, adiponectin; BB, beta-blocker; BDNF, brain-derived neurotrophic factor; CMR, cardiac magnetic resonance imaging; Cx, connexin; DMD, Duchenne muscular dystrophy; DPC, dystrophin-associated protein complex; Duchenne muscular dystrophy; FFA, free fatty acid; HF, heart failure; LNP, lipid nanoparticle; LV, left ventricular; LVEF, left ventricular ejection fraction; NIV, noninvasive ventilation; Nrf2, nuclear factor erythroid 2-related factor 2; PKA, protein kinase A; PTX3, pentraxin 3; Px, pannexin; RNP, ribonucleoprotein complexes; RT-qPCR, reverse transcription-quantitative polymerase chain reaction; RyR2, ryanodine receptor isoform 2; SR, sarcoplasmic reticulum; TRPV2, transient receptor potential cation channel, subfamily V, member 2; TrkB, tyrosine kinase B; arrhythmias; cardiomyopathy; inflammatory modulators; miR, microRNA; myocardial fibrosis; sgRNA, single guide RNA.

Graphical abstract

Figure 1

Dystrophin Acts as a Molecular Scaffold and Influences Mechanisms of Calcium Handling in Cardiomyocytes (A) Dystrophin present: Cytosolic Ca²⁺ is regulated primarily by LTCC, SACs, and NCX. In normal excitation–contraction (E-C) coupling, small influx of Ca²⁺ through LTCCs stimulates Ca²⁺ release from the SR through RYR2. Ca²⁺ activates nNOS within the dystrophin complex in a calmodulin-dependent manner. NO subsequently further activates SR Ca²⁺ turnover through s-nitrosylation of RYR2, IP₃, and SERCA2. NO also augments E-C coupling through production of cGMP, which also reduces cardiac afterload by stimulating vasodilation. Normal physiological stretch activates NOX-2–dependent ROS production, which increases Ca²⁺ influx through SACs. Phospholamban (PLN) negatively regulates SERCA2 and β-adrenergic activation leads to PLN phosphorylation and dissociation from SERCA2, with a resultant increase in SR Ca²⁺ reuptake. Dystrophin helps to stabilize the sarcolemmal membrane during repeated stretch–relaxation cycling. (B) Dystrophin absent: Sarcolemmal influx of Ca²⁺ increases through disruption of the normal function of LTCCs, NCX, SACs, and microtears in the membrane. Mislocalization of nNOS disrupts NO signaling, which reduces s-nitrosylation of the SR channels and contributes to SR Ca²⁺ leak. Increased cytosolic Ca²⁺ also actives CAMKII, PKC, and the purinergic signaling cascade, leading to further increase in intracellular Ca²⁺. Lower NO levels also reduce mitochondrial ATP production leading to increased ROS generation. Increased intracellular ROS, combined with mitochondrial energetics dysregulation and the high intracellular Ca²⁺, induce inflammatory, apoptotic, and necrotic pathway activation. The CamKII = calcium/calmodulin-dependent protein kinase II; cyt c = cytochrome c; IP₃ = inositol triphosphate receptor; LTCC = L-type calcium channel; MCU = mitochondrial Ca²⁺ uniporter; mNCX = mitochondrial Na⁺-Ca²⁺ exchanger; NCX = Na⁺-Ca²⁺ exchanger; nNOS = neuronal nitric oxide synthase; NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells; NOX-2 = NADPH oxidase 2; P₂X₇ = P₂X₇ purinergic receptor; PKC = protein kinase C; PLC = phospholipase C; PLN = phospholamban; Px = pannexin channels; ROS = reactive oxygen species; RYR2 = ryanodine receptor type 2; SAC = stretch-activated channels; SERCA2 = sarco/endoplasmic reticulum Ca²⁺-ATPase 2; SR = sarcoplasmic reticulum; VGCC = voltage-gated Ca²⁺ channels.

Central Illustration

Cardiomyopathy in Duchenne Muscular Dystrophy: Potential Therapeutic Targets Duchenne muscular dystrophy (DMD) has several systemic effects, including cardiomyopathy. DMD cardiomyopathy is characterized by cardiac fibrosis, arrhythmias, and heart failure. Inflammatory modulation and mitochondrial regulation could reduce cardiac fibrosis associated with DMD. In addition, gap junction regulation and therapy with antiarrhythmic agents could reduce incidence of arrhythmia in DMD. Furthermore, gene therapy and neurohormonal modulation could be beneficial in reducing heart failure in DMD. BDNF = brain-derived neurotrophic factor; Cas9 = CRISPR associated protein 9; CRISPR = clustered regularly interspaced short palindromic repeats; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; Lox = lysyl oxidase; NLRP3 = NOD-LRR-and pyrin domain-containing protein3; Nox4 = NADPH oxidase 4; Nrf2 = nuclear factor-erythroid factor 2-related factor; PARKIN = E3 ubiquitin ligase; PINK1 = PTEN-induced kinase; PTX3 = pentraxin 3; TrkB = tropomyosin receptor kinase B.