Advances in Medical Sciences 66 (2021) 52–71 Contents lists available at ScienceDirect Advances in Medical Sciences journal homepage: www.elsevier.com/locate/advms Review article Essential roles of the dystrophin-glycoprotein complex in different cardiac pathologies Isela C. Valera a, Amanda L. Wacker a, Hyun Seok Hwang a, Christina Holmes b, Orlando Laitano a, Andrew P. Landstrom c,d, Michelle S. Parvatiyar a,* a Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, FL, USA b Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University College of Engineering, Tallahassee, FL, USA c Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, NC, USA d Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA ARTICLE INFO ABSTRACT Keywords: The dystrophin-glycoprotein complex (DGC), situated at the sarcolemma dynamically remodels during cardiac Dystrophin-glycoprotein complex disease. This review examines DGC remodeling as a common denominator in diseases affecting heart function and Genetic cardiomyopathies health. Dystrophin and the DGC serve as broad cytoskeletal integrators that are critical for maintaining stability of Muscular dystrophies muscle membranes. The presence of pathogenic variants in genes encoding proteins of the DGC can cause absence Cardiac injury and regeneration of the protein and/or alterations in other complex members leading to muscular dystrophies. Targeted studies Acquired cardiomyopathies have allowed the individual functions of affected proteins to be defined. The DGC has demonstrated its dynamic function, remodeling under a number of conditions that stress the heart. Beyond genetic causes, pathogenic processes also impinge on the DGC, causing alterations in the abundance of dystrophin and associated proteins during cardiac insult such as ischemia-reperfusion injury, mechanical unloading, and myocarditis. When considering new therapeutic strategies, it is important to assess DGC remodeling as a common factor in various heart diseases. The DGC connects the internal F-actin–based cytoskeleton to laminin-211 of the extracellular space, playing an important role in the transmission of mechanical force to the extracellular matrix. The essential functions of dystrophin and the DGC have been long recognized. DGC based therapeutic approaches have been primarily focused on muscular dystrophies, however it may be a beneficial target in a number of disorders that affect the heart. This review provides an account of what we now know, and discusses how this knowledge can benefit persistent health conditions in the clinic. 1. Introduction transcripts (14-Kb) that each contain a unique first intron and spliced to share the remaining 78 exons [3]. In cardiomyocytes, the dystrophin 1.1. Dystrophin and the dystrophin-glycoprotein complex isoforms Dp427 and Dp71 are expressed in contrast to skeletal muscle that expresses only Dp427 (Byers TJ, Leiden Muscular Dystrophy Pages: 1.1.1. Dystrophin Dystrophin isoforms, http://www.dmd.nl/isoforms.html, Mar 5, 2006). Dystrophin is a major component of the subsarcolemmal scaffold of Dystrophin associates with a number of peripheral and membrane-bound muscle cells. It is a large rod-shaped cytoskeletal protein with four main proteins designated as the dystrophin-glycoprotein complex (DGC). functional domains that is localized at the cytoplasmic side of the Identification of the integral components of the DGC was defined on the sarcolemma [1,2]. Dystrophin is encoded on the X chromosome (Xp21) basis of four distinct biochemical and cellular characteristics, which in a large gene designated as DYS1. It spans a total of 79 exons and has eliminated less-tightly bound proteins such as caveolin-3 (Cav-3) [4] and seven promoters known to initiate dystrophin transcription. Three of the neuronal nitric oxide synthase (nNOS) [5]. A related protein, utrophin, is promoters are located at the 5’ end of the gene: (B) brain, (M) muscle, an autosomal homologue of dystrophin that is expressed ubiquitously and (P) purkinje promoters generate full length dystrophin protein and earlier in development than dystrophin that is not localized at the * Corresponding author. Department of Nutrition, Food and Exercise Sciences, Florida State University, 107 Chieftan Way Biomedical Research Facility 238, Tal- lahassee, FL, 32306-1490, USA. E-mail address: [email protected] (M.S. Parvatiyar). https://doi.org/10.1016/j.advms.2020.12.004 Received 1 July 2020; Received in revised form 12 December 2020; Accepted 17 December 2020 1896-1126/© 2020 The Authors. Published by Elsevier B.V. on behalf of Medical University of Bialystok. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). I.C. Valera et al. Advances in Medical Sciences 66 (2021) 52–71 sarcolemma of mature cardiomyocytes [6]. Utrophin has been found to changes may become a chronic maladaptation. A study by Kaprielian be expressed at the sarcolemma in dystrophinopathies, a group of dis- et al. [31] utilized single- and double-label immune-confocal microscopy orders arising from a lack of dystrophin [7]. A schematic is provided in and high-resolution immunogold fracture-label electron microscopy and Fig. 1 for visualization of the proteins of the DGC and associated proteins identified a population of dystrophin that partially colocalizes with that will be highlighted in this review. costameric vinculin in non-diseased and hypertrophied myocytes but is Dystrophin loss has an important role in cardiomyocyte destabiliza- lost in degenerating cells. In contrast to studies performed in rat car- tion, causing membrane instability and increased cell permeability [8,9]. diomyocytes, the dystrophin network in human cardiomyocytes is This suggests that dystrophin plays a primarily mechanical role in enriched at costameres [31,32]. Costameric distribution of cardiac DGC maintenance of cell membrane integrity. Numerous studies have as well as colocalization with proteins of the vinculin-talin-integrin sys- enumerated the connection between loss of dystrophin and development tem at the sarcomeric region that aligns with sarcomeric I bands suggest a of contractile dysfunction in the failing heart and progression to heart force transductive role for the cardiac DGC [32]. The presence of dys- failure [10–13]. After pressure overload is introduced in mice by aortic trophin in cardiac T-tubule membranes but not in skeletal muscle sug- constriction, dystrophin mRNA is significantly increased, which is gests that dystrophin has even more roles in defining the organization of anticipated to be an adaptive measure to preserve sarcolemma integrity membrane domains [31]. In a study using DMD-null mice (lacking Dp427 [14]. The fundamental structural role of dystrophin in the heart can be and Dp71 dystrophin isoforms) compared to mdx mice (lacking Dp427 seen by the development of dilated cardiomyopathy (DCM) in genetic but expressing Dp71) it was shown that cardiomyopathy develops pri- diseases caused by the reduction or loss of dystrophin protein expression marily due to a loss of full-length Dp427. It was also shown that Dp427 is e.g. Becker muscular dystrophy (BMD), Duchenne muscular dystrophy present in the cardiac sarcolemma and T-tubules, whereas Dp71 is spe- (DMD) and X-linked DCM respectively [11,15]. Loss of dystrophin from cifically only localized at the T-tubules [33]. Dystrophin remodeling the sarcolemma has been observed in a number of different cardiomy- occurs in end-stage human heart failure [34] and is increased in hyper- opathies caused by vastly different etiologies including post-viral trophied T-tubules [31]. In heart failure, remodeling of T-tubules has myocarditis [16], myocardial infarction [17], septic cardiomyopathy been found accompanied by increased wheat germ agglutinin (WGA) [18], induced Chagas disease [19,20] and several pharmaceuticals labeling, a lectin known to bind to glycosylated proteins in the DGC. including the beta-adrenergic agonist isoproterenol [21,22] and Along with these changes, a large increase in type IV collagen (Col-VI) chemotherapy drug doxorubicin [23]. These distinct cardiomyopathies abundance was detected in the T-tubule lumen and by displaced sarco- involve cleavage of dystrophin and other cytoskeletal and sub- lemmal labeling of dystrophin [35]. Therefore, dystrophin and collagen membranous proteins by proteolytic enzymes such as calpains [10,13,17, remodeling in the ventricles appear to be fundamental steps along the 26,27], causing - disappearance of these proteins from the sarcolemma path to heart failure. This demonstrates that alterations in both extra- [24–26]. Additional studies indicate that the N-terminus of dystrophin is cellular and intracellular myocardial architecture represent a wide range cleaved in the failing heart, leading to contractile dysfunction and DCM of targets to reverse classical pathological remodeling of the heart. [28,29]. At high doses, isoproterenol causes disruption of dystrophin and Collectively, these findings suggest that dystrophin provides important its translocation from the sarcolemma to the myoplasm [21]. Several structural support to the heart and is remodeled along with alterations in studies have shown that dystrophin loss can be detected prior to devel- its dynamic function. Understanding how these changes in dystrophin opment of cardiac systolic and diastolic dysfunction [30]. Therefore,