Multiomic Approaches to Uncover the Complexities of Dystrophin-Associated Cardiomyopathy

Abstract

Despite major progress in treating skeletal muscle disease associated with dystrophinopathies, cardiomyopathy is emerging as a major cause of death in people carrying dystrophin gene mutations that remain without a targeted cure even with new treatment directions and advances in modelling abilities. The reasons for the stunted progress in ameliorating dystrophin-associated cardiomyopathy (DAC) can be explained by the difficulties in detecting pathophysiological mechanisms which can also be efficiently targeted within the heart in the widest patient population. New perspectives are clearly required to effectively address the unanswered questions concerning the identification of authentic and effectual readouts of DAC occurrence and severity. A potential way forward to achieve further therapy breakthroughs lies in combining multiomic analysis with advanced preclinical precision models. This review presents the fundamental discoveries made using relevant models of DAC and how omics approaches have been incorporated to date.

DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies

“…Experimental studies suggest that mutations in DMD and TTN share a number of pathophysiological mechanisms, including changes in force transmission, resistance to mechanical stress, cell signaling, myocardial energetics, and cell survival. 33,34 Titin transcripts show extensive alternative splicing, and assessing PSI scores has become a cornerstone of clinical variant interpretation for TTN tv. 13 Here, for the first time, we derived PSI scores for cardiac dystrophin and found that unlike titin, most dystrophin exons are highly used across all transcripts.…”

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?

“…Proteomic surveys of dystrophin-deficient hearts have been carried out by both top-down/gel-based proteomics and bottom-up proteomics [ 323 , 324 , 325 ]. Cardioproteomics is an established field within the systems biological multi-omics approach to determine the underlying mechanisms of heart disease [ 326 , 327 , 328 , 329 ].…”

“…Multi-omics approaches have a great potential to improve our understanding of complex human disease mechanisms [ 473 ] and establish systems biological concepts [ 474 ], including the systems biology of skeletal muscles [ 475 ]. The application of multi-omics has already been used to study crucial aspects of skeletal muscle cell biology in health and disease [ 476 , 477 , 478 , 479 ] and been applied to certain aspects of the field of dystrophinopathy research, including the integrative screening of dystrophic animal models [ 277 , 480 , 481 , 482 ], the evaluation of immune responses in muscular dystrophy [ 483 ], myogenic remodeling by human pluripotent stem cells [ 484 ], astrocyte-related abnormalities [ 485 ] and dystrophinopathy-associated cardiomyopathy [ 324 , 331 ]. The main techniques used for proteomics-centric and multi-omics studies have been recently reviewed by Rajczewski et al [ 486 ].…”

Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy

“…Important aspects of the molecular and cellular pathogenesis of dystrophinopathy-associated cardiomyopathy were determined by studying dystrophic mouse and pig models [ 139 , 232 , 331 ]. Systematic proteomic surveys of the dystrophin-deficient heart have revealed drastic changes in the dystrophin-associated glycoprotein complex [ 114 ], which in turn triggers an abnormal expression pattern of proteins involved in cytoskeletal networks, the extracellular matrix, the cardiac contractile apparatus, energy metabolism, signalling mechanisms and the cellular stress response [ 142 ]. On the subcellular and molecular level, the dystrophic heart is primarily characterised by sarcolemmal disintegration and significantly reduced levels of laminin, nidogen and annexin [ 232 ].…”