Ion Channels of the Sarcolemma and Intracellular Organelles in Duchenne Muscular Dystrophy: A Role in the Dysregulation of Ion Homeostasis and a Possible Target for Therapy

Abstract

Duchenne muscular dystrophy (DMD) is caused by the absence of the dystrophin protein and a properly functioning dystrophin-associated protein complex (DAPC) in muscle cells. DAPC components act as molecular scaffolds coordinating the assembly of various signaling molecules including ion channels. DMD shows a significant change in the functioning of the ion channels of the sarcolemma and intracellular organelles and, above all, the sarcoplasmic reticulum and mitochondria regulating ion homeostasis, which is necessary for the correct excitation and relaxation of muscles. This review is devoted to the analysis of current data on changes in the structure, functioning, and regulation of the activity of ion channels in striated muscles in DMD and their contribution to the disruption of muscle function and the development of pathology. We note the prospects of therapy based on targeting the channels of the sarcolemma and organelles for the correction and alleviation of pathology, and the problems that arise in the interpretation of data obtained on model dystrophin-deficient objects.

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

“…In healthy muscles, the dystrophin-containing node of the sarcolemma is defined as the integrating structure of the intracellular cytoskeleton, the central provider of lateral force transmission, the plasmalemmal hub of fiber stabilization and a key point for cellular signaling mechanisms at the myofiber periphery. In muscular dystrophy, the collapse of the dystrophin node results in impaired sarcolemmal integrity, reduced lateral force transmission at weakened costamere structures, and pathophysiological Ca 2+ influx into the sarcosol, which in turn triggers an increase in proteolytic degradation of muscle proteins [ 255 , 256 , 257 ]. The main feature of the cellular pathogenesis of DMD is progressive myonecrosis, which is accompanied by chronic inflammation, reactive myofibrosis and an impaired regenerative capacity due to satellite cell dysfunction, as recently reviewed [ 258 ].…”

“…Besides testing novel pharmacological strategies [ 257 , 381 , 382 , 383 , 384 ] and immunomodulatory interventions [ 355 , 356 , 357 , 358 , 364 ], a variety of innovative therapeutic approaches are currently evaluated in the field of muscular dystrophy [ 385 , 386 , 387 , 388 , 389 ], including exon skipping [ 148 , 390 , 391 , 392 , 393 ], genomic editing [ 394 , 395 , 396 ], codon read-through [ 397 ], gene replacement with the help of adeno-associated viral vectors [ 398 , 399 , 400 , 401 , 402 ], dystrophin substitution with its autosomal homolog utrophin [ 403 , 404 , 405 ], and muscle stem cell therapy [ 406 , 407 , 408 , 409 ]. Hence, for the optimum pre-clinical testing of new therapies, the clinical evaluation of diverse patient cohorts during the various phases of clinal studies/trials, and long-term therapeutic monitoring, robust and specific biomarkers for the routine screening of the status of dystrophic patients are required [ 144 , 264 , 265 , 410 , 411 ].…”

Mitochondrial Transplantation Therapy Ameliorates Muscular Dystrophy in mdx Mouse Model

“…Maintaining the quality of the mitochondrial network plays an important role in the development and functioning of muscle tissue. Indeed, pharmacological modulation of mitochondrial function has been shown to be useful in the treatment of induced and genetic myopathies and significantly improves muscle state and the quality of life of experimental animals [ 1 , 2 ]. Along with this, one of the discussed areas of modern biomedicine is mitochondrial transplantation therapy (MTT) based on the replacement of defective mitochondria with healthy ones.…”

Advancing Biomarker Discovery and Therapeutic Targets in Duchenne Muscular Dystrophy: A Comprehensive Review

“…The absence of dystrophin disrupts the contraction machinery, and the continuous degeneration/regeneration cycles in dystrophic muscles lead to persistent muscular injury and inhibition of regenerative potential caused by the depletion of satellite cells. This scenario culminates in the disruption of interactions between ion channels and components of the dystrophin glycoprotein complex, resulting in the dysfunction of transient receptor potential canonical (TRPC) and cardiac L-type calcium channels [ 3 ] as well as potassium and sodium channels, which contribute to developing cardiomyopathy [ 4 ].…”