Epigenetic modifications in muscle regeneration and progression of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a multisystemic disorder that affects 1:5000 boys. The severity of the phenotype varies dependent on the mutation site in the DMD gene and the resultant dystrophin expression profile. In skeletal muscle, dystrophin loss is associated with the disintegration of myofibers and their ineffective regeneration due to defective expansion and differentiation of the muscle stem cell pool. Some of these phenotypic alterations stem from the dystrophin absence-mediated serine–threonine protein kinase 2 (MARK2) misplacement/downregulation in activated muscle stem (satellite) cells and neuronal nitric oxide synthase loss in cells committed to myogenesis. Here, we trace changes in DNA methylation, histone modifications, and expression of regulatory noncoding RNAs during muscle regeneration, from the stage of satellite cells to myofibers. Furthermore, we describe the abrogation of these epigenetic regulatory processes due to changes in signal transduction in DMD and point to therapeutic treatments increasing the regenerative potential of diseased muscles based on this acquired knowledge.

Therapeutic aspects of cell signaling and communication in Duchenne muscular dystrophy

“…Some of the dystrophin-related roles pertain to its mechanical functions and widespread interactions with transmembrane as well as cytoskeletal proteins, such as ankyrins, microtubules, plectin, γ-actin and cyotokeratins that enable efficient transmission of forces and structural plasticity [66,226,227]. The dystrophinglycoprotein complex together with its associated proteins, however, is also responsible for the interaction with various signaling molecules [25,184,228] that regulate cell proliferation, migration or maintenance via, in some instances, epigenetic and transcriptional changes, such as in the process of myofiber repair [8,9,11]. Importantly, in addition to intracellular signaling, cell-to-cell communication is also affected in dystrophin deficiency, as shown, e.g., by vasoconstriction related to nNOS downregulation and displacement from the sarcolemma [121][122][123][124], abrogated satellite cell activation due to dysregulated Notch signaling [199], or changes in the production of myokines that affect the bone [71,93,98,104].…”

“…Quiescence of SCs in resting muscle is maintained by expression of the paired box 7 (Pax7) gene controlled by the Notch pathway, which is activated by binding of Notch ligands distributed at the sarcolemma to Notch receptors located on the SC membrane [177] as well as various epigenetic mechanisms [11]. Specifically, nonmethylated Pax7 protein limits the expression of myogenic factor 5 (Myf5) while its methylation enables recruitment of epigenetic machinery to the Myf5 promoter and in turn SC activation, division and differentiation into myotubes [178].…”

“…DMD is caused by mutations in the DMD gene that lead to the absence of functional dystrophin protein. A number of research studies have revealed that a lack of functional dystrophin results in aberrant signal transduction, which leads to epigenome modifications and altered gene expression in affected muscle tissues [8][9][10][11]. Although still limited, knowledge regarding dystrophin absence-associated disturbed signaling resulted in the first experimental therapies and clinical trials based on gene expression modulation.…”

Partial resistance to HDAC inhibitors in FAPs of dystrophic muscles at late stages of disease is associated to epigenetic and transcriptional features of cellular senescence

“…Genetic correction by restoration of dys expression with gene therapy approaches [3][4][5] is predicted to recover the biochemical and functional integrity of the dystrophin-associated protein complex (DAPC) 6, and thereby protect myofiber sarcolemma stability post-contraction 7 . However, a number of "secondary" pathogenic events caused by dys deficiency can contribute to DMD progression [8][9][10][11][12][13] and might persist even after gene therapy. Targeting these DMD-associated "secondary" events might therefore be necessary to achieve complete and long-lasting therapeutic recovery in DMD patients.…”

A Comprehensive In Silico Perspective For Discovery of Novel Inhibitory Candidates Targeting Versatile Transcriptional Repressor MBD2

“…Methylation on CpG dinucleotides near and/or inside promoter sequences reveals a well-known hallmark for DNA-binding proteins, and thus gene transcription is repressed due to avoidance of transcription factors and machinery 5,6 . Besides its importance in normal development and cellular function 7 , methylation status of related genes also constitutes a signi cant diagnostic marker, causation and therapeutic target in a variety of human diseases such as cancer 8 , birth defects and syndromes 9 , metabolic disorders 10 , autoimmune diseases 11 , muscular dystrophies 12 , cardiovascular diseases 13 , aging 14 , neurological dysfunctions 15 . Correspondingly, miscellaneous epigenetic/genetic arrangements, mostly deacetylation of histones along related regions by Histone Deacetylases (HDACs), are accompanied and coordinated with DNA methylation in order to furtherly cement electrostatic interactions between histone core and DNA strands, resulting in compacted chromatin, which downregulates transcription 16,17 .…”