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

Abstract

Duchenne muscular dystrophy is a highly progressive muscle wasting disorder due to primary abnormalities in one of the largest genes in the human genome, the DMD gene, which encodes various tissue-specific isoforms of the protein dystrophin. Although dystrophinopathies are classified as primary neuromuscular disorders, the body-wide abnormalities that are associated with this disorder and the occurrence of organ crosstalk suggest that a multi-systems pathophysiological view should be taken for a better overall understanding of the complex aetiology of X-linked muscular dystrophy. This article reviews the molecular and cellular effects of deficiency in dystrophin isoforms in relation to voluntary striated muscles, the cardio-respiratory system, the kidney, the liver, the gastrointestinal tract, the nervous system and the immune system. Based on the establishment of comprehensive biomarker signatures of X-linked muscular dystrophy using large-scale screening of both patient specimens and genetic animal models, this article also discusses the potential usefulness of novel disease markers for more inclusive approaches to differential diagnosis, prognosis and therapy monitoring that also take into account multi-systems aspects of dystrophinopathy. Current therapeutic approaches to combat muscular dystrophy are summarised.

Keywords: Duchenne muscular dystrophy; Dystrophin; Fibrosis; Inflammation; Muscle degeneration; Organ crosstalk.

Fig. 1

Overview of the DMD gene, its promoter structure and tissue-specific expression pattern of dystrophin isoforms. Abbreviations used: B, brain; B/K, brain/kidney; Dp, dystrophin protein; G, general; M, muscle; P, Purkinje cell; R, retina; S, Schwann cell

Fig. 2

Domain structure of full-length dystrophin, shorter dystrophin isoforms and the main types of dystrophin-related proteins. Abbreviations used: B, brain; B/K, brain/kidney; CT, carboxy-terminus; CR, cysteine-rich domain; Dp, dystrophin protein; G, general; DYB, dystrobrevin; H, proline-rich hinge region; M, muscle; NT, amino-terminus; P, Purkinje cell; R, retina; S, Schwann cell; SLR, spectrin-like rod domain; WW, conserved region with signature tryptophan residues; Up, utrophin

Fig. 3

Interaction sites of dystrophin isoform Dp427-M and overview of the dystrophin-glycoprotein complex at the sarcolemma of skeletal muscle fibres. Abbreviations used: ABD, actin-binding domain; CT, carboxy-terminus; CR, cysteine-rich domain; DG, dystroglycan; DYB, dystrobrevin; Dp427-M, muscle-specific dystrophin isoform of 427 kDa; H, proline-rich hinge region; nNOS, neuronal isoform of nitric oxide synthase; NT, amino-terminus; SG, sarcoglycan; SLR, spectrin-like rod domain; SSPN, sarcospan; SYN, syntrophin; WW, conserved region with signature tryptophan residues

Fig. 4

Summary of developmental stages of dystrophinopathy and muscle symptoms

Fig. 5

Absence of dystrophin isoform Dp427-M in X-linked muscular dystrophy and key histopathological features of dystrophinopathy. Shown is the immunofluorescence microscopical analysis (using monoclonal antibody NCL-DYS1 to dystrophin and Hoechst-33342 labelling of nuclei) and histological comparison (using haematoxylin and eosin staining; H&E) of skeletal muscle cryosections from wild type (wt) versus the mdx-4cv mouse model of Duchenne muscular dystrophy. Bar equals 40 μm

Fig. 6

Pathophysiological role of chronic inflammation, reactive myofibrosis and abnormal calcium handling in the molecular and cellular pathogenesis of dystrophinopathy. Abbreviations used: COL, collagen; DAMPs, damage-associated molecular patterns; ECM, extracellular matrix; MMP, matrix metalloproteinase; PA, plasminogen activator; TIMP, tissue inhibitor of metalloproteinases; TGF, transforming growth factor; TNF, tumour necrosis factor; NF-κB, nuclear factor kappa B

Fig. 7

Overview of skeletal muscular degeneration, multi-systems pathophysiology and organ crosstalk in Duchenne muscular dystrophy