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.

Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function

“…Genes from monogenic muscle disease groups are enriched in distinct subsets of myocyte and nonmyocyte nuclei in three muscle types Among the monogenic disorders, muscle disease phenotypes are a well characterized subset and are known to arise from mutations in genes that are expressed in myocytes (e.g., structural genes involved in contraction) and/ or other cells in the surrounding tissue (e.g., NMJ, ECM, and adipose tissue) (118)(119)(120)(121). We leveraged the three muscle types represented in our atlas-cardiac, skeletal, and smooth muscle-to map 605 well-curated monogenic muscle disease genes (118) (table S10), recovering known biology and extending hypotheses beyond those obtained from bulk-tissue RNA-seq (122,123).…”

P2 Receptor Signaling in Motor Units in Muscular Dystrophy

“…Duchenne muscular dystrophy primarily affects boys, with 1 out of every 3500–5000 newborn males suffering from this condition [ 2 ]. This type of dystrophy is often classified in the same group as Becker’s myodystrophy (incidence: 1 per 20,000 newborns) [ 3 ]. Duchenne and Becker myodystrophy are inherited in an X-linked recessive manner [ 4 ].…”

“…Practically, for all these forms of muscular dystrophy, no effective treatment has been found [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ].…”

Co-Administration of Simvastatin Does Not Potentiate the Benefit of Gene Therapy in the mdx Mouse Model for Duchenne Muscular Dystrophy

“…An alternative but non-mutually exclusive explanation for the only modest functional improvement in clinical trials is that perhaps the restored dystrophin cannot completely reverse some of the pathological manifestations in the dystrophic muscle. Indeed, the patients' dystrophic tissues present evidence for a complex array of pathological changes, including myofiber degeneration/regeneration, increased sarcolemma Ca 2 + level, perturbed nNOS signaling, TGF beta signaling and fibrosis, energy metabolism dysregulation, lipid accumulation, calcification, necrosis, and inflammation [1,8,9]. It is reasonable to hypothesize that some of these pathological changes cannot be completely reversed by the sole restoration of dystrophin.…”