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

Abstract

This perspective article is concerned with the question of how proteomics, which is a core technique of systems biology that is deeply embedded in the multi-omics field of modern bioresearch, can help us better understand the molecular pathogenesis of complex diseases. As an illustrative example of a monogenetic disorder that primarily affects the neuromuscular system but is characterized by a plethora of multi-system pathophysiological alterations, the muscle-wasting disease Duchenne muscular dystrophy was examined. Recent achievements in the field of dystrophinopathy research are described with special reference to the proteome-wide complexity of neuromuscular changes and body-wide alterations/adaptations. Based on a description of the current applications of top-down versus bottom-up proteomic approaches and their technical challenges, future systems biological approaches are outlined. The envisaged holistic and integromic bioanalysis would encompass the integration of diverse omics-type studies including inter- and intra-proteomics as the core disciplines for systematic protein evaluations, with sophisticated biomolecular analyses, including physiology, molecular biology, biochemistry and histochemistry. Integrated proteomic findings promise to be instrumental in improving our detailed knowledge of pathogenic mechanisms and multi-system dysfunction, widening the available biomarker signature of dystrophinopathy for improved diagnostic/prognostic procedures, and advancing the identification of novel therapeutic targets to treat Duchenne muscular dystrophy.

Proteomic reference map for sarcopenia research: mass spectrometric identification of key muscle proteins located in the sarcomere, cytoskeleton and the extracellular matrix

“…Proteomics is an ideal bioanalytical tool to study the complexity of neuromuscular changes and multi-systems disturbances in dystrophinopathy, as recently discussed in a review on pathophysiological crosstalk in X-linked muscular dystrophy. 87 Reactive myofibrosis is a characteristic hallmark of Duchenne muscular dystrophy and this was confirmed here by the drastic increase in the matricellular component periostin and a specific isoform of collagen. 56 Since the presence of periostin, a protein that is almost absent from normal skeletal muscle, was clearly established in senescent mdx-4cv mouse hindlimb muscle, the dystrophic phenotype appears to be characterized by high levels of reactive myofibrosis.…”