Wasting mechanisms in muscular dystrophy

Abstract

Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy.

Concurrent Label-Free Mass Spectrometric Analysis of Dystrophin Isoform Dp427 and the Myofibrosis Marker Collagen in Crude Extracts from mdx-4cv Skeletal Muscles

“…Progressive diseases of skeletal and cardiac muscles with primary abnormalities in the dystrophin gene include Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy [10,11,12]. In X-linked muscular dystrophy, the almost complete absence of full-length dystrophin triggers a significant reduction in the dystrophin-associated glycoprotein complex and a plethora of down-stream pathophysiological changes, such as an altered coupling between neuronal excitation and muscle contraction, stretch-induced fiber injury, higher levels of plasmalemmal calcium influx, impaired luminal calcium buffering, and an accelerated proteolytic degradation rate [13,14,15]. In order to elucidate the enormous complexity and potential interconnectivity of these many secondary changes, damage pathways in dystrophic muscles involved in fiber degeneration, inflammation, fatty deposition, and progressive fibrosis are ideally studied by large-scale and comprehensive bioanalytical approaches, such as mass spectrometry-based proteomics [16].…”

How Do Skeletal Muscles Die? An Overview

“…Yet it is worthwhile to note that some muscle fiber changes are reversible (hypertrophy and atrophy), some partially reversible (sarcopenia) (Mendelsohn and Larrick 2014), and some irreversible (dystrophy and cachexia) (Shin et al 2013). An understanding of the fundamental roots of muscle tissue plasticity is essential for primary and secondary prevention.…”

Signaling mechanisms in regenerative myogenesis.

“…Recent studies using genetic mouse models and pharmacological approaches have provided strong evidence that the modulation of activity of specific signaling pathways has enormous potential to reduce the severity of disease progression in muscular dystrophy (16,17,127).…”

“…Initial fiber necrosis due to sarcolemmal instability causes severe inflammatory response in skeletal muscle which includes infiltration of macrophages and neutrophils in dystrophic muscle and increased levels of proinflammatory cytokines leading to hastening of fiber necrosis and disease progression in DMD (17,127). Muscle-derived factors appear to be some of the important contributors of chronic inflammation in mdx myofibers supported by the findings that the activation of proinflammatory transcription factors such as NF-κB and activator protein-1 (AP-1) and levels of various inflammatory cytokines (e.g.…”

“…However, given the progressive degenerative nature of DMD and the convoluted involvement of many secondary processes, developing a pan therapeutic strategy that proves beneficial during the course of the disease has been challenging. Indeed, recent studies have provided evidence that combinatorial approaches which involve simultaneous intonation of multiple pathological pathways would be more effective therapies for DMD (17,(22)(23)(24). While it is clear that pathogenesis of muscular dystrophy involves aberrant activation of multiple signaling pathways, it remains unknown whether they are activated through upstream activation of a common signaling network or they are independently regulated.…”