Abstract
Muscular dystrophies (MDs) are a heterogeneous group of congenital neuromuscular disorders whose clinical signs include myalgia, skeletal muscle weakness, hypotonia, and atrophy that leads to progressive muscle disability and loss of ambulation. MDs can also affect cardiac and respiratory muscles, impairing life-expectancy. MDs in clude Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy. These and other MDs are caused by mutations in genes that encode proteins responsible for the structure and function of skeletal muscles, such as components of the dystrophin-glycoprotein-complex that connect the sarcomeric-actin with the extracellular matrix, allowing contractile force transmission and providing stability during muscle contraction. Consequently, in dystrophic conditions in which such proteins are affected, muscle integrity is disrupted, leading to local inflammatory responses, oxidative stress, Ca2+-dyshomeostasis and muscle degeneration. In this scenario, dysregulation of connexin hemichannels seem to be an early disruptor of the homeostasis that further plays a relevant role in these processes. The interaction between all these elements constitutes a positive feedback loop that contributes to the worsening of the diseases. Thus, we discuss here the interplay between inflammation, oxidative stress and connexin hemichannels in the progression of MDs and their potential as therapeutic targets.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
50 genes have been associated with at least 70 different types of Muscular dystrophies (MDs), which have been classified in nine different categories: Becker muscular dystrophy (BMD), congenital muscular dystrophy (CMD), distal muscular dystrophies (DiMD), Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDMD), facioscapulohumeral muscular dystrophy (FSHD), limb-girdle muscular dystrophy (LGMD), myotonic dystrophy (MiD), and occulopharyngeal muscular dystrophy (OMD)
MDs-causing mutations affect proteins critical to skeletal muscle integrity and homeostasis. Their defective forms or absence does cause particular cellular defects, and activate signaling pathways that lead to oxidative stress (OS) and inflammation involving a positive feedback loop that contributes to the progression of MDs
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. 50 genes have been associated with at least 70 different types of MD, which have been classified in nine different categories (see Table 1): Becker muscular dystrophy (BMD), congenital muscular dystrophy (CMD), distal muscular dystrophies (DiMD), Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDMD), facioscapulohumeral muscular dystrophy (FSHD), limb-girdle muscular dystrophy (LGMD), myotonic dystrophy (MiD), and occulopharyngeal muscular dystrophy (OMD) These MDs’ classifications are based on the clinical traits and age at onset, and they are subclassified according to their inheritance and the genetic bases of the disease [3,4]. The persistent abundance of macrophages promotes the release of pro-fibrotic agents, including the transforming growth factor (TGF-β), that lead to excessive accumulation of extracellular matrix components, collagen, and contribute to the formation of fibrotic tissue [5] Another common feature in many MDs is the presence of oxidative stress (OS), which is characterized by the oxidation of lipids and proteins, and by the unbalance of the endogenous antioxidant systems [6]. Their defective forms or absence does cause particular cellular defects, and activate signaling pathways that lead to OS and inflammation involving a positive feedback loop that contributes to the progression of MDs
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