Oxidative Stress, Inflammation and Connexin Hemichannels in Muscular Dystrophies

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.

Role of Matrix Metalloproteinases in Musculoskeletal Diseases

“…MDs are a set of inherited disorders characterized by gradual muscular deterioration and disintegration [ 94 ]. Muscular dystrophy is characterized by progressive muscle weakness associated with abnormalities in the interaction between the muscle cell membrane and the ECM [ 95 ].…”

Deletion of Dux ameliorates muscular dystrophy in mdx mice by attenuating oxidative stress via Nrf2

“…11 In DMD patients and animal models, muscle biopsies showed elevated levels of protein oxidation and lipid peroxidation, and decreased glutathione and antioxidant enzyme activity. 12 Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a key role in the oxidative stress response. 13 Nrf2 reduced the production of reactive oxygen species (ROS), promoted the proliferation and viability of myoblasts, and it appeared to be essential for the survival of muscle satellite cells.…”

“…Increased oxidative stress is evident in dystrophic muscle and seems to underlie many structural, functional, and biochemical changes in myotonic dystrophy 11 . In DMD patients and animal models, muscle biopsies showed elevated levels of protein oxidation and lipid peroxidation, and decreased glutathione and antioxidant enzyme activity 12 . Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a transcription factor that plays a key role in the oxidative stress response 13 .…”

Calcium Regulation of Connexin Hemichannels

“…Lost or abnormal HC activity at the plasma membrane has been associated with inflammatory conditions [ 110 , 111 ] and inherited diseases, like muscular dystrophy [ 112 ], syndromic and non-syndromic deafness [ 113 ], keratitis and hystrix-like ichthyosis deafness (KID/HID) syndrome [ 114 ], the X-linked form of Charcot–Marie–Tooth neuropathy (CMT1X) [ 115 ], oculodentodigital dysplasia (ODDD) [ 116 ], keratoderma–hypotrichosis–leukonychia totalis syndrome (KHLS) [ 117 ], erythrokeratodermia variabilis (EKV) [ 118 ], and congenital cataracts [ 119 ]. A single amino acid substitution in the connexin sequence can severely affect the correct HC function, leading to uncontrolled ionic leakage and release of molecules altering extracellular signalling pathways and potentially toxic for neighboring cells [ 120 , 121 , 122 , 123 , 124 ].…”