Oxidative Damage in Muscular Dystrophy Correlates with the Severity of the Pathology: Role of Glutathione Metabolism

Abstract

Muscular dystrophies (MDs) such as Duchenne muscular dystrophy (DMD), sarcoglycanopathy (Sgpy) and dysferlinopathy (Dysfy) are recessive genetic neuromuscular diseases that display muscle degeneration. Although these MDs have comparable endpoints of muscle pathology, the onset, severity and the course of these diseases are diverse. Different mechanisms downstream of genetic mutations might underlie the disparity in these pathologies. We surmised that oxidative damage and altered antioxidant function might contribute to these differences. The oxidant and antioxidant markers in the muscle biopsies from patients with DMD (n = 15), Sgpy (n = 15) and Dysfy (n = 15) were compared to controls (n = 10). Protein oxidation and lipid peroxidation was evident in all MDs and correlated with the severity of pathology, with DMD, the most severe dystrophic condition showing maximum damage, followed by Sgpy and Dysfy. Oxidative damage in DMD and Sgpy was attributed to the depletion of glutathione (GSH) and lowered antioxidant activities while loss of GSH peroxidase and GSH-S-transferase activities was observed in Dysfy. Lower GSH level in DMD was due to lowered activity of gamma-glutamyl cysteine ligase, the rate limiting enzyme in GSH synthesis. Similar analysis in cardiotoxin (CTX) mouse model of MD showed that the dystrophic muscle pathology correlated with GSH depletion and lipid peroxidation. Depletion of GSH prior to CTX exposure in C2C12 myoblasts exacerbated oxidative damage and myotoxicity. We deduce that the pro and anti-oxidant mechanisms could be correlated to the severity of MD and might influence the dystrophic pathology to a different extent in various MDs. On a therapeutic note, this could help in evolving novel therapies that offer myoprotection in MD.

Low intensity training of mdx mice reduces carbonylation and increases expression levels of proteins involved in energy metabolism and muscle contraction

“…Protein carbonylation in skeletal muscle of nonexercised mdx mice Elevated total protein carbonylation levels have been reported in muscle of mdx mice and DMD patients [17,20]. However, the targets Table 3 Identity of proteins whose expression and protein-protein interactions differs in mdx gastrocnemius, in comparison with wild type.…”

“…Studies reported an abnormal oxidative stress in skeletal muscle of DMD patients and mdx mice [17,18]. Indeed, myofibers lacking dystrophin were highly susceptible to oxidant-induced injury [19] and thus, the Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/freeradbiomed protein carbonylation level correlated with the degree of the disease [20]. In the absence of dystrophin, oxidative stress acts together with mechanical stress to worsen fiber damage [17].…”

Redox Control of Skeletal Muscle Regeneration

“…The increase of oxidative stress in muscular dystrophy, which was acknowledged a long time ago (132,228), has been shown to correlate with the severity of the pathology (274) and is considered to contribute to the pathology of several muscular dystrophies (173). Interestingly, mutations in the antioxidant sepn1 gene cause SEPN1-related myopathy, a different class of muscle disease (14).…”

Neurotrophins, cytokines, oxidative parameters and funcionality in Progressive Muscular Dystrophies

“…Oxidative stress has been postulated to play an important role in several degenerative conditions (Moosmann and Behl 2002). In the dystrophic muscle, oxidative stress is a potential pathogenetic factor which may determine the severity of the pathology (Kim et al 2013, Renjini et al 2012. In this study, it was shown that DMD and SMD patients present a decrease of SOD activity in the serum without alteration in the others oxidative parameters.…”