N-Acetylcysteine treatment reduces TNF-α levels and myonecrosis in diaphragm muscle of mdx mice

Pinto, Rafael de Senzi Moraes; Ferretti, Renato; Moraes, Luís Henrique Rapucci; Neto, Humberto Santo; Marques, Maria Júlia; Minatel, Elaine

doi:10.1016/j.clnu.2012.06.001

Cited by 47 publications

(52 citation statements)

References 15 publications

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“…A sampling of these includes: CT GalNAc transferase ( Galgt2 ) [73], ADAM12 [114], heregulin [115], L-arginine [116,117], activated calcineurin-A alpha [118], N-acetylcysteine [119-121], activated Akt [108,109], GW501516 (activates PPAR beta/delta) [122], artificial gene Jazz [123], and biglycan [124]. Several studies have now revealed that SSPN can be added to this list of secondary proteins that modify utrophin expression [19,69].…”

Section: Discussionmentioning

confidence: 99%

Sarcospan: a small protein with large potential for Duchenne muscular dystrophy

Marshall

Crosbie-Watson

2013

Skeletal Muscle

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Purification of the proteins associated with dystrophin, the gene product responsible for Duchenne muscular dystrophy, led to the discovery of the dystrophin-glycoprotein complex. Sarcospan, a 25-kDa transmembrane protein, was the last component to be identified and its function in skeletal muscle has been elusive. This review will focus on progress over the last decade revealing that sarcospan is an important regulator of muscle cell adhesion, strength, and regeneration. Investigations using several transgenic mouse models demonstrate that overexpression of sarcospan in the mouse model for Duchenne muscular dystrophy ameliorates pathology and restores muscle cell binding to laminin. Sarcospan improves cell surface expression of the dystrophin- and utrophin-glycoprotein complexes as well as α7β1 integrin, which are the three major laminin-binding complexes in muscle. Utrophin and α7β1 integrin compensate for the loss of dystrophin and the finding that sarcospan increases their abundance at the extra-synaptic sarcolemma supports the use of sarcospan as a therapeutic target. Newly discovered phenotypes in sarcospan-deficient mice, including a reduction in specific force output and increased drop in force in the diaphragm muscle, result from decreased utrophin and dystrophin expression and further reveal sarcospan’s role in determining abundance of these complexes. Dystrophin protein levels and the specific force output of the diaphragm muscle are further reduced upon genetic removal of α7 integrin (Itga7) in SSPN-deficient mice, demonstrating that interactions between integrin and sarcospan are critical for maintenance of the dystrophin-glycoprotein complex and force production of the diaphragm muscle. Sarcospan is a major regulator of Akt signaling pathways and sarcospan-deficiency significantly impairs muscle regeneration, a process that is dependent on Akt activation. Intriguingly, sarcospan regulates glycosylation of a specific subpopulation of α-dystroglycan, the laminin-binding receptor associated with dystrophin and utrophin, localized to the neuromuscular junction. Understanding the basic mechanisms responsible for assembly and trafficking of the dystrophin- and utrophin-glycoprotein complexes to the cell surface is lacking and recent studies suggest that sarcospan plays a role in these essential processes.

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Section: Discussionmentioning

confidence: 99%

Sarcospan: a small protein with large potential for Duchenne muscular dystrophy

Marshall

Crosbie-Watson

2013

Skeletal Muscle

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“…Treatment of mdx mice with NAC or OTC reduces muscle pathology, as shown by decreased myofibre necrosis, inflammatory cells and TNF levels, and improved grip strength [19], [20], [23], [24], [25]. NAC and OTC are derivatives of the amino acid cysteine, and can increase tissue content of both cysteine and GSH, two major cellular thiol antioxidants [27], [28].…”

Section: Introductionmentioning

confidence: 99%

Levels of inflammation and oxidative stress, and a role for taurine in dystropathology of the Golden Retriever Muscular Dystrophy dog model for Duchenne Muscular Dystrophy

et al. 2016

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Duchenne Muscular Dystrophy (DMD) is a fatal skeletal muscle wasting disease presenting with excessive myofibre necrosis and increased inflammation and oxidative stress. In the mdx mouse model of DMD, homeostasis of the amino acid taurine is altered, and taurine administration drastically decreases muscle necrosis, dystropathology, inflammation and protein thiol oxidation. Since the severe pathology of the Golden Retriever Muscular Dystrophy (GRMD) dog model more closely resembles the human DMD condition, we aimed to assess the generation of oxidants by inflammatory cells and taurine metabolism in this species. In muscles of 8 month GRMD dogs there was an increase in the content of neutrophils and macrophages, and an associated increase in elevated myeloperoxidase, a protein secreted by neutrophils that catalyses production of the highly reactive hypochlorous acid (HOCl). There was also increased chlorination of tyrosines, a marker of HOCl generation, increased thiol oxidation of many proteins and irreversible oxidative protein damage. Taurine, which functions as an antioxidant by trapping HOCl, was reduced in GRMD plasma; however taurine was increased in GRMD muscle tissue, potentially due to increased muscle taurine transport and synthesis. These data indicate a role for HOCl generated by neutrophils in the severe dystropathology of GRMD dogs, which may be exacerbated by decreased availability of taurine in the blood. These novel data support continued research into the precise roles of oxidative stress and taurine in DMD and emphasise the value of the GRMD dogs as a suitable pre-clinical model for testing taurine as a therapeutic intervention for DMD boys.

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“…[2][3][4][5][6] The dystrophin-deficient muscle fibers of patients with DMD and of the mdx mice (an experimental model of DMD) display elevated levels of oxidative stress markers and lipid peroxidation by-products. [6][7][8][9] In addition, dystrophin-deficient cells appear to be more susceptible than normal cells to cellular injury when exposed to reactive oxygen species (ROS) in vitro, in particular to hydrogen peroxide (H 2 O 2 ). 6 Previous studies showed that the antioxidant Nacetylcysteine (NAC) provided considerable protection against the ongoing muscle degeneration and the elevated inflammatory processes in mdx mice.…”

Section: Introductionmentioning

confidence: 99%