Prevention of muscle fibrosis and myonecrosis in <i>mdx</i> mice by suramin, a TGF‐β1 blocker

Taniguti, Ana Paula Tiemi; Pertille, Adriana; Matsumura, Cíntia Yuri; Neto, Humberto Santo; Marques, Maria Júlia

doi:10.1002/mus.21869

Cited by 85 publications

(94 citation statements)

References 39 publications

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“…Immune system modulation had always been a promising tool to almost delay onset and slow progression of DMD symptoms. To date, steroids are the most effective and utilized treatment, but new immune-modulatory drugs have been experimented to improve muscle repair by reducing inflammation and fibrosis of DMD animal models as anticytokines (anti-TNFα), 30 IL-6r blockade, 31 TGF-β blocker (suramin and pirfenidone) 32,33 and, more recently, Treg expansion. 13 Several evidences suggested that the proteasome is directly involved in the pathophysiology of organ fibrosis: inhibition of the proteasome could block TGF-β1 induced gene expression in primary human lung fibroblasts from healthy individuals and patients with IPF 34,35 and could reduce lung fibrosis in some animal models.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

et al. 2016

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Duchenne muscular dystrophy is an inherited fatal genetic disease characterized by mutations in dystrophin gene, causing membrane fragility leading to myofiber necrosis and inflammatory cell recruitment in dystrophic muscles. The resulting environment enriched in proinflammatory cytokines, like IFN-γ and TNF-α, determines the transformation of myofiber constitutive proteasome into the immunoproteasome, a multisubunit complex involved in the activation of cell-mediate immunity. This event has a fundamental role in producing peptides for antigen presentation by MHC class I, for the immune response and also for cytokine production and T-cell differentiation. Here, we characterized for the first time the presence of T-lymphocytes activated against revertant dystrophin epitopes, in the animal model of Duchenne muscular dystrophy, the mdx mice. Moreover, we specifically blocked i-proteasome subunit LMP7, which was up-regulated in dystrophic skeletal muscles, and we demonstrated the rescue of the dystrophin expression and the amelioration of the dystrophic phenotype. The i-proteasome blocking lowered myofiber MHC class I expression and self-antigen presentation to T cells, thus reducing the specific antidystrophin T cell response, the muscular cell infiltrate, and proinflammatory cytokine production, together with muscle force recovery. We suggest that i-proteasome inhibition should be considered as new promising therapeutic approach for Duchenne muscular dystrophy pathology.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

et al. 2016

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“…Western blots were performed as previously described (Taniguti et al, 2011). Briefly, the muscles were lysed in assay lysis buffer (1% Triton, 10 mM sodium pyrophosphate, 100 mM NaF, 10 g/ml aprotinin, 1 mM PMSF and 0.25 mM Na 3 VO).…”

Section: Western Blottingmentioning

confidence: 99%

Evaluation of skeletal muscle regeneration in experimental model after malnutrition

et al. 2017

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The aim of this study was to analyze muscle regeneration after cryoinjury in the tibialis anterior muscle of young rats that were malnourished and then recovered. Forty Wistar rats were divided into a nourished group that received a normal protein diet (14% casein) for 90 days and a malnourished and recovered rats group (MR) that was submitted to 45 days of malnutrition with a hypoproteic diet (6% casein) followed by 45 days of a normal protein diet (14% casein). After the recovery period, all of the animals underwent cryoinjury in the right tibialis anterior muscle and euthanasia after 7, 14 and 21 days. The amount of connective tissue and the inflammation area was higher in the malnutrition recovered injury MR group (MRI) at 14 days post-injury (p < 0.05). Additionally, the cross-sectional area (CSA) of the regenerated fibers was decreased in the MRI (p < 0.05). The MyoD and myogenin protein levels were higher in the nourished injury group. Similar levels of TGF-β1 were found between groups. The proposed malnutrition protocol was effective in showing delayed changes in the regeneration process of the tibialis anterior muscle of young rats. Furthermore, we observed a delay in muscle repair even after nutritional recovery.Keywords: skeletal muscle, protein malnutrition, cryolesion, myogenic regulatory factors, muscle healing process. Avaliação da regeneração do músculo esquelético em modelo experimental após desnutriçãoResumo O objetivo do presente estudo foi analisar a regeneração muscular após criolesão no músculo tibial anterior de ratos jovens desnutridos e recuperados. Foram utilizados 40 ratos da linhagem Wistar, divididos em 2 grupos: ratos nutridos receberam dieta normoproteica (14% de caseína) por 90 dias; e ratos desnutridos e recuperado submetidos a duas fases nutricionais pós-desmame, correspondendo a 45 dias de desnutrição com dieta hipoproteica (6% caseína), seguida por 45 dias de dieta normoproteica (14% caseína). Ao completar a fase de recuperação, todos os animais foram submetidos à criolesão no músculo tibial anterior direito e a eutanasia ocorreu 7, 14 e 21 dias após a lesão. A quantidade de tecido conjuntivo e a área de inflamação 14 dias pós-lesão foi maior no grupo desnutrido, recuperado e lesado (MRI -malnourished, recovered and injured group) (p < 0,05). A área de secção transversa (AST) das fibras regeneradas do grupo MRI foi menor (p < 0,05). O conteúdo das proteínas MyoD e Miogenina foi maior no grupo nutridos e lesados. A citocina TGF-β1 não apresentou diferença entre os grupos. O protocolo proposto foi eficaz para demonstrar alterações no processo de regeneração do músculo tibial anterior de ratos jovens, atrasando o reparo muscular mesmo após a recuperação nutricional.Palavras-chave: músculo esquelético, desnutrição proteica, criolesão, fatores de regulação miogênica, processo de recuperação do músculo.

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“…TGF-␤ induces the transformation of fibroblasts into myofibroblasts, which extensively promote fibrosis by secreting collagens and fibronectin (Barnes and Gorin, 2011). Inhibition of the TGF-␤ signal and inflammatory response is a therapeutic strategy for DMD (Huang et al, 2009;Taniguti et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Ameliorates Muscular Pathology in the Dystrophic mdx Mouse, a Model for Duchenne Muscular Dystrophy

Hori¹,

Kuno²,

Hosoda³

et al. 2011

J Pharmacol Exp Ther

150

173

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Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. We previously showed that resveratrol (3,5,4Ј-trihydroxy-trans-stilbene), an antioxidant and activator of the NAD ϩ -dependent protein deacetylase SIRT1, delays the progression of heart failure and prolongs the lifespan of ␦-sarcoglycan-deficient hamsters. Because a defect of dystroglycan complex causes muscular dystrophies, and ␦-sarcoglycan is a component of this complex, we hypothesized that resveratrol might be a new therapeutic tool for muscular dystrophies. Here, we examined resveratrol's effect in mdx mice, an animal model of Duchenne muscular dystrophy. mdx mice that received resveratrol in the diet for 32 weeks (4 g/kg diet) showed significantly less muscle mass loss and nonmuscle interstitial tissue in the biceps femoris compared with mdx mice fed a control diet. In the muscles of these mice, resveratrol significantly decreased oxidative damage shown by the immunostaining of nitrotyrosine and 8-hydroxy-2Ј-deoxyguanosine and suppressed the up-regulation of NADPH oxidase subunits Nox4, Duox1, and p47 phox . Resveratrol also reduced the number of ␣-smooth muscle actin (␣-SMA) ϩ myofibroblast cells and endomysial fibrosis in the biceps femoris, although the infiltration of CD45ϩ inflammatory cells and increase in transforming growth factor-␤1 (TGF-␤1) were still observed. In C2C12 myoblast cells, resveratrol pretreatment suppressed the TGF-␤1-induced increase in reactive oxygen species, fibronectin production, and expression of ␣-SMA, and SIRT1 knockdown blocked these inhibitory effects. SIRT1 small interfering RNA also increased the expression of Nox4, p47 phox , and ␣-SMA in C2C12 cells. Taken together, these findings indicate that SIRT1 activation may be a useful strategy for treating muscular dystrophies.

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Prevention of muscle fibrosis and myonecrosis in mdx mice by suramin, a TGF‐β1 blocker

Cited by 85 publications

References 39 publications

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy

Evaluation of skeletal muscle regeneration in experimental model after malnutrition

Resveratrol Ameliorates Muscular Pathology in the Dystrophic mdx Mouse, a Model for Duchenne Muscular Dystrophy

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