Chile – a angiotensina 1-7 pertence ao sistema renina-angiotensina e tem efeito oposto ao da angiotensina II que é fibrosante através da TGF beta1. Neste estudo em camundongos com distrofia muscular o uso da angiotensina 1-7 dada por via oral reduziu a sinalização da TGF beta 1, reduziu a fibrose e o desaranjo muscular e aumentou a força muscular.

O resumo em inglês pode ser lido abaixo:

(Human Molecular Genetics, 2013) Restoration of muscle strength in dystrophic muscle by Angiotensin-1-7 through inhibition of TGF-β signaling

María José Acuña, Patrizia Pessina, Hugo Olguin, Daniel Cabrera, Carlos P. Vio, Michael Bader, Pura Muñoz-Canoves, Robson A. Santos, Claudio Cabello-Verrugio, and Enrique Brandan – Chile

Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease, and is characterized by the lack of dystrophin, muscle wasting, increased transforming growth factor (TGF)-β Smad dependent signaling and fibrosis. Acting via the Mas receptor, Angiotensin-1-7 (Ang-(1-7)) is part of the renin–angiotensin system, with the opposite effect to that of angiotensin II. We hypothesized that the Ang-(1-7)/Mas receptor axis might protects chronically damaged tissues as in skeletal muscle of the DMD mouse model mdx. Infusion or oral administration of Ang-(1-7) in mdx mice normalized skeletal muscle architecture, decreased local fibrosis and improved muscle function in vitro and in vivo. These positive effects were mediated by the inhibition of TGF-β Smad signaling, which in turn, led to reduction of the pro-fibrotic microRNA miR-21 concomitant with a reduction in the number of TCF4 expressing fibroblasts. Mdx mice infused with Mas antagonist (A-779) and mdx deficient for the Mas receptor showed highly deteriorated muscular architecture, increased fibrosis and TGF-β signaling with diminished muscle strength. These results suggest that this novel compound Ang-(1-7) might be used to improve quality of life and delay death in individuals with DMD and this drug should be investigated in further pre-clinical trials.

Japão – o tratamento com corticóides é o único que retarda a evolução da distrofia muscular de Duchenne mas poucas informações existem sobre seu efeito sobre a função psicomotora. Os autores observaram um aumento do quociente de inteligência (QI) nos meninos tratados com corticóides, em especial naqueles com mutação sem sentido (mutação de ponto). Além disso os tratados com corticóides tiveram aumento de força muscular e apresentaram redução do peptídeo natriurético cerebral, que normalizou-se em 73% dos casos.

O resumo em inglês pode ser lido abaixo:

(Pediatric Neurology, 2013) Corticosteroid Therapy for Duchenne Muscular Dystrophy: Improvement of Psychomotor Function

Background:

Of the numerous clinical trials for Duchenne muscular dystrophy, only the corticosteroid prednisolone has shown potential for temporal improvement in motor ability. In this study, the effects of prednisolone on intellectual ability are examined in 29 cases of Duchenne muscular dystrophy because little information has been reported. And also, motor functions and cardiac functions were evaluated.

Methods

The treated group was administered prednisolone (0.75 mg/kg) orally on alternate days and the compared with the untreated control group. Gene mutations were investigated. The patients were examined for intelligence quotient adequate for age, brain natriuretic peptide, creatine kinase, and manual muscle testing before treatment and after the period 6 months to 2 years.

Results

Intelligence quotient scores of the treated increased to 6.5 ± 11.9 (mean ± standard deviation) were compared with the controls 2.1 ± 4.9 (P = 0.009). Intelligence quotient scores of the patients with nonsense point mutations improved significantly (21.0 ± 7.9) more than those with deletion or duplication (1.9 ± 9.0; P = 0.015). Motor function, such as time to stand up, of those treated improved significantly and brain natriuretic peptide level was reduced to a normal level after treatment in 15 patients (73%).

Conclusions

Our results demonstrate the effectiveness of prednisolone in improving intellectual impairment as well as in preserving motor function and brain natriuretic peptide levels. We presume that prednisolone has a read-through effect on the stop codons in the central nervous systems of Duchenne muscular dystrophy because intelligence quotient of point mutation case was improved significantly.

Fonte:http://distrofiamuscular.net/noticias.htm

USA – camundongos com distrofia muscular congênita merosina negativa foram tratados com laminina-111. A droga demonstrou aumento da capacidade de regeneração dos músculos com aumento do número e tamanho das fibras e aumento da expressão de proteínas de recuperação muscular.

O resumo em inglês pode ser lido abaixo:

(Hum. Mol. Genet., Sep 2013) Laminin-111 improves muscle repair in a mouse model of Merosin Deficient Congenital Muscular Dystrophy

Pam M. Van Ry, Priscilla Minogue, Bradley L. Hodges, and Dean J. Burkin

Merosin-deficient congenital muscular dystrophy type 1A is a severe and fatal muscle wasting disease with no cure. MDC1A patients and the dyW-/- mouse model exhibit severe muscle weakness, demyelinating neuropathy, failed muscle regeneration and premature death. We have recently shown that laminin-111, a form of laminin found in embryonic skeletal muscle, can substitute for the loss of laminin-211/221 and prevent muscle disease progression in the dyW-/- mouse model. What is unclear from these studies is if laminin-111 can restore failed regeneration to laminin-α2 deficient muscle. To investigate the potential of laminin-111 protein therapy to improve muscle regeneration, laminin-111 or PBS treated laminin-α2 deficient muscle was damaged with cardiotoxin and muscle regeneration quantified. Our results show laminin-111 treatment promoted an increase in myofiber size and number, and an increased expression of α7β1 integrin, Pax7, myogenin and embryonic myosin heavy chain, indicating a restoration of the muscle regenerative program. Together our results show laminin-111 restores muscle regeneration to laminin-α2 deficient muscle and further supports laminin-111 protein as a therapy for the treatment of MDC1A.

França – As medidas tradicionais de função respiratória em crianças com distrofia muscular de Duchenne ( DMD) são baseadas em pressão inspiratória máxima ( PImax ) e capacidade vital (CV ) . Nesta pesquisa a medida da pressão inspiratória nasal, mais fácil de obter em crianças com distrofia muscular de Duchenne, foi utilizada no acompanhamento de longo prazo das crianças em comparação a prova de função pulmonar. tradicional. A pressão inspiratória nasal conseguiu detectar alterações mais precocemente, permitindo o acompanhamento dos pacientes mesmo quando a capacidade vital estava em valores normais.

O resumo em inglês pode ser lido abaixo:

(Eur. Respir. J., Sep 2013; 42: 671 – 680) Sniff nasal inspiratory pressure in the longitudinal assessment of young Duchenne muscular dystrophy children

Véronique Nève, Jean-Marie Cuisset, Jean-Louis Edmé, Alain Carpentier, Mike Howsam, Olivier Leclerc, and Régis Matran

Abstract

Traditional measures of respiratory function in children with Duchenne muscular dystrophy (DMD) are based on maximal inspiratory pressure (PImax) and vital capacity (VC). Sniff nasal inspiratory pressure (SNIP) measurements are easily performed by young children with neuromuscular disorders. The clinical value of SNIP in the longitudinal assessment of respiratory weakness remains to be assessed. The objective of the present study was to assess longitudinally the changes in SNIP, PImax and VC with age in DMD children. We hypothesised that their longitudinal assessment would show an earlier decline in SNIP than VC.

A 3-year, prospective follow-up, at 6-month intervals of, 33 steroid-naïve, 5–20-year-old DMD patients was analysed using a linear mixed model.

SNIP measurements were reliable (within-session coefficient of variation 8%). SNIP and VC increased until 10.5 and 12.5 years of age, respectively, and declined thereafter, while PImax did not change with age.

SNIP was an earlier marker of decline in respiratory muscle strength (at 10.5 years) than VC (at 12.5 years) in young DMD patients. SNIP longitudinal assessment is useful in the detection of inspiratory strength decline in young DMD patients when VC values remain within normal values and as an outcome measure in clinical trials for emerging therapeutics in young DMD patients from the age of 5 years

Leia mais sobre o artigo aqui.

USA – Este estudo foi feito com a análise das informações de 5 centros de tratamento americano com 462 meninos com Duchenne acompanhados de 1982 a 2005. O início da cardiomiopatia foi significantemente mais tarde entre os tratados com corticóides. Na idade média de 14,3 anos, 63% dos não tratados com corticóides tinham cardiomiopatia contra 36% dos tratados. A conclusão dos autores é que o uso de corticóides retarda o aparecimento da cardiomiopatia e que o uso de corticóides por 5 anos pode resultar na diminuição de 20% na possibilidade de aparecimento das manifestações cardíacas.

O resumo em inglês pode ser lido abaixo:

(J Pediatr 2013) Oral Corticosteroids and Onset of Cardiomyopathy in Duchenne Muscular Dystrophy

Brent J. Barber, Jennifer G. Andrews, Zhenqiang Lu, Nancy A. West, F. John Meaney, Elinora T. Price, Ashley Gray, Daniel W. Sheehan, Shree Pandya, Michele Yang and Christopher Cunniff

Objective

To estimate the age when cardiomyopathy develops in boys with Duchenne muscular dystrophy (DMD) and to analyze the effect of corticosteroid treatment on the age of cardiomyopathy onset.

Study design

We identified a population-based sample of 462 boys with DMD, born between 1982 and 2005, in 5 surveillance sites in the US. Echocardiographic and corticosteroid treatment data were collected. Cardiomyopathy was defined by a reduced fractional shortening (<28%) or ejection fraction (<55%). The age of cardiomyopathy onset was determined. Survival analysis was performed to determine the effects of corticosteroid treatment on cardiomyopathy onset.

Results

The mean (SD) age of cardiomyopathy onset was 14.3 (4.2) years for the entire population and 15.2 (3.4) years in corticosteroid-treated vs 13.1 (4. in non-treated boys. Survival analysis described a significant delay of cardiomyopathy onset for boys treated with corticosteroids (P< .02). By 14.3 years of age, 63% of non-treated boys had developed cardiomyopathy vs only 36% of those treated. Among boys treated with corticosteroids, there is a significant positive effect of duration of corticosteroid treatment on cardiomyopathy onset (P< .0001). For every year of corticosteroid treatment, the probability of developing cardiomyopathy decreased by 4%.

Conclusions

Oral corticosteroid treatment was associated with delayed cardiomyopathy onset. The duration of corticosteroid treatmentalsocorrelated positively with delayed cardiomyopathy onset.Our analysis suggests that a boy with DMD treated for 5 years with corticosteroids might experience a 20% decrease in the likelihood of developing cardiomyopathy compared with untreated boys.

Austrália – o stress oxidativo tem sido implicado na fisiopatologia da distrofia muscular de Duchenne (DMD) e vários antioxidantes têm sido investigados como terapêutica potencial, incluindo a N-acetilcisteina (NAC) e seus precursores como a cisteína e glutationa. Neste estudo a droga L-2-oxotiazolidina-4-carboxilato (OTC) precursora da cisteína e que não é antioxidante foi adminsitrada em camundongos com distrofia muscular. A droga OTC, como a NAC, diminui a oxidação tiol da proteína, diminui a patologia e aumenta a força dos músculos. Os músculos distróficos não apresentaram deficiência em cisteína, mas é deficiente em taurina, uma deficiência que é melhorada pelo tratamento de OTC. Estes dados sugerem que, em músculos distróficos, além da forte associação do aumento do estresse oxidativo e oxidação de proteínas tiol outro grande problema é uma insuficiência de taurina que pode ser corrigido através do aumento da disponibilidade de cisteína. Este estudo fornece uma nova visão sobre o mecanismo molecular de melhora com N-acetilcisteína na distrofia muscular e suporta o uso de OTC como uma droga alternativa para potenciais aplicações clínicas para a DMD.

O resumo em inglês pode ser lido abaixo:

(The International Journal of Biochemistry & Cell Biology, 2013)Treatment with the cysteine precursor L-2-Oxothiazolidine-4-Carboxylate (OTC) implicates taurine deficiency in severity of dystropathology in mdx mice

Jessica R. Terrill, Amber Boyatzis, Miranda D. Grounds, Peter G. Arthur – Australia

Abstract

Oxidative stress has been implicated in the pathology of the lethal skeletal muscle disease Duchenne Muscular Dystrophy (DMD), and various antioxidants have been investigated as a potential therapy. Recently, treatment of the mdx mouse model for DMD with the antioxidant and cysteine and glutathione (GSH) precursor n-acetylcysteine (NAC) was shown to decrease protein thiol oxidation and improve muscle pathology and ex vivo muscle strength. This study further investigates the mechanism for the benefits of NAC on dystrophic muscle by administering L-2-Oxothiazolidine-4-Carboxylate (OTC) which also upregulates intracellular cysteine and GSH, but does not directly function as an antioxidant. We observed that OTC, like NAC, decreases protein thiol oxidation, decreases pathology and increases strength, suggesting that the both NAC and OTC function via increasing cysteine and GSH content of dystrophic muscle. We demonstrate that mdx muscle is not deficient in either cysteine or GSH and that these are not increased by OTC treatment. However, we show that dystrophic muscle of 12 week old mdx mice is deficient in taurine, a by-product of disposal of excess cysteine, a deficiency that is ameliorated by OTC treatment. These data suggest that in dystrophic muscles, apart from the strong association of increased oxidative stress and protein thiol oxidation with dystropathology, another major issue is an insufficiency in taurine that can be corrected by increasing the availability of cysteine. This study provides new insight into the molecular mechanism underlying the benefits of NAC in muscular dystrophy and supports the use of OTC as an alternative drug for potential clinical applications to DMD.