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• Avaliação da atividade física e preservação da função muscular na distrofia muscular de Duchenne: há alguma estratégia preventiva  (24/11/07)

Itália - os autores deste artigo fazem uma discussão sobre os métodos de avaliação da atividade física na distrofia muscular e a quantidade de atividade física que é benéfica para retardar a evolução da doença. É um assunto ainda controverso já que a atividade física excessiva pode ser prejudicial ao músculo. Por outro lado a redução da atividade física associada a um baixo gasto de energia e excesso de alimentação contribui para a obesidade que prejudica o desempenho físico. Há necessidade de estudos experimentais em animais e em humanos para determinar o ponto de equilíbrio em que a atividade física colabora para retardar a evolução da doença.

• Uso de oligonucleotídeos trata a miotonia da distrofia miotônica de camundongos (16/11/07)

USA - a miotonia, ou a incapacidade de relaxamento muscular, é um sinal característico da distrofia miotônica. Pesquisadores americanos identificaram o canal de cloreto relacionado com este sintoma, que está deficiente nesta forma de distrofia. Com a utilização de oligonucleotídeos eles conseguiram que o camundongo com distrofia miotônica apresentasse a expressão da proteína deste receptor e com isto o camundongo não apresentou mais miotonia. O resumo em inglês do artigo pode ser lido abaixo:

(Journal of Clinical Investigation, 2007) Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy

Thurman M. Wheeler¹, John D. Lueck², Maurice S. Swanson³, Robert T. Dirksen² and Charles A. Thornton¹ - USA

In myotonic dystrophy (dystrophia myotonica [DM]), an increase in the excitability of skeletal muscle leads to repetitive action potentials, stiffness, and delayed relaxation. This constellation of features, collectively known as myotonia, is associated with abnormal alternative splicing of the muscle-specific chloride channel (ClC-1) and reduced conductance of chloride ions in the sarcolemma. However, the mechanistic basis of the chloride channelopathy and its relationship to the development of myotonia are uncertain. Here we show that a morpholino antisense oligonucleotide (AON) targeting the 3′ splice site of ClC-1 exon 7a reversed the defect of ClC-1 alternative splicing in 2 mouse models of DM. By repressing the inclusion of this exon, the AON restored the full-length reading frame in ClC-1 mRNA, upregulated the level of ClC-1 mRNA, increased the expression of ClC-1 protein in the surface membrane, normalized muscle ClC-1 current density and deactivation kinetics, and eliminated myotonic discharges. These observations indicate that the myotonia and chloride channelopathy observed in DM both result from abnormal alternative splicing of ClC-1 and that antisense-induced exon skipping offers a powerful method for correcting alternative splicing defects in DM.

• Células tronco derivadas do tecido adiposo melhoram a distrofia muscular de camundongos (15//11/07)

China  -  células tronco derivadas do tecido adiposo foram cultivadas e estimuladas a se diferenciar em células musculares. A aplicação destas células em camundongos com distrofia muscular causou expressão da distrofina e redução do dano muscular. Além disto houve diferenciação destas células tronco em endoteliais o que pode contribuir para a regeneração dos músculos por aumento da vascularização.

• Células tronco derivadas do tecido adiposo restauram a expressão da distrofina em células musculares de Duchenne  in vitro (14//11/07)

Brasil -  o tecido adiposo contém células tronco multipotentes que podem se transformar em músculos como já foi descrito em camundongos; nesta pesquisa as células tronco multipotentes do tecido adiposo obtidas de pacientes que fizeram lipoaspiração foram colocadas em cultura, in vitro,  em contato com células musculares de portadores de distrofia muscular de  Duchenne. A células musculares de Duchenne passaram a expressar distrofina, mostrando o potencial terapêutico destas células, que são descartadas após a lipoaspiração.

• Resumos que serão apresentados no 47th Encontro Anual da Sociedade Americana de Biologia Celular (14//11/07)

USA -  neste encontro que ocorrerá em dezembro de 2007serão apresentados poucos artigos relacionados com a distrofia muscular. Os artigos relacionados com terapia em distrofia muscular são os que analisam a influência da inibição do fator NF-kappa B e da ativação da PI3kinase/Akt na regeneração muscular de camundongos distróficos e o estudo da olopatadina, um inibidor da degranulação dos mástócitos em camundongos com distrofia muscular. Os resumos em inglês podem ser lidos abaixo:

(47th Annual Meeting of American Society of Cell Biology, December 2007)

The Potential Influence of NF-kappaB Down Regulation on the Activity of the PI3/AkT Pathway in Dystrophic (mdx) Skeletal Muscle

B. Lee,¹ G. W. Millman,¹ E. C. Turin,¹ A. Samadi,² C. G. Carlson¹; ¹Physiology, A.T. Still University of Health Sciences, Kirksville, MO, ²Biochemistry, A.T. Still University of Health Sciences, Kirksville, MO

Recent evidence indicating that treatments to reduce the activity of the NF-kappaB pathway may be useful in treating Duchenne and Becker muscular dystrophy (Carlson et al., Neurobiology of Disease, 20 (3):719-730, 2005; Messina et al., Experimental Neurology 198:234-241, 2006; Acharyya et al., J. Clin. Invest. 117, 889-901, 2007) provides the rationale for ongoing experiments which are directed at identifying specific phenotypic endpoints for assessing drug efficacy using the mdx mouse model for Duchenne muscular dystrophy. Consideration of the central importance of the PI3kinase/Akt pathway in promoting the growth and regeneration of skeletal muscle, however, suggests that a combined treatment to reduce the activity of the NF-kappaB pathway and increase PI3kinase/Akt activation may be an appropriate therapy for this group of diseases. In order to investigate this possibility, we have begun to examine the status of the PI3kinase/Akt pathway in costal diaphragm cytosolic extracts obtained from mdx mice treated either acutely or chronically with two inhibitors of the NF-kappaB pathway, pyrrolidine dithiocarbamate (PDTC; 50 mg/kg) and sulfasalazine (SS; 100 mg/kg). Western blots of phosphorylated and total Akt indicate that a single injection of either of these two agents does not modify the activity of the PI3kinase/Akt pathway. Initial experiments suggest that daily treatment of mdx mice with PDTC for a period of at least 30 days may activate the PI3kinase/Akt pathway, but that corresponding treatment with sulfasalazine has no effect on the proportion of phosphorylated Akt. Although it is currently unclear whether chronic treatment with these established NF-kappaB inhibitors effectively down regulates nuclear NF-kappaB activation in dystrophic skeletal muscle, these preliminary results suggest that chronic treatment with NF-kappaB inhibitors that reduce IkappaB-alpha kinase activity (IKK) may be used in conjunction with PI3kinase/Akt activation to judiciously enhance muscle regeneration in dystrophic skeletal muscle.

Evaluation of the Effectiveness of a Mast Cell Degranulation Inhibitor in Dystrophic mdx Mice

D. D. Araujo,^1,2 F. S. M. Pires,² T. T. Fuzisaki,² J. C. S. Bizario,² M. R. Costa^1,2; ¹Cellular Molecular Biology, University of São Paulo, Ribeirão Preto, Brazil, ²Medicine School, University of Ribeirão Preto, Ribeirão Preto, Brazil

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration which results from the absence of dystrophin. The dystrophin deficient mdx mouse, the most widely used animal model for DMD, shows milder phenotype that can be intensified by compulsory physical activity. Inflammatory response and immune cells contribute to muscle degeneration and/or regeneration. Mast cells are recruited to the injury sites and liberate mediators that increase collagen production, attract other inflammatory cells and intensify tissue damage. Olopatadine, an H1-histamine antagonist and a mast cell degranulation inhibitor, decreases Ca²⁺ influx and the liberation of histamine, tryptase, leukotrienes and prostaglandins. In this study, we evaluated the effect of 10 mg/kg/day olopatadine in male mdx mice submitted to physical activity (20 minutes of treadmill running at 20 cm/s, 3 times a week, during 5 weeks). To characterize the experimental groups (treated and untreated) before (4 week old mdx) and after (9 week old mdx) of the physical activity program, we used the following parameters: i) measurement of body weight and serum creatine kinase; ii) qualitative and quantitative histopathological analyses of gastrocnemius and diaphragm (Evans Blue Dye infiltration and H&E staining to evaluate myofibers morphology, the presence of inflammatory infiltrates, peripherally and centrally nucleated myofibers, and grouped regenerating myofibers). The results showed that the 9 week old olopatadine treated mice presented significant reduction in the CK levels and amelioration of the muscular condition. We detected significant reduction in the number of myofibers with sarcolemma injury but no difference in the number of centrally nucleated myofibers. The analysis of the individual values suggests a trend to reduction in the inflammatory infiltrate area and in the degeneration/regeneration ratio. These data suggest that the inhibition of mast cell is beneficial to retard the dystrophinopathy progress and can be considered as an option to clinical trials for DMD.

• Empresa neozelandeza divulga avanço no tratamento da distrofia muscular em camundongos (14/11/07)

Nova Zelândia - a empresa Orico, que tem patentes de várias substâncias que podem inibir a miostatina, anunciou que teve bons resultados em camundongos com distrofia muscular no aumento da regeneração e retardo na evolução da doença. Não se trata de um tratamento para curar a doença mas sim para retardar a sua evolução. A droga ainda precisa ser testada em seres humanos. As informações fornecidas pela empresa são genéricas como poder ser vista no site: http://www.orico.co.nz/muscle_therapeutic_development_program/; as patentes que a droga possuí podem ser vistas nesta página: http://www.orico.co.nz/intellectual_property_and_publications/

• Resumos apresentados no Encontro Anual da Associação Americana de Cardiologia (10/11/07)

USA - nesta semana, no Encontro Anual da Associação Americana de Cardiologia, foram apresentados 3 trabalhos relacionados com as distrofias. O primeiro refere-se ao uso do carvedilol no tratamento da disfunção cardíaca da distrofia muscular de Duchenne. Neste estudo os autores estudam a dosagem da troponina, uma proteína presente somente no músculo cardiaco e relacionada ao dano do músculo cardíaco e que se reduz no sangue dos pacientes tratados com carvedilol. No segundo trabalho, em camundongos com distrofia tipo cinturas, os pesquisadores injetaram por via venosa um vetor viral com o gene para corrigir a doença. Os camundongos tratados apresentaram expressão do gene no miocárdio, com prevenção do dano muscular cardíaco. O terceiro trabalho analisa o dano cardíaco através da ressonância nuclear magnética. Os resumos estão apresentados abaixo:

(American Heart Association Annual Meeting, 2007) 1) Minor Myocardial Damage and LV Dysfunction in Patients with Duchenne Muscular Dystrophy -The Preventive Efficacy of Carvedilol on Plasma Cardiac Troponin I-

Takao Nishizawa; Fumihiko Yasuma; Motoko Sakai; Satoshi Kuru; Seigo Kimura; Rei Shibata; Taiki Ohashi; Akiko Noda; Hideo Izawa; Kohzo Nagata; Mitsuhiro Yokota; Masaaki Konagaya; Toyoaki Murohara - Japan

Background: Cardiac dysfunction is one of the major prognostic factors in patients with Duchenne muscular dystrophy (DMD). Minor myocardial damage assessed by plasma cardiac troponin I (cTnI) is often observed in patients with DMD. However, it is unclear that how the minor myocardial damage occurs to which patient with DMD and how it relates to LV dysfunction. Therefore, we assessed the hypothesis that minor myocardial damage is associated with LV dysfunction, the evaluation of plasma cTnI helps the prediction of LV functional deterioration, and carvedilol prevents elevation of plasma cTnI in patients with DMD.

Methods: Plasma cTnI were repeatedly (every 3 months) measured for 2 years and LV function was assessed by echocardiography in 58 patients with DMD. Carvedilol (2.5–5 mg/day) was orally administered for a year to the patients who have shown plasma cTnI elevation (positive cTnI, cut off 0.06ng/mL).

Results: There were 3 differential groups regarding the progression rate of LV systolic dysfunction, i.e. rapid (19% of total, LVEF < 50% in their 10^th), slow (50% of total, LVEF > 50% in their 20 –30^th), and unchanged group (31% of total, LVEF < 50% in their 20 –30^th). The episode of positive cTnI was observed in 27 (46%) of total patients with DMD. LVEF was lower in patients with positive cTnI than that with negative cTnI (42 ± 2 vs. 52 ± 2%, p < 0.05). Positive cTnI was observed in all patients in rapid group, 84% of patients in slow group, and only 6% of patients in unchanged group. Fourteen differential dystrophin gene mutations were recognized in 48 patients but they were not associated with those 3 differential groups or patients with positive cTnI. Administration of carvedilol in 13 patients (LVEF 40 ± 3) decreased the cTnI detection rate (from 44 ± 5% to 26 ± 10%, p < 0.05), while it was unchanged in 14 patients (LVEF 41 ± 3) without carvedilol treatment (from 44 ± 7% to 39 ± 6%) during same observation period.

Conclusions: The elevation of plasma cTnI was associated with LV systolic dysfunction in patients with DMD. The prediction of LV dysfunction in patients with DMD may be feasible with combinations of age, LVEF, and plasma cTnI elevation. Carvedilol could be a new therapeutic strategy to prevent minor myocardial damage in patients with DMD.

2) Prevention of Heart Failure in delta-Sarcoglycan Knock-Out Mice after Intravenous Gene Transfer with Targeted Adeno-Associated Viral (AAV) Vectors

Caroline Goehringer; Désirée Rutschow; Stefanie Schinkel; Raffi Bekeredjian; Ralf Bauer; Dieter Weichenhan; Jürgen A Kleinschmidt; Hugo A Katus; Oliver J Müller - Germany

Background: Delta-Sarcoglycan (SGCD) is a member of the dystrophin-associated glycoprotein complex. Mutations may result in isolated dilated cardiomyopathy or limb-girdle muscle dystrophy 2F with variable cardiac involvement. A potential gene therapeutic approach requires an efficient myocardial gene transfer. AAV vectors are suitable for cardiac gene transfer. Novel AAV serotypes such as AAV-8 or -9 even enable a systemic gene transfer in rodents. Aim of our study was to establish a vector for efficient systemic cardiac gene transfer and its subsequent use to prevent heart failure by expressing the SGCD cDNA in SGCD knock out mice.

Material and Methods: 10¹¹ genomic particles of AAV-8 and -9 vectors harboring a luciferase reporter gene under control of the CMV-enhanced myosin light chain promoter were intravenously injected into adult NMRI mice (n=6 and n=10, respectively). After 4 weeks, reporter activities were determined in representative organs. Analogous, 2x10¹¹ AAV-9 SGCD and AAV-9 EGFP vectors were intravenously injected in SGCD knock out mice (n=9 and n=7, respectively). Cardiac function (fraction of shortening) was assed by echocardiography at the beginning and the end of the study after 6 months. Running distances were measured using voluntary wheel running.

Results: Reporter gene transfer with AAV-9 vectors resulted in increased cardiac luciferase activities compared to AAV-8 (3.8x10⁸ ±4.4x10⁸ relative light units [RLU]/mg protein versus 0.10x10⁸ ±0.08x10⁸ RLU/mg protein, p=0.05) with increased specificity. In comparison to EGFP controls, AAV-9 delta-sarcoglycan gene transfer resulted in a significant increase in running distance and a significant decrease in decline in fraction of shortening (67.6% to 65.0% versus 69.9% to 58.1%; p=0.04). Immunohistochemical analyses in AAV-9 SGCD treated knock-out mice revealed a transmural reconstitution of more than 90% of cardiomyocytes.

Conclusion: Intravenous injections of AAV-9 SGCD vectors enable an efficient transmural cardiac gene transfer in adult mice and prevent deterioration of left ventricular function in SGCD knock out mice. Therefore, this vector system may be suitable for validation of novel targets for cardiac diseases

3) Abnormal Myocardial Circumferential Strain Precedes Global Functional Decline in Duchenne Muscular Dystrophy: A Cardiac Magnetic Resonance Tagging Study Using HARP Analysis

Kan N Hor; Larry W Markham; Janaka Wansapura; Wojciech Mazur; Linda Cripe; D. Woodrow Benson; William M Gottliebson - USA

BACKGROUND: Duchenne Muscular Dystrophy (DMD), an x-linked myopathy, is characterized by progressive cardiac dysfunction and myocardial fibrosis late in the disease process. We hypothesized that left ventricular myocardial peak circumferential strain (_cc) abnormalities would exist in DMD prior to global systolic functional abnormalities regardless of age or left ventricular ejection fraction (EF).

METHODS: We evaluated 33 DMD males undergoing clinical cardiac MRI. Comparison was made to 13 age-matched healthy volunteers. Standard imaging included short-axis cine stack, cine myocardial tagging and myocardial delayed enhancement (MDE). Cardiac functional analysis was performed using Medis MASS software. Tagged images of only the mid-LV were analyzed using HARP software. For analysis, DMD males were subdivided by age: < or > 10 years. All subjects < 10 years had normal EF (>55%); none exhibited MDE. Subjects >10 years were divided by MDE status and EF (>55% or <55%). Student’s t-test was used to test for differences between groups.

RESULTS: DMD subjects with normal EF had abnormal _cc at an early age (<10 years) compared to control subjects (p< 0.05). DMD subjects >10 years with normal EF had further decline in =_cc compared to younger DMD boys (p<0.05). There was further decline with age in =_cc in subjects with lower EF (p<0.05) without MDE. In the oldest males studied with MDE and reduced EF, _cc was even lower (figure).

CONCLUSIONS: Myocardial strain abnormalities are prevalent in the early stages of DMD existing in the setting of normal EF and progressing with advances in age. Such strain analysis may provide an early marker to guide the efficacy of preventive or gene therapy in DMD.

• Entrevista da Dra Ana Lúcia na TV Gazeta sobre as distrofias musculares (04/11/07)
• Santhera divulga primeiros resultados com a droga SNT-MC17 em pacientes com distrofia muscular de Duchenne  (02/11/07)

Suiça - a empresa suiça Santhera divulgou esta semana os primeiros resultados da fase IIa do tratamento de pacientes com distrofia muscular de Duchenne por 12 meses com a droga SNT-MC17. A pesquisa foi realizada em 21 pacientes com idade de 8 a 16 anos.  Oito receberam a droga e 8 foram acompanhados sem o tratamento. Não houve efeitos colaterais nos pacientes tratados e a tolerância do medicamento foi boa. Houve uma tendência para a melhora da função cardíaca e melhora da função respiratória nestes pacientes tratados. A empresa vai prosseguir com os estudos da droga aumentando o número de pacientes tratados.

• Novo vídeo sobre alongamento na distrofia muscular de Duchenne (02/11/07)

USA - o vídeo foi produzido e distribuído pelo Parent Project USA e mostra exercícios de alongamento que podem ser realizados pelas próprias crianças e pelos pais. A descrição dos exercícios está em inglês mas permite pelas imagens entender o que deve ser feito.