Muscular dystrophy is a genetic disease which affects the morphology, physiology and biochemical nature of the muscle fiber. This study was designed to examine the progressive effects of muscular dystrophy on the differentiation process of skeletal muscle. Chapter 1 examines the neonatal development of muscle spindles and their intrafusal fibers in the soleus and extensor digitorum longus (EDL) of genetically dystrophic mice according to histochemical, quantitative, and ultrastructural parameters. Despite alterations in the surrounding extrafusal fibers, muscle spindles and their intrafusal fibers appeared enzymatically and histologically unaffected in incipient stages of murine dystrophy. In the second chapter the distribution and concentration of parvalbumin (PV), a calcium-binding protein, in 32 and 2-week-old dystrophic mice was mapped by immunohistochemical and biochemical procedures. The number of parvalbumin-immunoreactive fibers was significantly reduced in the adult dystrophic EDL but slightly increased in the adult dystrophic soleus. No differences between strains were observed in the 2-week samples. These findings were supported by routine myosin ATPase histochemistry. Parvalbumin was isolated on SDS-PAGE gels and the concentration of PV was estimated by a RIA. These results confirmed the immunohistochemical data in that PV content was dramatically reduced in the adult dystrophic EDL and significantly increased in the dystrophic soleus. No changes were detected in the samples of the 2-week-old muscles. The similarity in the distribution and content of PV between the fast and slow dystrophic muscles at 32 weeks of age suggests an alteration in the distribution and phenotypic expression of fiber types in muscular dystrophy and supports the hypothesis that dystrophy alters the normal differentiation process of skeletal muscle. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Introduction/Aims Duchenne and Becker muscular dystrophies (DBMD) are X-linked neuromuscular disorders characterized by progressive muscle weakness, leading to decreased mobility and multisystem complications. We estimate productivity costs attributable to time spent by a parent caring for a male child under the age of 18 y with DBMD, with particular focus on female caregivers of boys with Duchenne muscular dystrophy (DMD) who have already lost ambulation. Methods Primary caregivers of males with DBMD in the Muscular Dystrophy Surveillance and Research Tracking Network (MD STARnet) were surveyed during 2011–2012 on family quality of life measures, including labor market outcomes. Of 211 respondents, 96 female caregivers of boys with DBMD were matched on state, year of survey, respondent's age, child's age, and number of minor children with controls constructed from Current Population Survey extracts. Regression analysis was used to estimate labor market outcomes and productivity costs. Results Caregivers of boys with DBMD worked 296 h less per year on average than caregivers of unaffected children, translating to a $8816 earnings loss in 2020 U.S. dollars. Caregivers of boys with DMD with ≥4 y of ambulation loss had a predicted loss in annualized earnings of $23,995, whereas caregivers of boys with DBMD of the same ages who remained ambulatory had no loss of earnings. Discussion Female caregivers of non-ambulatory boys with DMD face additional household budget constraints through income loss. Failure to include informal care costs in economic studies could understate the societal cost-effectiveness of strategies for managing DMD that might prolong ambulation.

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Skeletal muscle regeneration is a multifaceted process requiring the spatial and temporal coordination of myogenesis as well as angiogenesis. While these processes are often studied independently, recent evidence from our lab has shown that the resident adult stem cell population within skeletal muscle, called satellite cells, begins secreting soluble growth factors likely to contribute to the proangiogenic response. The overall aim of this study is to investigate the role of pro-angiogenic factors secreted by satellite cells during skeletal muscle regeneration. Results from the study indicate that Hepatocyte Growth Factor (HGF) is a critical protein for the proangiogenic effect of satellite cells. It was also shown that in hypoxic environments, such as those seen in an injury state, it appears that satellite cells decrease their proangiogenic effect if oxygen levels fall below a threshold level. This decrease in pro-angiogenic effect in the hypoxic environment appears to be due to the decrease in HGF expression and protein secretion and is not compensated for by the increase in Vascular Endothelial Growth Factor secretion also seen in the hypoxic response. Furthermore, the regulation of HGF in these hypoxic conditions appears to be in part due to increased levels of hypoxia inducible factor, which are acting on the hypoxia response element site found on the HGF promoter. In the last set of experiments, this injury response was further investigated as the effect of satellite cell mediated angiogenesis was examined in the disease state of muscular dystrophy. Here, we also observed a reduction in angiogenesis from media conditioned by satellite cells from dystrophic muscle compared to healthy muscle. Overall, this study further strengthens the case for satellite cells as important mediators of the angiogenic response in regenerating muscle and may serve as a potential site for therapeutic intervention in the future.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused, in most cases, by the complete absence of the 427 kD cytoskeletal protein, dystrophin. Without dystrophin, the dystrophin-associated protein complex (DAPC) does not form and the plasma membrane is destabilised. There is no effective treatment and affected individuals die from respiratory failure and cardiomyopathy by age 30. This thesis describes experiments in which in vivo cardiac function was measured using non-invasive magnetic resonance imaging in a number of mouse models relevant to muscular dystrophy. As syncoilin forms a link from the DAPC to the cytoskeleton, it was postulated in Chapter 3 that the syncoilin knockout mouse would have cardiac defects similar to those caused by the loss of dystrophin. However, the loss of syncoilin did not alter the protein levels of its binding partners, measured by western blotting, and caused no defect in heart function or structure, measured using histological staining. Similarly, in Chapter 4, a mouse with a mutation in the transient receptor potential channel canonical type 3 (TRPC3), a receptor/stretch-activated cation channel thought to be involved in the pathogenesis of DMD, was found to have no functional or morphological cardiac defect. In the mdx mouse, a mouse model of DMD that lacks dystrophin, cardiomyopathy was prevented by either increasing levels of the dystrophin related protein, utrophin, or of dystrophin, in the diaphragm, which thereby restored diaphragm function. In Chapter 5 it was found that in a transgenic mdx mouse in which utrophin was over-expressed in skeletal muscle and diaphragm, but not in the heart, cardiac function was restored to wild-type levels. However, histologically the transgenic heart showed more fibrosis and immune cell infiltration than that of untreated mdx controls. In Chapter 6 it was found that in mdx mice treated with a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO), that resulted in high dystrophin restoration in skeletal muscle and diaphragm only, cardiac function was also restored to wild-type levels. In Chapter 6 it was also found that in dystrophin/utrophin-deficient double-knockout (dKO) mice, a more severely affected animal model of DMD, treatment with a PPMO again produced high levels of dystrophin only in skeletal muscle and diaphragm, and once more restored cardiac function to wild-type levels. In the dKO mouse, there was no difference in heart function between treatment of the diaphragm plus the heart and treatment of the diaphragm alone. Restoration of diaphragm and other respiratory muscle function, irrespective of the method used, was sufficient to prevent cardiomyopathy in dystrophic mice. The novel mechanism of treating respiratory muscles to prevent cardiomyopathy in dystrophic mice has implications for the study of heart function in the current DMD mouse models and suggests a new approach to treatment.

Introdução: A Distrofia Muscular de Duchenne (DMD) é uma doença genética que causa limitações físicas e motoras progressivas, além de alterações da função pulmonar em fase mais tardia. A escala da medida da função motora (MFM) e do teste de caminhada de 6 minutos (TC6) são ferramentas confiáveis e precisas para avaliar pacientes com DMD. A capacidade de realização desses testes pode ser influenciada pela condição cardiorrespiratória, resistência e força muscular, mas ainda não está bem definido qual, ou quais, destas variáveis podem interferir de forma mais significativa na função motora e na capacidade funcional de exercício. Objetivo: Avaliar a função motora por meio da MFM e correlacionar com a função pulmonar e capacidade funcional de exercício em pacientes com DMD. Métodos: Trata-se de um estudo transversal que envolveu 61 voluntários com DMD submetidos a um protocolo de avaliação composto por informações pessoais, antropometria, escala MFM, espirometria (CVF,VEF1,VEF1/CVF, FEF25-75, PFE, CVL, VVM), ventilometria (VC, VM e CVL), pico de fluxo expiratório (PFE) e pico de fluxo de tosse (PFT) no medidor portátil, pressão inspiratória máxima (PImax) e pressão expiratória máxima (PEmax), pressão inspiratória nasal (SNIP), oscilometria de impulso (R5, R20, R5-R20, X5) e TC6. Foi realizada a análise de correlação entre as variáveis e posteriormente a comparação entre os grupos de voluntários deambuladores e não deambuladores. Resultados: A média de idade dos voluntários foi de 13,70±3,93. Na espirometria, houve correlação positiva do escore total, domínios 1(D1) e 2 (D2) da MFM com a porcentagem do previsto da CVF% (r=0,58, r=0,51, r=0,57, respectivamente), correlação negativa do escore total, domínios 1, 2 e 3 com VEF1/CVF (r=-0,61, r=-0,57, r=-0,49 e r=-0,49, respectivamente), correlação negativa do escore total, domínio 1 e domínio 3 com o FEF25-75% (r=-0,48, -0,47, -0,42, respectivamente). Na manobra de PFE realizada no medidor portátil, houve correlação do PFE% com o escore total e todos os domínios da MFM. O escore total, domínio 1, 2 e 3 se correlacionaram positivamente com os valores percentuais da PEmax (r=0,67, r=0,60, r=0,63 e 0,42, respectivamente) e SNIP (r=0,56, r=0,42, r=0,64 e r=0,45, respectivamente). Na oscilometria de impulso (IOS), houve correlação da resistência total (R5) com o escore total, domínio 1 e 2 (r=0,55; r=0,52 e r=0,50, respectivamente) e resistência central (R20) com o escore total, domínios 1 e 2 (r=0,52; r=0,51 e r=0,45, respectivamente); correlação da resistência periférica (R5-R20) com o escore total (r = 0,46) e domínio 2 (r=0,49), e da reatância (X5) com o escore total, D1 e D2(r=-0,43; r=- 0,40 e r=-0,36, respectivamente). No TC6, a distância em metros foi de 294,75±96,97 e se correlacionou fortemente com a MFM, e a percepção da dispneia relatada no TC6 se correlacionou negativamente com o domínio 3 daMFM (r=-0,75). Na análise comparativa entre os grupos de deambuladores (D) e não deambuladores (ND), o IOS demonstrou valores obtidos significativamente menores no grupo ND de R5, R20, R5-R20, X5 e da porcentagem do previsto de R5-20. No mesmo grupo (ND), a espirometria demonstrou valores obtidos significativamente maiores de VVM, da VEF1/CVF, FEF25-75 e porcentagem do previsto de VEF1/CVF, além da diminuição da porcentagem do previsto da CVF, PFE no medidor portátil, PEmax, SNIP e MFM (escore total e domínios 1,2 e 3). Conclusão: A diminuição da MFM se correlacionou com a diminuição da resistência e reatância das vias aéreas, com a diminuição da PEmax, SNIP e da CVF. Além desses parâmetros, houve correlação da diminuição da MFM com o aumento dos valores de PFE, FEF25-75 e VEF1/CVF. Na comparação entre os grupos, os resultados confirmam o que foi encontrado nas correlações no grupo de pacientes que não deambulavam, com diminuição das resistências e reatância das vias aéreas, da força muscular respiratória e valores maiores de volume (VEF1/CVF) e fluxo pulmonar (FEF25-75). Apesar da forte correlação entre a distância percorrida no teste de caminhada com a função motora, não houve alteração dos dados vitais, o que pode indicar que os pacientes não atingiram o esforço submáximo estimado / Introduction: Duchenne Muscular Dystrophy (DMD) is a genetic disease which causes progressive physical and motor limitations, including alterations to the pulmonary function in later stages. The scale of the motor function measure (MFM) and of the six minute walking test (TC6) are reliable and precise tools to assess DMD patients. The possibility of performing these tests may be influenced both by the patient\'s cardiopulmonary condition, resistance and muscular strength. However, it has not been yet demonstrated which of these variables can have the most significant impact on the patient\'s motor function and functional capacity of exercise. Objective: To assess the motor function though the application of the MFM scale and correlate it with the pulmonary function and functional capacity of exercise on DMD patients. Methodology: The approach adopted in this study consisted of a transversal analysis involving sixty one DMD patients who have volunteered to submit themselves to an evaluation protocol which includes the following parameters: personal information, anthropometry, MFM scale, spirometry (CVF,VEF1,VEF1/CVF, FEF25-75, PFE, CVL, VVM), ventilometry (VC, VM e CVL), peak expiratory flow (PFE) and peak cough flow (PFT) according to the portable meter measurements, maximum inspiratory pressure (PImax), maximum expiratory pressure (PEmax), nasal inspiratory pressure (SNIP), impulse oscillometry (R5, R20, R5-R20, X5) and TC6. The study focused on the analysis of the correlation between variables, followed by a comparison between two groups of patients: wanderers and non-wanderers. Results: The average age of patients was 13,70±3,93. On spirometry, there was a positive correlation between the total score, domains 1(D1) and 2 (D2) of the MFM and the expected CVF percentage (r=0,58, r=0,51, r=0,57, respectively); there was a negative correlation between the total score, domains 1, 2 and 3 and VEF1/CVF (r=-0,61, r=-0,57, r=-0,49 and r=-0,49, respectively), as well as a negative correlation between domain 1, domain 3 and FEF25-75% (r=-0,48, -0,47, -0,42, respectively). On the PFE maneuver performed using the portable meter, there was a correlation between the expected PFE percentage, the total score and all MFM domains. The total score and domains 1, 2 and 3 had a positive correlation with the percentage values of PEmax (r=0,67, r=0,60, r=0,63 and 0,42, respectively) and SNIP (r=0,56, r=0,42, r=0,64 and r=0,45, respectively). Regarding the impulse oscillometry system (IOS), there was a correlation between the total resistance (R5), the total score and domains 1 and 2 (r=0,55; r=0,52 and r=0,50, respectively); and between the central resistance (R20) and total score, domains 1 and 2 (r=0,52; r=0,51 and r=0,45, respectively); in addition, there were correlations between the peripheral resistance (R5-R20), the total score (r = 0,46) and domain 2 (r=0,49), as well as between the reactance (X5) and total score, D1 and D2(r=-0,43; r=-0,40 and r=-0,36, respectively). Thedistance in meters reached in the TC6 was of 294,75±96,97 and had a strong correlation with the MFM. The perception of dyspnoea reported through the TC6 had a negative correlation with domain 3 of the MFM (r=-0,75). On the comparative analysis between groups of wanderers (D) and non-wanderers (ND), the IOS has shown significantly lower values in the group of ND (R5, R20, R5- R20, X5), as well as on the expected percentage of R5-20. In the same group (ND), the spirometry has shown significantly higher values of VVM, VEF1/CVF, FEF25-75 and the expected percentage of VEF1/CVF; in addition to a reduction of the expected percentage of CVF and PFE on the portable meter, PEmax, SNIP e MFM (total score and domains 1, 2 and 3). Conclusion: The reduction of the MFM correlates with the reduction of airways resistance and reactance, and with the reduction of PEmax, SNIP and CVF. In addition to these parameters, there was a correlation between the MFM reduction and the increase of the PFE, FEF25- 75 e VEF1/CVF values. In the comparison between groups, the results confirm the findings in the correlations of the non-wanderers group, with reduction of the airways resistance and reactance, of the respiratory muscular strength and higher volume values (VEF1/CVF) and pulmonary flow (FEF25-75). Despite the strong correlation between the distance covered during the walking test and the motor function, there was no alteration on vital indicators, which may point out to the fact that the patients did not achieve the expected sub-maximum effort level

O objetivo deste estudo foi avaliar o efeito do uso noturno ou diurno da ankle-foot orthosis (AFO) na biomecânica da marcha de pacientes com DMD. Foram avaliados 20 pacientes deambuladores, do Ambulatório de Miopatias Infantis do CER do HCFMRP-USP, com diagnóstico de distrofia muscular de Duchenne (DMD), com idades entre 4 e 12 anos. Foi realizada a avaliação inicial (Av1) em todos os pacientes e, 7 pacientes foram reavaliados após 6 meses (Av2). Na Av1, os pacientes foram agrupados conforme o uso da órtese: grupo sem órtese (SO; n=7), grupo órtese noturna (ON; n=7), grupo órtese diurna (OD; n=6). Na Av1 e na Av2 foram obtidos dados de massa corporal, altura, composição corporal pela bioimpedância elétrica, escore funcional pela escala medida da função motora, amplitude passiva de movimento articular, força muscular isométrica pelo dinamômetro Handheld e avaliação biomecânica da marcha, na velocidade habitual do paciente. Os pacientes que faziam uso da órtese diurna foram avaliados sem e com órtese, sendo denominados grupos ODs e ODc, respectivamente. Os dados foram analisados de três formas: duas transversais e uma longitudinal. Nas análises transversais, foram realizados dois procedimentos: (i) comparando dados dos grupos SO x ON x ODs; (ii) comparando dados dos grupos SO x ON x ODc. Nestas, foi utilizado o teste ANOVA, considerando um nível de significância de 5%. Na análise longitudinal, foi realizada a análise descritiva comparando os dados obtidos na Av1 e Av2, individualmente para os 7 pacientes reavaliados. Transversalmente, o grupo ODc apresentou maiores picos do ângulo de dorsiflexão e do momento dorsiflexor, menor ângulo de flexão plantar e menor geração de potência de tornozelo (p<0,05) que o grupo SO. Porém, ao caminhar sem a AFO (grupo ODs) estes resultados não foram observados (p>0,05). Em relação ao grupo ON, o grupo ODc obteve menores picos do ângulo de flexão do quadril, de absorção de potência de quadril, do ângulo de flexão plantar e maior pico do momento dorsiflexor (p<0,05), sendo que ao retirar a AFO (ODs) essas diferenças não foram observadas (p>0,05). E ainda, o grupo ON obteve maior pico do ângulo de flexão do joelho e menor momento flexor de quadril (p<0,05) em relação ao grupo ON. Na comparação dos dados entre os grupos SO e ON, o grupo ON obteve maior pico do ângulo de flexão do joelho e maior absorção de potência de quadril (p<0,05). Na análise longitudinal individual foi observado que os 2 pacientes que iniciaram precocemente e mantiveram o uso noturno da AFO apresentaram na Av2 maior velocidade da marcha, maiores momentos extensor de quadril e flexor plantar e maior geração de potência de tornozelo, contrariamente aos paciente que interromperam o uso (noturno ou diurno) da AFO. Conclui-se que o uso diurno da AFO acarretou alterações positivas na biomecânica da marcha, minimizando compensações típicas da DMD na articulação do tornozelo. O uso noturno da AFO, quando iniciado precocemente, também afetou positivamente a marcha dos pacientes. Assim, sugere-se o início precoce e contínuo do uso diurno e noturno da AFO aos pacientes com DMD. / The aim of this study was to evaluate the effect of the ankle-foot orthosis (AFO) during nocturnal or daytime usage of the gait biomechanics in patients with Duchenne Muscular Dystrophy (DMD). Twenty ambulant patients from the Myopathies Infant Ambulatory of CER - HCFMRP-USP, were diagnosed with DMD between the ages of 4 and13 years and were evaluated. The initial evaluation (Ev1) was performed in all patients, and 7 patients were reevaluated after 6 months (Ev2). In Av1, patients were grouped according to orthosis use: group without orthosis (NoO, n = 7), group with nocturnal orthosis (NiO, n = 7), group with daytime orthosis (DO, n = 6). In Ev1 and Ev2 data were obtained according to the weight, height, body composition (bioelectrical impedance), functional score (Measure scale of motor function), passive joint range of motion, isometric muscle strength (dynamometer Handheld) and biomechanical gait analyses (usual velocity for the patient). Patients who used the daytime orthosis were evaluated with and without bracing, respectively. The data were analyzed in three ways; the first two were cross-sectional and the other one was longitudinal. In the cross-sectional analyzes, an exploratory analysis of the data from each evaluation was performed, and subsequently, the variables were compared between groups, considering the means and standard deviations. ANOVA test was used, and it was considered a significant level of 5%. In the longitudinal analysis, the description of the data obtained in the evaluation 1 compared to the data obtained in the evaluation 2 was individually performed in the 7 patients who were reevaluated. A cross-sectional analysis compared the data between NoO x NiO x DO groups considering the gait analysis data from the DO group without the orthosis (barefoot), being named DOno. The other cross-sectional analysis compared the data between NoO x NiO x DO groups considering the gait analysis data from the OD group with orthosis, being named DOwith. In individual longitudinal analysis, it was observed that patients who had started early and kept the nocturnal usage of AFO which has been already showed, in six months, an increment of gait velocity, hip extensor and plantar flexor moments and also the increment of ankle power generation, which is the opposite of the patient who has discontinued the AFO usage (daytime or nocturnal). In the cross-sectional analyzes it was observed that, compared to the NoO group, the DOwith group had a higher dorsiflexion angle peak and higher dorsiflexor moment peak (p<0.05). However, when they walked without the device these results were not maintained. There was no difference (p>0.05) between DOno and NoO groups for the kinematic parameters. And, the DOno group had lower plantar flexor moment maximum peak than the SO group (p>0.05). It was concluded that AFO daytime use cause positive changes in gait biomechanics, minimizing typical compensation of DMD in the ankle joint. The night use of AFO, when started early, also positively affected the gait of patients. Thus, it is suggested early prescription of daytime and nocturnal usage of AFO for DMD patients.

A distrofia muscular de Duchenne constitui um distúrbio genético de caráter recessivo e caracteriza-se pela deficiência ou ausência da proteína distrofina na superfície da membrana da célula muscular, podendo acometer a musculatura cardíaca e o sistema nervoso. O cão da raça Golden Retriever afetado pela distrofia muscular (GRDM), é considerado um excelente modelo para o estudo, devido às muitas similaridades entre cães afetados e meninos com distrofia muscular de Duchenne. Sabe-se que os animais do modelo GRMD apresentam fraqueza muscular progressiva, o que gera adaptações importantes na sua marcha. O conhecimento destas adaptações na ausência da musculatura esquelética pode esclarecer a evolução da doença neste modelo, bem como contribuir com uma nova ferramenta de avaliação quantitativa de futuros tratamentos da DMD. Portando este estudo abordou as variáveis da marcha do cão GRDM com o objetivo de estabelecer uma ferramenta de avaliação quantitativa da marcha neste modelo experimental que possa contribuir para futuras pesquisas terapêuticas além de colaborar com o conhecimento e aplicabilidade da biomecânica na marcha animal. Foram utilizados seis animais distróficos selecionados da colônia de cães GRMD Brasil. Foram feitas mensuração dos segmentos corporais, analise cinemáticas através da utilização de imagens e análise dinâmica resultando da utilização de uma plataforma de força. Nos resultados da biometria obtivemos a média dos segmentos corporais dos seis animais estudados: braço: 16,69cm; antebraço 17,12cm; carpo 5,16cm; coxa 18,91cm; perna 19,03cm; tarso 10,98cm; tórax 67.54cm; altura 52,14cm; e peso 20,44kg. Nos resultados referentes à análise cinemática obtivemos o grau de flexão e extensão das seguintes articulações: escapuloumeral (flexão: 121.44° e extensão 152.76°), umeroradioulnar (flexão 121.68° e extensão 153.24°), carpo (flexão 122.2° e extensão 152.84°), coxofemoral (flexão 122.08° e extensão 153.96°), femortibiopatelar (flexão 121.2° e extensão 151.64°), tarso (flexão 121.48° e extensão 153.44°). Na análise dinâmica obtida através da plataforma de força obtivemos a média dos valores dos picos de força de reação ao solo de cada um dos animais: Biz 141N, Gaspar 128N, Lola 180N, 183N, 150N, 135N. Com esses resultados podemos concluir que a articulação femortibiopatelar foi a que teve um grau de amplitude maior em relação às outras articulações; os picos de flexão e extensão articular variam de acordo com cada articulação; os picos de flexão e extensão variam mais no membro pélvico do que no membro torácico. Os resultados obtidos podem ser úteis em avaliações pré-clinicas utilizando o modelo canino GRMD. / Duchenne muscular dystrophy is a genetic disorder with a recessive trait and is characterized by a deficiency or absence of dystrophin protein on the membrane surface of muscle cells, affecting the heart muscles and nervous system. The dog Golden Retriever affected by muscular dystrophy (GRDM) is considered an excellent model for the study because of the many similarities between affected dogs and boys with Duchenne muscular dystrophy. It is known that the animal model GRMD have progressive muscle weakness, which leads to major changes in their gait. Knowlege of these adaptations in the absence of skeletal muscles can account for disease progression in this model as well as helping with a new tool for quantitative evaluation of future treatments for DMD. Porting this study addresses the variables of walking the dog GRDM in order to establish a tool for quantitative assessment of gait in this experimental model that may contribute to future therapeutic research and collaborate with the knowledge and applicability of animal gait biomechanics. We used six dystrophy animals selected from the colony of dogs GRMD Brazil. Analysis was carried out of the body segments of biometrics, using kinematic and dynamic analysis of resulting from image and use of a force platform. The results obtained from the average of the biometrics body segments of the six animals studied: arm: 16,69cm; forearm17,12cm; carpus 5,16cm; thigh18,91cm; leg 19,03cm; tarsus 10,98cm; chest 67.54cm; height 52,14cm; e weight 20,44kg. In the kinematic analysis results obtained regarding the degree of flexion and extension of the following joints: escapuloumeral (flexion: 121.44° and extension 152.76°), umeroradioulnar (flexion 121.68° and extension 153.24°), carpo (flexion 122.2° and extension 152.84°), coxofemoral (flexion 122.08° and extension 153.96°), femortibiopatelar (flexion 121.2° and extension 151.64°), tarsus (flexion 121.48° and extension 153.44°). In dynamic analysis obtained from the force plataform the average values of peak groun reaction force of each animal were: Biz 141N, Gaspar 128N, Lola 180N, Luck 183N, Monstra 150N, Winner135N. Whith these results we conclude that the join femortibiopatelar was the one whith a degree of magnitude higher than in the other joints; peak flexion and extension vary according to each joint; peak flexion and extension vary more in the hind limb when comapred to the fore limb. The results obtained can be useful in pre-clinical evaluation using a canine model.

o cão GRMD (Golden Retriever Muscular Dystrophy) é um excelente modelo de estudo sobre a ação da terapia celular para aplicação a DMD - Distrofia Muscular de Duchenne, que ocorre em humanos, devido à similaridade clínica entre ambos. Estas doenças têm em comum a herança recessiva ligada ao cromossomo X; e são causadas pela ausência de uma proteína chamada distrofina, a qual está presente no sarcolema das fibras musculares. O ponto da estrutura da mutação no gene da distrofina é responsável pelo fenótipo GRMD; e é possível encontrarmos indivíduos com características clínicas bem diferentes uns dos outros. Atualmente não existe um tratamento específico para a distrofia muscular de Duchenne; e os estudos sobre o desenvolvimento clínico e morfológico da distrofia muscular visam, através de avaliações constantes, estabelecer uma padronização fenotípica para estes animais com vistas a controlar resultados pré-clínicos adequadamente e assegurar-Ihes uma boa qualidade de vida; para que tenham condições de ser submetidos aos protocolos de terapia celular em desenvolvimento no canil GRMD Brasil; e, com isto, conhecer claramente a ação efetiva da terapia celular versus desenvolvimento morfológico desta doença degenerativa progressiva dos cães. Realizou-se o acompanhamento clínico e morfológico. de 12 cães GRMD, 06 fêmeas e 06 machos, do nascimento aos 12 meses de idade. Avaliando-se o aparelho locomotor, notou-se que entre a primeira (cinco meses de idade) e última avaliação (12 meses), houve uma piora com evolução significativa na assimetria postural, aumento do ângulo do tarso e carpo, adução dos membros, dissociação da cintura pélvica, além de alterações na mobilidade ativa dos joelhos durante a atividade de marcha. A avaliação andrológica dos cães distróficos indicou maiores taxas de anormalidade espermática (defeitos maiores e menores) comparada à de cães normais aos 12 meses de idade; ao passo que as fêmeas manifestaram maturidade sexual aos 09 meses. O acompanhamento hematológico mensal mostrou valores próximos do ideal para cães saudáveis, sendo que os exames realizados com os animais entre seis e doze meses de idade foram aqueles que indicaram maiores alterações em relação aos valores de referência para a espécie. Concentrações médias para hemácias, hemoglobina e hematócrito foram menores que a média para esta faixa etária. Quanto às avaliações bioquímicas séricas, CK é uma ferramenta importante para diagnóstico e acompanhamento da distrofia muscular em cães, devido às suas oscilações e aumentos indiscutíveis em indivíduos doentes. AL T e AST também demonstraram aumentos muito acima dos valores normais durante todas as faixas etárias avaliadas. Finalmente, os parâmetros cardíacos avaliados nos cães distróficos foram significantemente diferentes comparados àqueles encontrados em cães sadios normais, porém sem deficit à fisiologia cardíaca nos GRMOs / The dog GRMD (Golden Retriever Muscular Dystrophy) is an excellent model to study the action of cell therapy for application to DMD - from Duchenne Muscular Dystrophy, which occurs in humans; clinic due to the similarity between the two. These diseases have in common the legacy recessive linked to chromosome X, and are caused by the absence of a protein called dystrophin, which is present in sarcolema of muscle fibers. The point of the structure of mutation in the dystrophin gene is responsible for the phenotype GRMD, and you can find individuais with c1inical features quite different from each other. Currently there is no specific treatment for Duchenne muscular dystrophy, and the studies on the c1inical development of muscular dystrophy and morphological aim, through constant assessments, establish a standardized phenotypic for these animais in order to monitor pre-clinical results properly and maintain a good quality of life for them so that they have conditions to be submitted to the protocols of cell therapy being developed as kennel GRMD Brazil, and with it, knowing clearly the effective action of cell therapy versus the morphological development of this progressive degenerative disease of dogs. It was checked the c1inical and morphological of 12 dogs GRMD, 06 females and 06 males, from birth to 12 months of age. Judging by the locomotive system, it was noted that among the first (five months old) and last assessment (12 months), there was a worsening trend with significant asymmetry in posture, increasing the angle of the tarsus and carpus, adduction of the members, decoupling of the pelvic belt, as well as changes in the mobility of active knees during the activity running. Reproductive assessment of dystrophic dogs indicated higher rates of abnormal sperm (defects larger and smaller) compared to normal dogs at 12 months of age, while females expressed sexual maturity to 09 months. The monthly blood monitoring showed values close to ideal for healthy dogs, and the examinations performed with the animais between six and twelve months of age were those who indicated major changes in relation to the baseline for the species. Average concentrations for red blood cells, hemoglobin and hematocrit were lower than the average for this age group. As for serum biochemical assessments, CK is an important tool for diagnosis and monitoring muscular dystrophy in dogs, due to its indisputable fluctuations and increases in individuais patients. AL T and AST also showed increases greatly above the normal values for ali ages evaluated. Finally, the cardiac parameters measured in dystrophics dogs were significantly different compared to those found in normal healthy dogs, but without the deficit in cardiac physiology GRMDs