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1.
FASEB J ; 35(9): e21861, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34416029

RESUMO

Duchenne muscular dystrophy (DMD) is an intractable genetic disease associated with progressive skeletal muscle weakness and degeneration. Recently, it was reported that intraperitoneal injections of ketone bodies partially ameliorated muscular dystrophy by increasing satellite cell (SC) proliferation. Here, we evaluated whether a ketogenic diet (KD) with medium-chain triglycerides (MCT-KD) could alter genetically mutated DMD in model rats. We found that the MCT-KD significantly increased muscle strength and fiber diameter in these rats. The MCT-KD significantly suppressed the key features of DMD, namely, muscle necrosis, inflammation, and subsequent fibrosis. Immunocytochemical analysis revealed that the MCT-KD promoted the proliferation of muscle SCs, suggesting enhanced muscle regeneration. The muscle strength of DMD model rats fed with MCT-KD was significantly improved even at the age of 9 months. Our findings suggested that the MCT-KD ameliorates muscular dystrophy by inhibiting myonecrosis and promoting the proliferation of muscle SCs. As far as we can ascertain, this is the first study to apply a functional diet as therapy for DMD in experimental animals. Further studies are needed to elucidate the underlying mechanisms of the MCT-KD-induced improvement of DMD.


Assuntos
Dieta Cetogênica , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologia , Distrofia Muscular de Duchenne/dietoterapia , Distrofia Muscular de Duchenne/fisiopatologia , Triglicerídeos/química , Triglicerídeos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose/dietoterapia , Fibrose/patologia , Inflamação/dietoterapia , Inflamação/patologia , Cetonas/sangue , Cetose , Masculino , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/patologia , Necrose/dietoterapia , Necrose/patologia , Ratos , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Triglicerídeos/uso terapêutico
2.
Muscle Nerve ; 64(4): 467-473, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34255858

RESUMO

INTRODUCTION/AIMS: There is considerable heterogenicity in clinical outcomes in Duchenne muscular dystrophy (DMD). The aim of this study was to assess whether dystrophin gene (DMD) pathogenic variant location influences upper or lower extremity motor function outcomes in a large prospective cohort. METHODS: We used longitudinal timed and quantitative motor function measurements obtained from 154 boys with DMD over a 10-y period by the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS) to understand how the trajectories of motor function differ based on proximal versus distal DMD pathogenic variants. Proximal variants were defined as located proximal to 5' DMD intron 44, and distal variants as those including nucleotides 3' DMD including intron 44. Distal DMD variants are predicted to alter the expression of short dystrophin isoforms (Dp140, Dp116, and Dp71). We compared various upper extremity and lower extremity motor function measures in these two groups, after adjusting for total lifetime corticosteroid use. RESULTS: The time to loss-of-ambulation and timed motor function measurements of both upper and lower limbs over a 10-y period were comparable between boys with proximal (n = 53) and distal (n = 101) DMD pathogenic variants. Age had a significant effect on several motor function outcomes. Boys younger than 7 y of age (n = 49) showed gain in function whereas boys 7 y and older (n = 71) declined, regardless of dystrophin pathogenic variant location. DISCUSSION: The longitudinal decline in upper and lower motor function is independent of proximal versus distal location of DMD pathogenic variants.


Assuntos
Distrofina/genética , Variação Genética/genética , Limitação da Mobilidade , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatologia , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Distrofia Muscular de Duchenne/diagnóstico , Estudos Prospectivos
3.
Am J Physiol Cell Physiol ; 321(2): C288-C296, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34191629

RESUMO

Impaired oxidative capacity and mitochondrial function contribute to the dystrophic pathology in muscles of patients with Duchenne muscular dystrophy (DMD) and in relevant mouse models of the disease. Emerging evidence suggests an association between disrupted core clock expression and mitochondrial quality control, but this has not been established in muscles lacking dystrophin. We examined the diurnal regulation of muscle core clock and mitochondrial quality control expression in dystrophin-deficient C57BL/10ScSn-Dmdmdx (mdx) mice, an established model of DMD. Male C57BL/10 (BL/10; n = 18) and mdx mice (n = 18) were examined every 4 h beginning at the dark cycle. Throughout the entire light-dark cycle, extensor digitorum longus (EDL) muscles from mdx mice had decreased core clock mRNA expression (Arntl, Cry1, Cry2, Nr1d2; P < 0.05) and disrupted mitochondrial quality control mRNA expression related to biogenesis (decreased; Ppargc1a, Esrra; P < 0.05), fission (increased; Dnm1l; P < 0.01), fusion (decreased; Opa1, Mfn1; P < 0.05), and autophagy/mitophagy (decreased: Bnip3; P < 0.05; increased: Becn1; P < 0.05). Cosinor analysis revealed a decrease in the rhythmicity parameters mesor and amplitude for Arntl, Cry1, Cry2, Per2, and Nr1d1 (P < 0.001) in mdx mice. Diurnal oscillations in Esrra, Sirt1, Map1lc3b, and Sqstm1 were absent in mdx mice, along with decreased mesor and amplitude of Ppargc1a mRNA expression (P < 0.01). The expression of proteins involved in mitochondrial biogenesis (decreased: PPARGC1A, P < 0.05) and autophagy/mitophagy (increased: MAP1LC3BII, SQSTM1, BNIP3; P < 0.05) were also dysregulated in tibialis anterior muscles of mdx mice. These findings suggest that dystrophin deficiency in mdx mice impairs the regulation of the core clock and mitochondrial quality control, with relevance to DMD and related disorders.


Assuntos
Distrofina/deficiência , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , Animais , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/metabolismo , Utrofina/deficiência
4.
Nutrients ; 13(5)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065946

RESUMO

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular childhood disorder that causes progressive muscle weakness and degeneration. A lack of dystrophin in DMD leads to inflammatory response, autophagic dysregulation, and oxidative stress in skeletal muscle fibers that play a key role in the progression of the pathology. ß-glucans can modulate immune function by modifying the phagocytic activity of immunocompetent cells, notably macrophages. Mitochondrial function is also involved in an important mechanism of the innate and adaptive immune responses, owing to high need for energy of immune cells. In the present study, the effects of 1,3-1,6 ß-glucans on five-day-old non-dystrophic and dystrophic (sapje) zebrafish larvae were investigated. The effects of the sonication of ß-glucans and the dechorionation of embryos were also evaluated. The results showed that the incidence of dystrophic phenotypes was reduced when dystrophic embryos were exposed to 2 and 4 mg L-1 of 1,3-1,6 ß-glucans. Moreover, when the dystrophic larvae underwent 8 mg L-1 treatment, an improvement of the locomotor performances and mitochondrial respiration were observed. In conclusion, the observed results demonstrated that 1,3-1,6 ß-glucans improve locomotor performances and mitochondrial function in dystrophic zebrafish. Therefore, for ameliorating their life quality, 1,3-1,6 ß-glucans look like a promising diet supplement for DMD patients, even though further investigations are required.


Assuntos
Suplementos Nutricionais , Locomoção/efeitos dos fármacos , Mitocôndrias Musculares/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , beta-Glucanas/uso terapêutico , Animais , Modelos Animais de Doenças , Larva , Mitocôndrias Musculares/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , Peixe-Zebra
5.
Neurology ; 97(5): e513-e522, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34162720

RESUMO

OBJECTIVE: To identify the best quantitative fat-water MRI biomarker for disease progression of leg muscles in Becker muscular dystrophy (BMD) by applying a stepwise approach based on standardized response mean (SRM) over 24 months, correlations with baseline ambulatory tests, and reproducibility. METHODS: Dixon fat-water imaging was performed at baseline (n = 24) and 24 months (n = 20). Fat fractions (FF) were calculated for 3 center slices and the whole muscles for 19 muscles and 6 muscle groups. Contractile cross-sectional area (cCSA) was obtained from the center slice. Functional assessments included knee extension and flexion force and 3 ambulatory tests (North Star Ambulatory Assessment [NSAA], 10-meter run, 6-minute walking test). MRI measures were selected using SRM (≥0.8) and correlation with all ambulatory tests (ρ ≤ -0.8). Measures were evaluated based on intraclass correlation coefficient (ICC) and SD of the difference. Sample sizes were calculated assuming 50% reduction in disease progression over 24 months in a clinical trial with 1:1 randomization. RESULTS: Median whole muscle FF increased between 0.2% and 2.6% without consistent cCSA changes. High SRMs and strong functional correlations were found for 8 FF but no cCSA measures. All measures showed excellent ICC (≥0.999) and similar SD of the interrater difference. Whole thigh 3 center slices FF was the best biomarker (SRM 1.04, correlations ρ ≤ -0.81, ICC 1.00, SD 0.23%, sample size 59) based on low SD and acquisition and analysis time. CONCLUSION: In BMD, median FF of all muscles increased over 24 months. Whole thigh 3 center slices FF reduced the sample size by approximately 40% compared to NSAA.


Assuntos
Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular de Duchenne/diagnóstico por imagem , Distrofia Muscular de Duchenne/diagnóstico , Tecido Adiposo/diagnóstico por imagem , Adulto , Biomarcadores/análise , Progressão da Doença , Feminino , Seguimentos , Humanos , Perna (Membro)/diagnóstico por imagem , Perna (Membro)/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Contração Muscular , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Coxa da Perna , Teste de Caminhada , Adulto Jovem
6.
Muscle Nerve ; 64(3): 357-361, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34105182

RESUMO

INTRODUCTION/AIM: This retrospective study aimed to quantify the changes in motor function in patients with Duchenne muscular dystrophy (DMD) due to the government-imposed travel restrictions associated with the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Twelve DMD patients were enrolled in this investigation (mean ± SD age: 9.8 ± 3.6 y). Their physical characteristics and motor function were evaluated approximately 3 mo before, immediately before, and approximately 3 mo after the travel restrictions were decreed. Statistical comparisons were performed of the changes in motor function before and after the travel restrictions. RESULTS: The change in range of motion (ROM) of ankle dorsiflexion was significantly decreased after the travel restrictions. Changes in body mass index and other motor function parameters were not significant. DISCUSSION: An apparent decrease in the amount of physical activity due to travel restrictions in response to COVID-19 negatively affected ankle dorsiflexion ROM but not other motor functions. A more sedentary lifestyle and lack of regular physical therapy services most likely contributed to this reduction. The use of remote rehabilitation tools with the involvement of physiotherapists may help mitigate such changes and prevent more severe physical decline.


Assuntos
COVID-19/prevenção & controle , Controle de Doenças Transmissíveis/métodos , Destreza Motora/fisiologia , Distrofia Muscular de Duchenne/terapia , Modalidades de Fisioterapia , Viagem , Adolescente , Criança , Pré-Escolar , Controle de Doenças Transmissíveis/tendências , Feminino , Humanos , Masculino , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/fisiopatologia , Modalidades de Fisioterapia/tendências , Amplitude de Movimento Articular/fisiologia , Estudos Retrospectivos , Viagem/tendências
7.
Am J Physiol Cell Physiol ; 321(2): C230-C246, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33979214

RESUMO

The MDX mouse is an animal model of Duchenne muscular dystrophy, a human disease marked by an absence of the cytoskeletal protein, dystrophin. We hypothesized that 1) dystrophin serves a complex mechanical role in skeletal muscles by contributing to passive compliance, viscoelastic properties, and contractile force production and 2) age is a modulator of passive mechanics of skeletal muscles of the MDX mouse. Using an in vitro biaxial mechanical testing apparatus, we measured passive length-tension relationships in the muscle fiber direction as well as transverse to the fibers, viscoelastic stress-relaxation curves, and isometric contractile properties. To avoid confounding secondary effects of muscle necrosis, inflammation, and fibrosis, we used very young 3-wk-old mice whose muscles reflected the prefibrotic and prenecrotic state. Compared with controls, 1) muscle extensibility and compliance were greater in both along fiber direction and transverse to fiber direction in MDX mice and 2) the relaxed elastic modulus was greater in dystrophin-deficient diaphragms. Furthermore, isometric contractile muscle stress was reduced in the presence and absence of transverse fiber passive stress. We also examined the effect of age on the diaphragm length-tension relationships and found that diaphragm muscles from 9-mo-old MDX mice were significantly less compliant and less extensible than those of muscles from very young MDX mice. Our data suggest that the age of the MDX mouse is a determinant of the passive mechanics of the diaphragm; in the prefibrotic/prenecrotic stage, muscle extensibility and compliance, as well as viscoelasticity, and muscle contractility are altered by loss of dystrophin.


Assuntos
Distrofina/deficiência , Contração Muscular/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Animais , Modelos Animais de Doenças , Contração Isométrica/fisiologia , Camundongos Transgênicos , Distrofia Muscular de Duchenne/fisiopatologia
8.
PLoS One ; 16(5): e0250420, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33939732

RESUMO

INTRODUCTION: Cognitive difficulties and neuropsychological alterations in Duchenne and Becker muscular dystrophy (DMD, BMD) boys are not yet sufficiently explored, although this topic could have a relevant impact, finding novel biomarkers of disease both at genetics and neuroimaging point of view. The current study aims to: 1) analyze the neuropsychological profile of a group of DMD and BMD boys without cognitive impairment with an assessment of their executive functions; 2) explore the structural connectivity in DMD, BMD, and age-matched controls focusing on cortico-subcortical tracts that connect frontal cortex, basal ganglia, and cerebellum via the thalamus; 3) explore possible correlations between altered structural connectivity and clinical neuropsychological measures. MATERIALS AND METHODS: This pilot study included 15 boys (5 DMD subjects, 5 BMD subjects, and 5 age-matched typically developing, TD). They were assessed using a neuropsychological assessment protocol including cognitive and executive functioning assessment and performed a 1.5T MRI brain exam including advance Diffusion Weighted Imaging (DWI) method for tractography. Structural connectivity measurements were extracted along three specific tracts: Cortico-Ponto-Cerebellar Tract (CPCT), Cerebellar-Thalamic Tract (CTT), and Superior Longitudinal Fasciculus (SLF). Cortical-Spinal Tract (CST) was selected for reference, as control tract. RESULTS: Regarding intellectual functioning, a major impairment in executive functions compared to the general intellectual functioning was observed both for DMD (mean score = 86.20; SD = 11.54) and for BMD children (mean score = 88; SD = 3.67). Mean FA resulted tendentially always lower in DMD compared to both BMD and TD groups for all the examined tracts. The differences in FA were statistically significant for the right CTT (DMD vs BMD, p = 0.002, and DMD vs TD, p = 0.0015) and the right CPCT (DMD vs TD, p = 0.008). Concerning DMD, significant correlations emerged between FA-R-CTT and intellectual quotients (FIQ, p = 0.044; ρs = 0.821), and executive functions (Denomination Total, p = 0.044, ρs = 0.821; Inhibition Total, p = 0.019, ρs = 0.900). BMD showed a significant correlation between FA-R-CPCT and working memory index (p = 0.007; ρs = 0.949). DISCUSSION AND CONCLUSION: In this pilot study, despite the limitation of sample size, the findings support the hypothesis of the involvement of a cerebellar-thalamo-cortical loop for the neuropsychological profile of DMD, as the CTT and the CPCT are involved in the network and the related brain structures are known to be implied in executive functions. Our results suggest that altered WM connectivity and reduced fibre organization in cerebellar tracts, probably due to the lack of dystrophin in the brain, may render less efficient some neuropsychological functions in children affected by dystrophinopathies. The wider multicentric study could help to better establish the role of cerebellar connectivity in neuropsychological profile for dystrophinopathies, identifying possible novel diagnostic and prognostic biomarkers.


Assuntos
Conectoma , Distrofia Muscular de Duchenne/diagnóstico por imagem , Criança , Cognição , Imagem de Tensor de Difusão , Função Executiva , Humanos , Masculino , Memória de Curto Prazo , Distrofia Muscular de Duchenne/fisiopatologia
9.
Sci Rep ; 11(1): 9779, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33963238

RESUMO

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder caused by loss of dystrophin. This lack also affects cardiac structure and function, and cardiovascular complications are a major cause of death in DMD. Newly developed therapies partially restore dystrophin expression. It is unclear whether this will be sufficient to prevent or ameliorate cardiac involvement in DMD. We here establish the cardiac electrophysiological and structural phenotype in young (2-3 months) and aged (6-13 months) dystrophin-deficient mdx mice expressing 100% human dystrophin (hDMD), 0% human dystrophin (hDMDdel52-null) or low levels (~ 5%) of human dystrophin (hDMDdel52-low). Compared to hDMD, young and aged hDMDdel52-null mice displayed conduction slowing and repolarisation abnormalities, while only aged hDMDdel52-null mice displayed increased myocardial fibrosis. Moreover, ventricular cardiomyocytes from young hDMDdel52-null animals displayed decreased sodium current and action potential (AP) upstroke velocity, and prolonged AP duration at 20% and 50% of repolarisation. Hence, cardiac electrical remodelling in hDMDdel52-null mice preceded development of structural alterations. In contrast to hDMDdel52-null, hDMDdel52-low mice showed similar electrophysiological and structural characteristics as hDMD, indicating prevention of the cardiac DMD phenotype by low levels of human dystrophin. Our findings are potentially relevant for the development of therapeutic strategies aimed at restoring dystrophin expression in DMD.


Assuntos
Eletrofisiologia Cardíaca , Distrofina , Distrofia Muscular de Duchenne , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Distrofina/genética , Distrofina/metabolismo , Camundongos , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia
10.
J Neuroeng Rehabil ; 18(1): 84, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34020668

RESUMO

BACKGROUND: Neuromuscular disorders (NMD) commonly affect the upper extremity. Due to muscle weakness, performance of daily activities becomes increasingly difficult, which leads to reduced independence and quality of life. In order to support the performance of upper extremity tasks, dynamic arm supports may be used. The Yumen Arm is a novel dynamic arm support specially developed for people with NMD. The aim of this study is to evaluate the feasibility and effectiveness of the Yumen Arm in persons with Duchenne Muscular Dystrophy (DMD) and persons with Spinal Muscular Atrophy (SMA). METHODS: Three persons with DMD and three persons with SMA participated in this study. All participants conducted a set of measures with and without the Yumen Arm. Outcome measures were: active range of motion of the arm and trunk (i.e. Reachable Workspace, Functional Workspace, and trunk movement), fatigue (OMNI-RPE), Performance of Upper Limb (PUL) scale and some additional activities of daily living. User experiences were collected using a questionnaire. RESULTS: The Yumen Arm could be used by all participants. Results showed a median increase in active range of motion (4% relative surface area), and a median increase of function ability (> 11% PUL score) when using the Yumen Arm. In addition, three out of four (data from 2 participants was missing) participants indicated that activity performance was less fatiguing when using the Yumen Arm. Four out of five (data from 1 participant was missing) participants indicated that they would like to use the Yumen Arm in their daily lives. CONCLUSION: This study is one of the first studies describing a range of objective measures to examine the effectiveness of a dynamic arm support. Based on these measurements we can conclude that the Yumen Arm effectively improves arm function in NMD patients, however the effectiveness varies a lot between individual subjects. We provided detailed recommendations for the improvement of the Yumen Arm, and possible also for the development of other dynamic arm supports. This study showed a lot of variability between individual subjects, which emphasizes the importance of tuning dynamic arm supports based on individual user characteristics, such as scoliosis, functional capacity and muscle strength.


Assuntos
Exoesqueleto Energizado , Atrofia Muscular Espinal/reabilitação , Distrofia Muscular de Duchenne/reabilitação , Atividades Cotidianas , Adolescente , Adulto , Braço/fisiopatologia , Criança , Estudos de Viabilidade , Feminino , Humanos , Masculino , Atrofia Muscular Espinal/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Qualidade de Vida , Amplitude de Movimento Articular/fisiologia , Adulto Jovem
11.
Muscle Nerve ; 64(2): 190-198, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33974714

RESUMO

INTRODUCTION/AIMS: Clinical trials addressing treatments for Duchenne muscular dystrophy (DMD) require reliable and valid measurement of muscle contractile function across all disease severity levels. In this work we aimed to evaluate a protocol combining voluntary and evoked contractions to measure strength and excitability of wrist extensor muscles for safety, feasibility, reliability, and discriminant validity between males with DMD and controls. METHODS: Wrist extensor muscle strength and excitability were assessed in males with DMD (N = 10; mean ± standard deviation: 15.4 ± 5.9 years of age), using the Brooke Upper Extremity Rating Scale (scored 1-6), and age-matched healthy male controls (N = 15; 15.5 ± 5.0 years of age). Torque and electromyographic (EMG) measurements were analyzed under maximum voluntary and stimulated conditions at two visits. RESULTS: A protocol of multiple maximal voluntary contractions (MVCs) and evoked twitch contractions was feasible and safe, with 96% of the participants completing the protocol and having a less than 7% strength decrement on either measure for both DMD patients and controls (P ≥ .074). Reliability was excellent for voluntary and evoked measurements of torque and EMG (intraclass correlation coefficient [ICC] over 0.90 and over 0.85 within and between visits, respectively). Torque, EMG, and timing of twitch-onset measurements discriminated between DMD and controls (P < .001). Twitch contraction time did not differ significantly between groups (P = .10). DISCUSSION: Findings from this study show that the protocol is a safe, feasible, reliable, and a valid method to measure strength and excitability of wrist extensors in males with DMD.


Assuntos
Contração Muscular/fisiologia , Força Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Adolescente , Adulto , Criança , Eletromiografia/métodos , Estudos de Viabilidade , Humanos , Contração Isométrica/fisiologia , Masculino , Adulto Jovem
12.
Muscle Nerve ; 64(2): 180-189, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34050939

RESUMO

INTRODUCTION: The Duchenne Video Assessment (DVA) assesses quality of movement as an indication of Duchenne muscular dystrophy (DMD) disease severity. Caregivers video record patients performing home-based movement tasks using a mobile application, and physical therapists (PTs) rate the videos using scorecards with prespecified compensatory movement criteria. Reliability and construct validity of the DVA were tested using video and Pediatric Outcomes Data Collection Instrument (PODCI) data from patients with DMD and healthy controls from a separate study. METHODS: Fifteen PTs were trained and certified as DVA raters. All raters scored videos of five subjects performing each movement task; nine raters rescored the same videos four weeks later. Three raters scored videos from an average of 25 subjects for each movement task. Aggregate scores were used to test construct validity. An expert DMD clinician assigned each video to a severity group for known-groups analyses. Differences between rater scores across severity groups were tested and correlations between DVA and PODCI scores were calculated. RESULTS: Inter-rater reliability (intraclass correlation coefficient [ICC]) between all 15 raters ranged from 0.70 to 0.97 for all movement tasks. Mean intra-rater reliability ICC for nine raters ranged from 0.82 to 0.98 for all movement tasks. There were statistically significant differences between known severity groups for all movement tasks. The DVA correlated strongly with related PODCI constructs of physical function and weakly with unrelated constructs. DISCUSSION: The DVA was found to be a reliable and valid tool for measuring quality of movement as an indication of disease severity.


Assuntos
Cuidadores , Movimento/fisiologia , Distrofia Muscular de Duchenne/fisiopatologia , Reprodutibilidade dos Testes , Adolescente , Criança , Pré-Escolar , Humanos , Masculino , Índice de Gravidade de Doença , Gravação em Vídeo/métodos
13.
Am J Physiol Heart Circ Physiol ; 321(1): H52-H58, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34048282

RESUMO

Dilated cardiomyopathy contributes to morbidity and mortality in Duchenne muscular dystrophy (DMD), an inheritable muscle-wasting disease caused by a mutation in the dystrophin gene. Preclinical studies in mouse models of muscular dystrophy have demonstrated reduced cardiomyopathy and improved cardiac function following oral treatment with the potent and selective thromboxane A2/prostanoid receptor (TPr) antagonist ifetroban. Furthermore, a phase 2 clinical trial (NCT03340675, Cumberland Pharmaceuticals) is currently recruiting subjects to determine whether ifetroban can improve cardiac function in patients with DMD. Although TPr is a promising therapeutic target for the treatment of dilated cardiomyopathy in DMD, little is known about TPr function in coronary arteries that perfuse blood through the cardiac tissue. In the current study, isolated coronary arteries from young (∼3-5 mo) and aged (∼9-12 mo) mdx mice, a widely used mouse model of DMD, and age-matched controls were examined using wire myography. Vasoconstriction to increasing concentrations of TPr agonist U-46619 (U4) was enhanced in young mdx mice versus controls. In addition, young mdx mice displayed a significant attenuation in endothelial cell-mediated vasodilation to increasing concentrations of the muscarinic agonist acetylcholine (ACh). Since TPr activation was enhanced in young mdx mice, U4-mediated vasoconstriction was measured in the absence and the presence of ifetroban. Ifetroban reduced U4-mediated vasoconstriction in young mdx mice and both aged mdx and control mice. Overall, our data demonstrate enhanced coronary arterial vasoconstriction to TPr activation in young mdx mice, a phenotype that could be reversed with ifetroban. These data could have important therapeutic implications for improving cardiovascular function in DMD.NEW & NOTEWORTHY This investigation revealed 1) impaired acetylcholine-mediated vasodilation, 2) increased U-46619-mediated vasoconstriction, and 3) reversal of the increase in U-46619-mediated vasoconstriction by the thromboxane A2/prostanoid receptor (TPr) antagonist ifetroban in left anterior descending coronary arteries isolated from young mdx mice, a model of Duchenne muscular dystrophy (DMD). Ifetroban has been used in preclinical studies to demonstrate improved cardiac function in mouse models of muscular dystrophy and is currently being investigated in a phase 2 clinical trial in patients with DMD. The current study supports the role of ifetroban in improving coronary artery function in preclinical DMD models, which may contribute to improved cardiovascular health.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Vasos Coronários/efeitos dos fármacos , Distrofia Muscular de Duchenne/complicações , Oxazóis/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Animais , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Distrofina/genética , Masculino , Camundongos , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/fisiopatologia
14.
Neuromuscul Disord ; 31(7): 603-606, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34049779

RESUMO

Due to their frailty and cardiorespiratory compromise adults with DMD are considered extremely vulnerable and at high risk of severe infection should they contract COVID-19. We report 7 adults with DMD aged 17-26 years who tested positive on a nasopharyngeal PCR swab for SARS-CoV-2. Despite long term corticosteroid treatment, severe respiratory compromise requiring night-time ventilation and receiving treatment for moderate to severe cardiomyopathy, none of the patients developed moderate to severe symptoms; in fact two remained asymptomatic and two developed only anosmia and reduced sensation. The remaining three developed transient fever with or without sore throat, cough and runny nose. All recovered fully without complication and no patient required hospitalization.


Assuntos
COVID-19/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Adolescente , Corticosteroides/uso terapêutico , Adulto , COVID-19/diagnóstico , COVID-19/epidemiologia , Comorbidade , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/epidemiologia , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto Jovem
15.
Invest Ophthalmol Vis Sci ; 62(4): 29, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33891680

RESUMO

Purpose: The purpose of this study was to characterize changes in the full-field flash electroretinogram (ERG) in association with psychophysical dark-adapted visual thresholds in patients with genetically characterized Duchenne muscular dystrophy (DMD) either lacking Dp427 (Up 30) or at least Dp260 in addition to Dp427 (Down 30). Methods: Twenty-one patients with DMD and 27 age-similar controls participated in this study. Dark-adapted (0.01, 3.0, and 10 cd.s/m² flashes) and light-adapted (3.0 cd.s/m² flash) ERGs were recorded following International Society for Clinical Electrophysiology of Vision (ISCEV) standard protocols. Visual detection thresholds to 625-nm (cone function) and 527-nm (rod function) light-emitting diode (LED) flashes (2 degree diameter) were measured during a dark adaptation period after a 1-minute exposure to a bleaching light (3000 cd/m²). Initially, 8 minutes of interleaved 625-nm and 527-nm thresholds were measured. After an additional 5 minutes of dark-adaptation, a second set of threshold measurements to 527-nm stimuli was performed during the subsequent 6 minutes. Results: Dark-adapted b-wave amplitude was significantly reduced to all strengths of flash and a-wave in response to the strong flash stimulus was delayed (15.6 vs. 14.7 ms, P < 0.05) in patients with Down 30 compared with controls. Dark-adapted cone thresholds did not differ among the groups (-2.0, -1.8, and -1.7 log cd/m² for Down 30, Up 30, and controls, respectively, P = 0.21). In contrast, dark-adapted rod thresholds were elevated (F(2,36) = 8.537, P = 0.001) in patients with Down 30 (mean = -3.2 ± 1.1 log cd/m²) relative to controls (mean = -4.2 ± 0.3 log cd/m²). Dark-adapted b-wave amplitudes were correlated with dark-adapted rod sensitivity in patients with DMD (Spearman Rho = 0.943, P = 0.005). The changes were much smaller or absent in patients with intact Dp260. Conclusions: Dp260 is particularly required for normal rod-system function in dark adaptation.


Assuntos
Adaptação à Escuridão/fisiologia , Eletrorretinografia/métodos , Distrofia Muscular de Duchenne/fisiopatologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Limiar Sensorial/fisiologia , Percepção Visual/fisiologia , Adolescente , Criança , Feminino , Humanos , Masculino , Distrofia Muscular de Duchenne/patologia , Estimulação Luminosa , Células Fotorreceptoras Retinianas Cones/patologia , Adulto Jovem
16.
Life Sci ; 279: 119482, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-33891939

RESUMO

AIM: Fibrosis is the most common complication from chronic diseases, and yet no therapy capable of mitigating its effects is available. Our goal is to unveil specific signaling regulating the fibrogenic process and to identify potential small molecule candidates that block fibrogenic differentiation of fibro/adipogenic progenitors. METHOD: We performed a large-scale drug screen using muscle-resident fibro/adipogenic progenitors from a mouse model expressing EGFP under the Collagen1a1 promotor. We first confirmed that the EGFP was expressed in response to TGFß1 stimulation in vitro. Then we treated cells with TGFß1 alone or with drugs from two libraries of known compounds. The drugs ability to block the fibrogenic differentiation was quantified by imaging and flow cytometry. From a two-rounds screening, positive hits were tested in vivo in the mice model for the Duchenne Muscular Dystrophy (mdx mice). The histopathology of the muscles was assessed with picrosirius red (fibrosis) and laminin staining (myofiber size). KEY FINDINGS: From the in vitro drug screening, we identified 21 drugs and tested 3 in vivo on the mdx mice. None of the three drugs significantly improved muscle histopathology. SIGNIFICANCE: The in vitro drug screen identified various efficient compounds, none of them strongly inhibited fibrosis in skeletal muscle of mdx mice. To explain these observations, we hypothesize that in Duchenne Muscular Dystrophy, in which fibrosis is a secondary event due to chronic degeneration and inflammation, the drugs tested could have adverse effect on regeneration or inflammation, balancing off any positive effects and leading to the absence of significant results.


Assuntos
Adipogenia , Fibrose/patologia , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Preparações Farmacêuticas/administração & dosagem , Fator de Crescimento Transformador beta1/administração & dosagem , Animais , Diferenciação Celular , Feminino , Fibrose/tratamento farmacológico , Fibrose/etiologia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos mdx , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo
17.
Rev Paul Pediatr ; 39: e2020045, 2021.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33656143

RESUMO

OBJECTIVE: To verify the interval of responsiveness to the scales Segmental Assessment of Trunk Control (SATCo-BR), Performance of Upper Limbs (PUL), and Jebsen Taylor Test (JTT) in patients with Duchenne Muscular Dystrophy (DMD). METHODS: We assessed patients with DMD aged 6 to 19 years old and with mini-mental (MMSE) score above 10 points. The assessments were performed individually, in a single session. The upper limb function was performed by PUL and JTT, and trunk control by SATCo-BR. Assessments were repeated six and 12 months after the initial assessment. The repeated-measures analysis of variance model and Bonferroni's multiple comparison method were employed as post hoc analysis; when the ANOVA assumptions were not met, the Friedman test was applied. RESULTS: The sample consisted of 28 patients evaluated in three moments (initial, and six and 12 months after the beginning). There was a time effect for the Upper Limb function performance in the total JTT, and for the subtests, except for subtests 1 and 6, which did not show a difference between the different moments. There was also a time effect for the score of total PUL, proximal PUL, intermediate PUL, and distal PUL. In the SATCo-BR, this effect was observed between the initial and 6 months, and between the initial and 12 months. CONCLUSIONS: The JTT, PUL, and SATCo-BR scales can detect changes over time, and they showed responsiveness to detect the evolution of the disease in the 6-month interval.


Assuntos
Distrofia Muscular de Duchenne/fisiopatologia , Equilíbrio Postural/fisiologia , Tronco/fisiopatologia , Extremidade Superior/fisiopatologia , Pesos e Medidas/normas , Adolescente , Antropometria/métodos , Criança , Progressão da Doença , Humanos , Estudos Longitudinais , Masculino , Testes de Estado Mental e Demência/estatística & dados numéricos , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/epidemiologia , Desempenho Físico Funcional , Fatores de Tempo , Adulto Jovem
18.
Muscle Nerve ; 63(6): 941-950, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33759456

RESUMO

INTRODUCTION: Surface electrical impedance myography (sEIM) has the potential for providing information on muscle composition and structure noninvasively. We sought to evaluate its use to predict myofiber size and connective tissue deposition in the D2-mdx model of Duchenne muscular dystrophy (DMD). METHODS: We applied a prediction algorithm, the least absolute shrinkage and selection operator, to select specific EIM measurements obtained with surface and ex vivo EIM data from D2-mdx and wild-type (WT) mice (analyzed together or separately). We assessed myofiber cross-sectional area histologically and hydroxyproline (HP), a surrogate measure for connective tissue content, biochemically. RESULTS: Using WT and D2-mdx impedance values together in the algorithm, sEIM gave average root-mean-square errors (RMSEs) of 26.6% for CSA and 45.8% for HP, which translate into mean errors of ±363 µm2 for a mean CSA of 1365 µm2 and of ±1.44 µg HP/mg muscle for a mean HP content of 3.15 µg HP/mg muscle. Stronger predictions were obtained by analyzing sEIM data from D2-mdx animals alone (RMSEs of 15.3% for CSA and 34.1% for HP content). Predictions made using ex vivo EIM data from D2-mdx animals alone were nearly equivalent to those obtained with sEIM data (RMSE of 16.59% for CSA), and slightly more accurate for HP (RMSE of 26.7%). DISCUSSION: Surface EIM combined with a predictive algorithm can provide estimates of muscle pathology comparable to values obtained using ex vivo EIM, and can be used as a surrogate measure of disease severity and progression and response to therapy.


Assuntos
Tecido Conjuntivo/fisiopatologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Animais , Impedância Elétrica , Eletromiografia , Camundongos Endogâmicos mdx , Fibras Musculares Esqueléticas/fisiologia
19.
Commun Biol ; 4(1): 427, 2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33782502

RESUMO

Parabiosis experiments suggest that molecular factors related to rejuvenation and aging circulate in the blood. Here, we show that miR-199-3p, which circulates in the blood as a cell-free miRNA, is significantly decreased in the blood of aged mice compared to young mice; and miR-199-3p has the ability to enhance myogenic differentiation and muscle regeneration. Administration of miR-199 mimics, which supply miR-199-3p, to aged mice resulted in muscle fiber hypertrophy and delayed loss of muscle strength. Systemic administration of miR-199 mimics to mdx mice, a well-known animal model of Duchenne muscular dystrophy (DMD), markedly improved the muscle strength of mice. Taken together, cell-free miR-199-3p in the blood may have an anti-aging effect such as a hypertrophic effect in aged muscle fibers and could have potential as a novel RNA therapeutic for DMD as well as age-related diseases. The findings provide us with new insights into blood-circulating miRNAs as age-related molecules.


Assuntos
Envelhecimento/fisiologia , MicroRNAs/metabolismo , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/genética , Regeneração/fisiologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/fisiopatologia , Regeneração/genética
20.
Muscle Nerve ; 63(2): 231-238, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33104257

RESUMO

BACKGROUND: Appendicular lean mass (ALM) trajectory in males with Duchenne muscular dystrophy (DMD) has potential applicability for treatment and research and has not been characterized. METHODS: This chart review included longitudinal data on 499 males with DMD receiving glucocorticoids and 693 controls, ages 5 to 22.9 y. ALM (kg) was measured by dual energy x-ray absorptiometry (DXA). Appendicular lean mass index (ALMI, kg/m2 ) was calculated for height adjustment. Reference centiles were generated using data from healthy controls, and ALM and ALMI Z-scores were calculated for patients with DMD. Generalized linear models were used to estimate median Z-scores by age and functional mobility status (FMS) score. ALM velocity by age was modeled using superimposition, translation and rotation (SITAR). RESULTS: Compared to controls, males with DMD had lower ALM from an early age. ALMI Z-scores dropped below 0 at age 8 y or FMS of 2, and below -2.0 at age 13 y or FMS of 3 (P < .05). Age at peak ALM velocity was similar in both groups, but the magnitude was higher in controls (3.5 vs. 0.7 kg/y, P < .0001). Patients with DMD had a transient loss of ALM around age 12 y, an increase at age 14 y, then a further decline at age 16 y, remaining low thereafter. CONCLUSIONS: Males with DMD have progressive decline in lean mass with age and worsening functional mobility. DXA measurement of ALM may be useful for monitoring lean mass status in patients with DMD, providing valuable information for individual treatment plans and research endeavors.


Assuntos
Composição Corporal , Extremidades/diagnóstico por imagem , Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular de Duchenne/diagnóstico por imagem , Absorciometria de Fóton , Adolescente , Fatores Etários , Estudos de Casos e Controles , Criança , Pré-Escolar , Progressão da Doença , Estado Funcional , Glucocorticoides/uso terapêutico , Humanos , Modelos Lineares , Masculino , Limitação da Mobilidade , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Tamanho do Órgão , Estudos Retrospectivos , Adulto Jovem
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