RESUMEN
BACKGROUND: Neuromuscular disease (NMD) research is experiencing tremendous growth as a result of progress in diagnostics and therapeutics yet there continues to be a significant clinical data shortage for these rare diseases. To maximize the development and impact of new therapies, the Muscular Dystrophy Association (MDA) created the neuroMuscular ObserVational Research Data Hub (MOVR) as an observational research study that collects disease-specific measures from individuals living with NMDs in the United States. OBJECTIVE: This manuscript provides a description of MOVR, participants enrolled in MOVR, and longitudinal data availability. METHODS: MOVR collects longitudinal data from individuals diagnosed with ALS, BMD, DMD, FSHD, LGMD, Pompe disease, or SMA, and who are seen for care at a participating MDA Care Center. Data are entered from medical records into standardized electronic case report forms (eCRFs). These eCRFs capture participants' demographics, diagnostic journeys, clinical visits, and discontinuation from the study. RESULTS: From January 2019 to May 2022, MOVR collected data from 50 participating care centers and 1,957 participants. Data from 1,923 participants who participated in MDA's pilot registry were migrated into MOVR, creating a total of 3,880 participants in MOVR. Initial analysis of aggregated data demonstrated that 91% of eCRFs were complete. Forty-three percent of participants had 3 or more encounters and 50% of all encounters were 5 months or less from the previous encounter. DISCUSSION: As a centralized data hub for multiple NMDs, MOVR serves as a platform that can be used to inform disease understanding, guide clinical trial design, and accelerate drug development for NMDs.
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Enfermedad del Almacenamiento de Glucógeno Tipo II , Distrofias Musculares , Enfermedades Neuromusculares , Humanos , Distrofias Musculares/diagnóstico , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/terapia , Enfermedades Raras , Sistema de RegistrosRESUMEN
Neuromuscular electrical stimulation (NMES) allows activation of muscle fibers in the absence of voluntary force generation. NMES could have the potential to promote muscle homeostasis in the context of muscle disease, but the impacts of NMES on diseased muscle are not well understood. We used the zebrafish Duchenne muscular dystrophy (dmd) mutant and a longitudinal design to elucidate the consequences of NMES on muscle health. We designed four neuromuscular stimulation paradigms loosely based on weightlifting regimens. Each paradigm differentially affected neuromuscular structure, function, and survival. Only endurance neuromuscular stimulation (eNMES) improved all outcome measures. We found that eNMES improves muscle and neuromuscular junction morphology, swimming, and survival. Heme oxygenase and integrin alpha7 are required for eNMES-mediated improvement. Our data indicate that neuromuscular stimulation can be beneficial, suggesting that the right type of activity may benefit patients with muscle disease.
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Distrofia Muscular de Duchenne , Animales , Estimulación Eléctrica , Humanos , Músculo Esquelético/fisiología , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Unión Neuromuscular/fisiología , Pez CebraRESUMEN
BACKGROUND: Secondary dystroglycanopathies are muscular dystrophies that result from mutations in genes that participate in Dystroglycan glycosylation. Glycosylation of Dystroglycan is essential for muscle fibers to adhere to the muscle extracellular matrix (myomatrix). Although the myomatrix is disrupted in a number of secondary dystroglycanopathies, it is unknown whether improving the myomatrix is beneficial for these conditions. We previously determined that either NAD+ supplementation or overexpression of Paxillin are sufficient to improve muscle structure and the myomatrix in a zebrafish model of primary dystroglycanopathy. Here, we investigate how these modulations affect neuromuscular phenotypes in zebrafish fukutin-related protein (fkrp) morphants modeling FKRP-associated secondary dystroglycanopathy. RESULTS: We found that NAD+ supplementation prior to muscle development improved muscle structure, myotendinous junction structure, and muscle function in fkrp morphants. However, Paxillin overexpression did not improve any of these parameters in fkrp morphants. As movement also requires neuromuscular junction formation, we examined early neuromuscular junction development in fkrp morphants. The length of neuromuscular junctions was disrupted in fkrp morphants. NAD+ supplementation prior to neuromuscular junction development improved length. We investigated NMJ formation in dystroglycan (dag1) morphants and found that although NMJ morphology is disrupted in dag1 morphants, NAD+ is not sufficient to improve NMJ morphology in dag1 morphants. Ubiquitous overexpression of Fkrp rescued the fkrp morphant phenotype but muscle-specific overexpression only improved myotendinous junction structure. CONCLUSIONS: These data indicate that Fkrp plays an early and essential role in muscle, myotendinous junction, and neuromuscular junction development. These data also indicate that, at least in the zebrafish model, FKRP-associated dystroglycanopathy does not exactly phenocopy DG-deficiency. Paxillin overexpression improves muscle structure in dag1 morphants but not fkrp morphants. In contrast, NAD+ supplementation improves NMJ morphology in fkrp morphants but not dag1 morphants. Finally, these data show that muscle-specific expression of Fkrp is insufficient to rescue muscle development and homeostasis.
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Distroglicanos/deficiencia , Distroglicanos/genética , Glicosiltransferasas/genética , Glicosiltransferasas/metabolismo , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/metabolismo , NAD/metabolismo , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Glicosilación , Humanos , Desarrollo de Músculos/genética , Desarrollo de Músculos/fisiología , Distrofia Muscular Animal/patología , Mutación , NAD/administración & dosificación , Unión Neuromuscular/genética , Unión Neuromuscular/crecimiento & desarrollo , Unión Neuromuscular/metabolismo , Paxillin/genética , Paxillin/metabolismo , Regulación hacia Arriba , Pez CebraRESUMEN
The proper development and function of skeletal muscle is vital for health throughout the lifespan. Skeletal muscle function enables posture, breathing, and locomotion; and also impacts systemic processes-such as metabolism, thermoregulation, and immunity. Diseases of skeletal muscle (myopathies, muscular dystrophies) and even some neurological, age-related, and metabolic diseases compromise muscle function and negatively affect health span and quality of life. There have been numerous, recent examples of studies on skeletal muscle development with exciting, therapeutic implications for muscle diseases. The zebrafish (Danio rerio) is a vertebrate model organism well accepted for developmental biology and biomedical research and thus an ideal system in which to elucidate the translational implications of mechanisms regulating skeletal muscle development and homeostasis. Muscle fiber types (slow- vs fast-twitch) are spatially segregated in zebrafish allowing for the opportunity to identify distinct mechanisms regulating fiber type specification during development as well as observe fiber type-specific effects in zebrafish models of muscle diseases. Accessible genetics coupled with transparent zebrafish embryos has enabled in vivo cell biology experiments allowing for the visualization and understanding of never-before-seen cellular processes occurring in muscle development, regeneration, and disease. In addition, high-throughput drug screening provides a platform for efficient drug discovery. The purpose of this chapter is to review the studies in zebrafish that significantly contributed to our understanding of cellular and molecular mechanisms regulating skeletal muscle development, homeostasis, or disease in vertebrates, with a particular emphasis on the basic developmental biology studies with promising therapeutic implications.
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Homeostasis , Desarrollo de Músculos , Enfermedades Musculares/patología , Pez Cebra/fisiología , Animales , Modelos Animales de Enfermedad , Músculo Esquelético/embriologíaRESUMEN
The orexin/hypocretin (ORX) system regulates motivation for natural rewards and drugs of abuse such as alcohol. ORX receptor antagonists, most commonly OX1R antagonists including SB-334867 (SB), decrease alcohol drinking, self-administration and reinstatement in both genetically-bred alcohol-preferring and outbred strains of rats. Importantly, levels of alcohol seeking and drinking in outbred rats are variable, as they are in humans. We have shown that OX1R antagonism selectively decreases homecage alcohol drinking in high-, but not low-alcohol-preferring rats. It is unknown, however, whether this effect is selective to homecage drinking or whether it also applies to alcohol seeking paradigms such as self-administration and reinstatement following extinction, in which motivation is high in the absence of alcohol. Here we trained Sprague Dawley rats to self-administer 20% ethanol paired with a light-tone cue on an FR3 regimen. Rats were then extinguished and subjected to cue-induced reinstatement. Rats were segregated into high- and low-ethanol-responding groups (HR and LR) based on self-administration levels. During self-administration and cue-induced reinstatement, rats were given SB or vehicle prior to ethanol seeking. In both conditions, OX1R antagonism decreased responding selectively in HR, but not LR rats. There were no non-specific effects of SB treatment on arousal or general behavior. These data indicate that ORX signaling at the OX1R receptor specifically regulates high levels of motivation for alcohol, even in the absence of direct alcohol reinforcement. This implicates the ORX system in the pathological motivation underlying alcohol abuse and alcoholism and demonstrates that the OX1R may be an important target for treating alcohol abuse.
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Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Benzoxazoles/farmacología , Depresores del Sistema Nervioso Central/administración & dosificación , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Etanol/administración & dosificación , Antagonistas de los Receptores de Orexina/farmacología , Urea/análogos & derivados , Consumo de Bebidas Alcohólicas/metabolismo , Trastornos Relacionados con Alcohol/tratamiento farmacológico , Trastornos Relacionados con Alcohol/metabolismo , Animales , Animales no Consanguíneos , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Señales (Psicología) , Modelos Animales de Enfermedad , Comportamiento de Búsqueda de Drogas/fisiología , Masculino , Motivación/efectos de los fármacos , Motivación/fisiología , Naftiridinas , Receptores de Orexina/metabolismo , Ratas Sprague-Dawley , Autoadministración , Urea/farmacologíaRESUMEN
The purpose of this study was to compare kinetic differences of static balance between female dancers (D) with at least seven years of dance experience and female non-dancers (ND) who were typical college students. Participants were tested in single-leg stance. Both the dominant leg (DL) and non-dominant leg (NDL) were tested with the participants shod (S) and barefoot (BF). Kinetic variables (vertical, medio-lateral [ML], antero-posterior [AP] maximum ground reaction forces (GRF), and center of pressure (COP) ML and AP) were measured by a Bertec force platform at 1000 Hz with participants S and BF. Each subject's stance was measured over 3 × 30-second intervals. No significant differences (p≥0.05) existed between groups for height, body mass, or age. Significant differences existed between groups for balance time, AP GRF in both BF and S conditions for both DL and NDL, and ML GRF in BF NDL and S DL and NDL conditions. D and ND in BF and S conditions with DL and NDL static stance demonstrate different AP and ML GRF when balancing over a 30-second time interval. Data may suggest that ND are more prone to lose their balance. Further investigation is warranted to understand whether individuals in the rehabilitative field and athletic populations can use dance therapy for injury prevention and rehabilitation.
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Orexin (ORX) (also known as hypocretin) neurons are located exclusively in the posterior hypothalamus, and are involved in a wide range of behaviours, including motivation for drugs of abuse such as alcohol. Hypothalamic subregions contain functionally distinct populations of ORX neurons that may play different roles in regulating drug-motivated and alcohol-motivated behaviours. To investigate the role of ORX neurons in ethanol (EtOH) seeking, we measured Fos activation of ORX neurons in rats following three different measures of EtOH seeking and preference: (i) context-induced reinstatement, or ABA renewal; (ii) cue-induced reinstatement of extinguished responding for EtOH; and (iii) a home cage task in which preference for EtOH (vs. water) was measured in the absence of either reinforcer. We found significant activation of ORX neurons in multiple subregions across all three behavioural tests. Notably, ORX neuron activation in the lateral hypothalamus correlated with the degree of seeking in context reinstatement and the degree of preference in home cage preference testing. In addition, Fos activation in ORX neurons in the dorsomedial hypothalamic and perifornical areas was correlated with context and home cage seeking/preference, respectively. Surprisingly, we found no relationship between the degree of cue-induced reinstatement and ORX neuron activation in any region, despite robust activation overall during reinstatement. These results demonstrate a strong relationship between ORX neuron activation and EtOH seeking/preference, but one that is differentially expressed across ORX field subregions, depending on reinstatement modality.