RESUMO
Dystroglycan, an extracellular matrix receptor, has essential functions in various tissues. Loss of α-dystroglycan-laminin interaction due to defective glycosylation of α-dystroglycan underlies a group of congenital muscular dystrophies often associated with brain malformations, referred to as dystroglycanopathies. The lack of isogenic human dystroglycanopathy cell models has limited our ability to test potential drugs in a human- and neural-specific context. Here, we generated induced pluripotent stem cells (iPSCs) from a severe dystroglycanopathy patient with homozygous FKRP (fukutin-related protein gene) mutation. We showed that CRISPR/Cas9-mediated gene correction of FKRP restored glycosylation of α-dystroglycan in iPSC-derived cortical neurons, whereas targeted gene mutation of FKRP in wild-type cells disrupted this glycosylation. In parallel, we screened 31,954 small molecule compounds using a mouse myoblast line for increased glycosylation of α-dystroglycan. Using human FKRP-iPSC-derived neural cells for hit validation, we demonstrated that compound 4-(4-bromophenyl)-6-ethylsulfanyl-2-oxo-3,4-dihydro-1H-pyridine-5-carbonitrile (4BPPNit) significantly augmented glycosylation of α-dystroglycan, in part through upregulation of LARGE1 glycosyltransferase gene expression. Together, isogenic human iPSC-derived cells represent a valuable platform for facilitating dystroglycanopathy drug discovery and therapeutic development.
Assuntos
Avaliação Pré-Clínica de Medicamentos , Distroglicanas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Sequência de Bases , Sistemas CRISPR-Cas , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos/métodos , Distroglicanas/genética , Edição de Genes , Marcação de Genes , Loci Gênicos , Glicosilação/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imagem Molecular , Distrofias Musculares/tratamento farmacológico , Distrofias Musculares/etiologia , Distrofias Musculares/metabolismo , Mutação , N-Acetilglucosaminiltransferases/genética , N-Acetilglucosaminiltransferases/metabolismo , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Pentosiltransferases/genética , Pentosiltransferases/metabolismoRESUMO
PURPOSE OF REVIEW: Muscle and bone are intrinsically linked, and therefore, it is not surprising that many muscular dystrophies are associated with impaired bone health and increased risk of osteoporosis. Osteoporotic fracture is an important and preventable cause of morbidity and mortality. This article will firstly review the general causes of impaired bone health in muscular dystrophies and then focus on the evidence available for the diagnosis and treatment of osteoporosis in specific conditions. RECENT FINDINGS: With the exception of DMD, there is a paucity of data regarding bone health in muscular dystrophies. However, it appears that in common with all types of muscular dystrophies that cause a significant level of muscle weakness and disability there is an increased risk of falls, fractures and decreased vitamin D levels. A better understanding of the extent of the impaired bone health and underlying causes could help to identify potential new therapeutic agents and aid clinical care. SUMMARY: It would be prudent for clinicians to assess fracture risk in their muscular dystrophy patients and if appropriate, arrange surveillance and recommend vitamin D supplementation. Additionally, fracture should be considered in any patient presenting with new-onset bone pain.
Assuntos
Doenças Ósseas/etiologia , Osso e Ossos/patologia , Distrofias Musculares/complicações , Distrofias Musculares/patologia , Doenças Ósseas/terapia , Humanos , Distrofias Musculares/etiologia , Distrofias Musculares/terapia , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/etiologia , Medição de RiscoRESUMO
This case report presents investigations of muscle problems in three male water buffaloes (1-2 years) kept extensively (loose housing, pasture). The bulls were presented because of listlessness and increased lying periods. They displayed difficulties to stand up, a stilted gait, and tremor in the legs. The determination of the selenium concentration by the measurement of glutathione peroxidase activity in whole blood samples (EDTA) demonstrated selenium deficiency in all three buffaloes. This confirmed the tentative diagnosis of nutritive myodystrophy due to selenium deficiency. Following a single injection of 1500 mg all-rac-alpha-tocopherol acetate and 11 mg sodium selenite, the bulls recovered clinically. The whole blood samples taken subsequently from seven adult water buffaloes on the farm showed selenium deficiency in all animals. Consequently, slow-release multi-trace element boluses were administered once orally - as far as possible - to all adult animals of the herd. After 1 year, a good to very good selenium supply was observed in all these buffaloes, except for one cow, in which bolus application had failed.
Assuntos
Búfalos , Deficiências Nutricionais/veterinária , Agricultura Orgânica , Selênio/deficiência , Criação de Animais Domésticos/métodos , Animais , Deficiências Nutricionais/complicações , Deficiências Nutricionais/tratamento farmacológico , Fazendas , Masculino , Distrofias Musculares/etiologia , Selenito de Sódio/administração & dosagem , alfa-Tocoferol/administração & dosagemRESUMO
Fecal incontinence is a common condition that causes major impairment of social life. Sacral nerve stimulation is a promising treatment in idiopathic fecal incontinence when conventional treatments have failed. However, new indications for sacral nerve stimulation are emerging. The present case shows that sacral nerve stimulation for treatment of fecal incontinence may be justified in other diseases in which fecal incontinence is a major problem.
Assuntos
Terapia por Estimulação Elétrica , Incontinência Fecal/etiologia , Incontinência Fecal/terapia , Plexo Lombossacral/fisiologia , Distrofias Musculares/etiologia , Eletrodos , Feminino , Humanos , Pessoa de Meia-Idade , Implantação de Prótese , Resultado do TratamentoRESUMO
The concentration of selenium (Se) and the activity of glutathione peroxidase (GSH-Px) in plasma and erythrocytes were measured in healthy men and in patients with Duchenne-type progressive muscular dystrophy (DMD). In healthy men, the Se concentration in erythrocytes showed a steep rise with aging and ascended gradually in plasma. The GSH-Px activity in both plasma and erythrocytes clearly increased with aging. The relationship between the Se concentration and the GSH-Px activity in healthy men showed a parallel rise with aging, but the coefficients of correlation were not very high (r = 0.44 and 0.56 in plasma and erythrocytes, respectively. In DMD patients, on the other hand, the Se concentration in erythrocytes decreased steeply with aging, and it decreased gradually in plasma. The GSH-Px activity in both plasma and erythrocytes apparently increased as in healthy men with aging, but the level was about 80% of that of healthy men. When selenite (Se+4) is added to the whole blood in vitro at 25 degrees C, it is rapidly taken up by erythrocytes (within several minutes) and is then released into plasma (a period of 30 min), then subsequent reuptake by erythrocytes is proceeded slowly. Our attention was attracted to the pattern of selenite release from erythrocytes of DMD patients.
Assuntos
Eritrócitos/metabolismo , Distrofias Musculares/sangue , Selênio/sangue , Oligoelementos/sangue , Adolescente , Adulto , Idoso , Envelhecimento/sangue , Criança , Glutationa Peroxidase/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/etiologiaAssuntos
Dor nas Costas/terapia , Terapia por Exercício , Vértebras Lombares , Denervação Muscular , Distrofias Musculares/terapia , Osteocondrite/complicações , Adolescente , Adulto , Dor nas Costas/etiologia , Terapia Combinada , Humanos , Contração Isométrica , Masculino , Pessoa de Meia-Idade , Distrofias Musculares/etiologiaRESUMO
A hypothesis is presented that an abnormality of nucleotide synthesis or metabolism might be a primary functional defect underlying Duchenne muscular dystrophy. One aim of this hypothesis is to demonstrate that it is possible to explain a variety of observations in dystrophy, neuromuscular and vascular, on a single hypothesis.
Assuntos
Nucleotídeos de Adenina/biossíntese , Distrofias Musculares/etiologia , Compostos Organofosforados/biossíntese , Nucleotídeos de Adenina/metabolismo , Difosfato de Adenosina/uso terapêutico , Humanos , Oxigenoterapia Hiperbárica , Músculos/irrigação sanguínea , Distrofias Musculares/terapia , Junção Neuromuscular/fisiologia , Compostos Organofosforados/metabolismoRESUMO
We are still a long way from discovering an unequivocal pathogenetic interpretation of progressive muscular dystrophy in man. Noteworthy efforts have been made in the experimental field; a recessive autosomic form found in the mouse seems to bear the closest resemblance to the human form from the genetic point of view. Myopathy due to lack of vitamin E and myopathy induced by certain viruses have much in common anatomically and pathologically with the human form. The authors induced myodystrophy in the rat by giving it a diet lacking in vitamin E. The pharmacological characteristics of vitamin E and the degenerative changes brought about by its deficiency, especially in the muscles, are illustrated. It is thus confirmed that the histological characteristics of myopathic rat muscle induced experimentally are extraordinarily similar to those of human myopathy as confirmed during biopsies performed at the Orthopaedic Traumatological Centre, Florence. The encouraging results obtained in various authoratative departments in myopathic patients by using anabolizing steroids have encouraged the authors to investigate the beneficial effects of one anabolizing agent (Dianabol, CIBA) at high doses in rats rendered myopathic by a diet deficient in vitamin E. In this way they obtained appreciable changes in body weight (increased from 50 to 70 g after forty days at a dose of 5 mg per day of anabolizing agent), but most of all they found histological changes due to "regenerative" changes in the muscle tissue, which however maintained its myopathic characteristics in the control animals that were not treated with the anabolizing agent. The authors conclude by affirming the undoubted efficacy of the anabolizing steroids in experimental myopathic disease, but they have reservations as to the transfer of the results into the human field, where high dosage cannot be carried out continuously because of the effects of the drug on virility; because the tissue injury too often occurs at an irreversible stage vis-a-vis the "regeneration" of the muscle tissue; and finally because the dystrophic injurious agent is certainly not the lack of vitamin E but something as yet unknown.