RESUMO
Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.
Assuntos
Ácidos Indolacéticos/uso terapêutico , Mitocôndrias Musculares/metabolismo , Miosite de Corpos de Inclusão/tratamento farmacológico , Fenilbutiratos/uso terapêutico , Trifosfato de Adenosina/biossíntese , Idoso , Idoso de 80 Anos ou mais , Butionina Sulfoximina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , DNA Mitocondrial/genética , Avaliação Pré-Clínica de Medicamentos , Dinaminas/biossíntese , Dinaminas/genética , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Fibroblastos/efeitos dos fármacos , GTP Fosfo-Hidrolases/biossíntese , GTP Fosfo-Hidrolases/genética , Fator 15 de Diferenciação de Crescimento/biossíntese , Fator 15 de Diferenciação de Crescimento/sangue , Fator 15 de Diferenciação de Crescimento/genética , Humanos , Ácidos Indolacéticos/farmacologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/patologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Mioblastos/ultraestrutura , Miosite de Corpos de Inclusão/metabolismo , Miosite de Corpos de Inclusão/patologia , Consumo de Oxigênio , Fenilbutiratos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Estudos RetrospectivosRESUMO
This case report describes a pregnant female patient who presented with new-onset congestive heart failure symptoms and prolonged QTc, with strong family history of sudden death. Endomyocardial biopsy and genetic testing revealed myocardial desmin accumulation and a previously described mutation in the DES (desmin) gene, as well as variants in two LQT genes, SCN5A and KCNH2. The case highlights the phenotypic variability for a particular desmin genotype, and the possible interaction of desminopathy with LQT variants not independently associated with large differences in current properties or QT prolongation from wild type.
Assuntos
Desmina/genética , Insuficiência Cardíaca/genética , Síndrome do QT Longo/genética , Mutação , Miosite de Corpos de Inclusão/genética , Complicações Cardiovasculares na Gravidez/genética , Adulto , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Canal de Potássio ERG1 , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Canais de Potássio Éter-A-Go-Go/genética , Éxons , Feminino , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Humanos , Síndrome do QT Longo/terapia , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/terapia , Canal de Sódio Disparado por Voltagem NAV1.5 , Gravidez , Canais de Sódio/genética , Resultado do TratamentoRESUMO
We report a patient with late-onset celiac disease and neurological manifestations including myopathy, polyneuropathy, and ataxia. Laboratory investigations showed anti-gliadin antibodies and severe vitamin E deficiency. Muscle biopsy revealed inflammatory infiltrates and rimmed vacuoles, similar to those found in inclusion-body myositis. A gluten-free diet and vitamin E supplementation reversed both the clinical neurological manifestations and the abnormalities in the muscle biopsy. Anti-gliadin antibodies were no longer present. This case illustrates the spectrum of neurological complications of celiac disease and documents the occurrence of reversible pathology resembling inclusion-body myopathy in the muscle.