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
α-Proteobacteria that can oxidize iodide (I(-)) to molecular iodine (I(2)) have only been isolated from iodide-rich natural and artificial environments, i.e., natural gas brine waters and seawaters supplemented with iodide, respectively. To understand the growth characteristics of such iodide-oxidizing bacteria (IOB) under iodide-rich environments, microcosms comprising natural seawater and 1 mM iodide were prepared, and the succession of microbial communities was monitored by culture-independent techniques. PCR-denaturing gradient gel electrophoresis and 16S rRNA gene sequence analysis showed that bacteria closely related with known IOB were predominant in the microcosms after several weeks of incubation. Quantitative PCR analysis targeting specific 16S rRNA gene regions of IOB showed that the relative abundance of IOB in the microcosms was 6-76% of the total bacterial population, whereas that in natural seawater was less than 1%. When 10(3) cells mL(-1) of IOB were inoculated into natural seawater supplemented with 0.1-1 mM iodide, significant growth (cell densities, 10(5)-10(6) cells mL(-1)) and I(2) production (6-32 µM) were observed. Interestingly, similar growth stimulation occurred when 12-44 µM of I(2) was added to seawater, instead of iodide. IOB were found to be more I(2) tolerant than the other heterotrophic bacteria in seawater. These results suggest that I(2) plays a key role in the growth stimulation of IOB in seawater. IOB could potentially attack other bacteria with I(2) to occupy their ecological niche in iodide-rich environments.