RESUMEN
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.
Asunto(s)
Ácidos Indolacéticos/uso terapéutico , Mitocondrias Musculares/metabolismo , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Fenilbutiratos/uso terapéutico , Adenosina Trifosfato/biosíntesis , Anciano , Anciano de 80 o más Años , Butionina Sulfoximina/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , ADN Mitocondrial/genética , Evaluación Preclínica de Medicamentos , Dinaminas/biosíntesis , Dinaminas/genética , Femenino , Factores de Crecimiento de Fibroblastos/sangre , Fibroblastos/efectos de los fármacos , GTP Fosfohidrolasas/biosíntesis , GTP Fosfohidrolasas/genética , Factor 15 de Diferenciación de Crecimiento/biosíntesis , Factor 15 de Diferenciación de Crecimiento/sangre , Factor 15 de Diferenciación de Crecimiento/genética , Humanos , Ácidos Indolacéticos/farmacología , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/patología , Mioblastos/efectos de los fármacos , Mioblastos/metabolismo , Mioblastos/ultraestructura , Miositis por Cuerpos de Inclusión/metabolismo , Miositis por Cuerpos de Inclusión/patología , Consumo de Oxígeno , Fenilbutiratos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Estudios RetrospectivosRESUMEN
The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 µg/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis-mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment.