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
We report an adult case of late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD) characterized by episodic recurrent rhabdomyolysis and acute renal failure after the age of 46. Muscle biopsy revealed lipid storage myopathy and the finding of serum acylcarnitine and urine organic acid analyses were consistent with MADD. A compound heterozygous mutation was identified in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene, including a novel missense mutation, which confirmed the diagnosis of MADD. After administration of riboflavin and L-carnitine, the muscle weakness and fatigability gradually improved. Acylcarnitine and urine organic acid were also normalized after supplementation. Thus, MADD should be included in one of the differential diagnoses for adult recurrent rhabdomyolysis. Gene analysis is useful to confirm the diagnosis, and early diagnosis is important because riboflavin treatment has been effective in a significant number of patients with MADD.