RESUMEN
Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive cell loss in the striatum and cerebral cortex, leading to a decline in motor control and eventually death. The mechanisms promoting motor dysfunction are not known, however loss of mitochondrial function and content has been observed, suggesting that mitochondrial dysfunction may contribute to HD phenotype. Recent work has demonstrated that voluntary wheel running reduces hindlimb clasping in the R6/1 mouse model of HD, which we hypothesized may be due to preservation of mitochondrial content with exercise. Therefore, we investigated the role of chronic exercise training on preventing symptom progression and the loss of mitochondrial content in HD. Exercising R6/1 mice began training at 7 wks of age and continued for 10 or 20 wks. At 17 wks of age, R6/1 mice displayed a clasping phenotype without showing changes in mitochondrial respiration or protein content in either the cortex or striatum, suggesting mitochondrial dysfunction is not necessary for the progression of symptoms. At 27 wks of age, R6/1 mice demonstrated no additional changes in mitochondrial content or respiration within the cortex, but displayed loss of protein in complexes I and III of the striatum, which was not present in exercise-trained R6/1 mice. Mitochondrial respiration was also elevated in the striatum of R6/1 mice at 27 wks, which was prevented with exercise training. Together, the present study provides evidence that mitochondrial dysfunction is not necessary for the progression of hindlimb clasping in R6/1 mice, and that exercise partially prevents changes in mitochondrial content and function that occur late in HD.
Asunto(s)
Cuerpo Estriado/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Terapia por Ejercicio/métodos , Enfermedad de Huntington/patología , Enfermedad de Huntington/rehabilitación , Factores de Edad , Animales , ADN Mitocondrial/metabolismo , Modelos Animales de Enfermedad , Complejo I de Transporte de Electrón/genética , Miembro Posterior/fisiopatología , Enfermedad de Huntington/genética , Masculino , Ratones , Ratones Transgénicos , Músculo Esquelético/fisiopatología , Condicionamiento Físico Animal/métodos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Repeticiones de Trinucleótidos/genéticaRESUMEN
Studies have shown increased incorporation of omega-3 fatty acids into whole skeletal muscle following supplementation, although little has been done to investigate the potential impact on the fatty acid composition of mitochondrial membranes and the functional consequences on mitochondrial bioenergetics. Therefore, we supplemented young healthy male subjects (n = 18) with fish oils [2 g eicosapentaenoic acid (EPA) and 1 g docosahexanoic acid (DHA) per day] for 12 weeks and skeletal muscle biopsies were taken prior to (Pre) and following (Post) supplementation for the analysis of mitochondrial membrane phospholipid composition and various assessments of mitochondrial bioenergetics. Total EPA and DHA content in mitochondrial membranes increased (P < 0.05) â¼450 and â¼320%, respectively, and displaced some omega-6 species in several phospholipid populations. Mitochondrial respiration, determined in permeabilized muscle fibres, demonstrated no change in maximal substrate-supported respiration, or in the sensitivity (apparent Km) and maximal capacity for pyruvate-supported respiration. In contrast, mitochondrial responses during ADP titrations demonstrated an enhanced ADP sensitivity (decreased apparent Km) that was independent of the creatine kinase shuttle. As the content of ANT1, ANT2, and subunits of the electron transport chain were unaltered by supplementation, these data suggest that prolonged omega-3 intake improves ADP kinetics in human skeletal muscle mitochondria through alterations in membrane structure and/or post-translational modification of ATP synthase and ANT isoforms. Omega-3 supplementation also increased the capacity for mitochondrial reactive oxygen species emission without altering the content of oxidative products, suggesting the absence of oxidative damage. The current data strongly emphasize a role for omega-3s in reorganizing the composition of mitochondrial membranes while promoting improvements in ADP sensitivity.