It is controversial whether mitochondrial dysfunction in skeletal muscle is the cause or consequence of metabolic disorders. Herein, we demonstrate that in vivo inhibition of mitochondrial ATP synthase in muscle alters whole‐body lipid homeostasis. Mice with restrained mitochondrial ATP synthase activity presented intrafiber lipid droplets, dysregulation of acyl‐glycerides, and higher visceral adipose tissue deposits, poising these animals to insulin resistance. This mitochondrial energy crisis increases lactate production, prevents fatty acid β‐oxidation, and forces the catabolism of branched‐chain amino acids (BCAA) to provide acetyl‐CoA for de novo lipid synthesis. In turn, muscle accumulation of acetyl‐CoA leads to acetylation‐dependent inhibition of mitochondrial respiratory complex II enhancing oxidative phosphorylation dysfunction which results in augmented ROS production. By screening 702 FDA‐approved drugs, we identified edaravone as a potent mitochondrial antioxidant and enhancer. Edaravone administration restored ROS and lipid homeostasis in skeletal muscle and reinstated insulin sensitivity. Our results suggest that muscular mitochondrial perturbations are causative of metabolic disorders and that edaravone is a potential treatment for these diseases.
Classifiers based on statistical pattern recognition analysis of MRSI data are becoming important tools for the non-invasive diagnosis of human brain tumors. Here we investigate the potential interest of perturbation-enhanced MRSI (PE-MRSI), in this case acute hyperglycemia, for improving the discrimination between mouse brain MRS patterns of glioblastoma multiforme (GBM), oligodendroglioma (ODG), and non-tumor brain parenchyma (NT). Six GBM-bearing mice and three ODG-bearing mice were scanned at 7 Tesla by PRESS-MRSI with 12 and 136 ms echo-time, during euglycemia (Eug) and also during induced acute hyperglycemia (Hyp), generating altogether four datasets per animal (echo time + glycemic condition): 12Eug, 136Eug, 12Hyp, and 136Hyp. For classifier development all spectral vectors (spv) selected from the MRSI matrix were unit length normalized (UL2) and used either as a training set (76 GBM spv, four mice; 70 ODG spv, two mice; 54 NT spv) or as an independent testing set (61 GBM spv, two mice; 31 ODG, one mouse; 23 NT spv). All Fisher's LDA classifiers obtained were evaluated as far as their descriptive performance-correctly classified cases of the training set (bootstrapping)-and predictive accuracy-balanced error rate of independent testing set classification. MRSI-based classifiers at 12Hyp were consistently more efficient in separating GBM, ODG, and NT regions, with overall accuracies always >80% and up to 95-96%; remaining classifiers were within the 48-85% range. This was also confirmed by user-independent selection of training and testing sets, using leave-one-out (LOO). This highlights the potential interest of perturbation-enhanced MRSI protocols for improving the non-invasive characterization of preclinical brain tumors.
Tubular aggregates (TA) are honeycomb-like arrays of sarcoplasmic-reticulum (SR) tubules affecting aged glycolytic fibers of male individuals and inducing severe sarcomere disorganization and muscular pain. TA develop in skeletal muscle from Tubular Aggregate Myopathy (TAM) patients as well as in other disorders including endocrine syndromes, diabetes, and ageing, being their primary cause unknown. Nowadays, there is no cure for TA. Intriguingly, both hypoxia and calcium dyshomeostasis prompt TA formation, pointing to a possible role for mitochondria in their setting. However, a functional link between mitochondrial dysfunctions and TA remains unknown. Herein, we investigate the alteration in muscle-proteome of TAM patients, the molecular mechanism of TA onset and a potential therapy in a preclinical mouse model of the disease. We show that in vivo chronic inhibition of the mitochondrial ATP synthase in muscle causes TA. Upon long-term restrained oxidative phosphorylation (OXPHOS), oxidative soleus experiments a metabolic and structural switch towards glycolytic fibers, increases mitochondrial fission, and activates mitophagy to recycle damaged mitochondria. TA result from the overresponse of the fission controller DRP1, that upregulates the Store-Operate-Calcium-Entry and increases the mitochondria-SR interaction in a futile attempt to buffer calcium overloads upon prolonged OXPHOS inhibition. Accordingly, hypoxic muscles cultured ex vivo show an increase in mitochondria/SR contact sites and autophagic/mitophagic zones, where TA clusters grow around defective mitochondria. Moreover, hypoxia triggered a stronger TA formation upon ATP synthase inhibition, and this effect was reduced by the DRP1 inhibitor mDIVI. Remarkably, the muscle proteome of TAM patients displays similar alterations in mitochondrial dynamics and in ATP synthase contents. In vivo edaravone treatment in mice with restrained OXPHOS restored a healthy phenotype by prompting mitogenesis and mitochondrial fusion. Altogether, our data provide a functional link between the ATP synthase/DRP1 axis and the setting of TA, and repurpose edaravone as a possible treatment for TA-associated disorders.
RESUMEN: La unión entre cuidado y mujer y el hecho de que sea una realidad social en continuo cambio hace que se trate de un campo estratégico desde el que analizar las implicaciones que las transformaciones socioeconómicas y culturales tienen en el sistema de género existente, así la crisis de cuidados lo que muestra es la crisis del sistema de género actual sobre el que se sustenta la sociedad patriarcal y se organiza la reproducción de la vida humana. En este contexto las familias han desarrollado estrategias para abordar los cuidados, siendo una de ellas externalizar parte del trabajo de cuidados en el ámbito doméstico mediante la contratación de mujeres migrantes. Con esta investigación nos proponemos explorar como se produce en los hogares abulenses la contratación de una mujer migrante para el cuidado de una persona mayor. Para ello se ha realizado una aproximación etnográfica al objeto de estudio, tomando como unidad de observación los hogares contratantes y como ámbito geográfico de estudio la provincia de Ávila. La técnica utilizada para recabar la información ha sido la entrevista en profundidad. Se ha entrevistado a quince personas que han contratado a mujeres inmigrantes para el cuidado de personas mayores. Se ha buscado la variabilidad de hombres y mujeres, el contexto rural o urbano y si las cuidadoras, inmigrantes latinoamericanas, realizaban los cuidados a tiempo total o parcial. Los resultados indican que la decisión
En el presente texto se discute sobre el miedo frente al desastre, alrededor de lo ocurrido en varias inundaciones en Valle de Chalco, municipio de la metrópolis de México. A partir de una postura socio-antropológica en este artículo se busca estudiar los conflictos socioambientales como un mélange de intersubjetividades para encontrar un tipo de acción política potencial y emergente. A través de una reflexión sobre el miedo líquido (BAUMAN, 2006) y sobre una perspectiva de análisis de conflictos llamada la comunidad hídrica imaginada (DE ALBA; SALAZAR; MARTIN, 2015) se intenta contribuir a un debate actual sobre los fenómenos hídricos de las metrópolis contemporáneas.
En este artículo se presenta una discusión teórica sobre la paradoja de ‘actuar’ y ‘creer’, para señalar la relevancia que adquiere la ciudad (donde se actúa) frente a los territorios que ocupan, en sus márgenes, los pueblos originarios (donde se cree). A partir de allí, se desarrolla un análisis del concepto prácticas de ciudadanía de dichos pueblos en relación con las ‘prácticas de ciudadanía’ urbanas, en particular, alrededor de los conflictos hídricos, que dibuja a la política como “una lucha por las mentes y los corazones” (Harbers et al., 2016).Se utiliza el caso de la comunidad de San Bartolo Ameyalco, localizado en el corazón de la metrópoli de México, para intentar demostrar cómo las prácticas de un actor político marginalizado —un pueblo originario—, se combinan en procesos de alta complejidad, que se trata de distinguirla como aquellos que viven una ‘ciudadanía de un día’.Se concluye que son necesarios más estudios —respecto a las prácticas de ciudadanía en la vida urbana— que permitan distinguir cuáles son sus diferencias y sus distinciones en cada una de sus periferias sociales o políticas.
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