RESUMEN
The microscopic worm Caenorhabditis elegans (C. elegans) is one of the most prominent animal models for aging studies. This is underscored by the fact that most of the genes and interventions that modulate the aging process, such as the insulin/IGF pathway, caloric restriction and mitochondrial signalling, were first identified in this organism. Remarkably, many features of the mammalian aging process are recapitulated in C. elegans: over time, damage to macromolecule accumulates, structural cellular components progressively deteriorate, physiological functions decline, resistance to stress and infections decreases, while morbidity and mortality rates increase. In humans, age represents risk factor number one for most diseases ultimately leading to death in industrialized countries, namely cardiovascular diseases, cancer and neurodegenerative disorders. Genes regulating aging in C. elegans are evolutionarily conserved and their deregulation is often involved in the development of age-associated diseases in humans. It is therefore likely that any intervention that extends C. elegans lifespan will indicate strategies to positively impact on healthy human longevity.
Asunto(s)
Envejecimiento/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Longevidad/fisiología , Modelos Animales , Adaptación Fisiológica/fisiología , Animales , HumanosRESUMEN
Satellite cells are the main source of myogenic progenitors in postnatal skeletal muscle, but their use in cell therapy for muscle disorders is limited because these cells cannot be delivered through circulation and they are rapidly exhausted in severe myopathies. The search for alternative donor cells is ongoing, but none of the candidates so far show all the features required for successful colonization and repair of diseased muscle. In this study, we show that bisperoxovanadium, a phospho-tyrosine phosphatase inhibitor, induces myogenic cells to acquire a gene expression profile and a differentiation potential consistent with the phenotype of a circulating precursors, while maintaining their myogenic potential. These effects are mediated, at least in part, by NF-kappaB activation through the Tyr42-IkappaB-alpha phosphorylation, as shown by the expression of the dominant negative mutant form of the p50 NF-kappaB subunit. Moreover, when bisperoxovanadium-treated cells are injected into the femoral artery of alpha-sarcoglican null dystrophic mice, they are able to circulate and to reach muscle tissue; importantly, they contribute to muscle regeneration, as shown by the expression of alpha-sarcoglican in some fibers. Our observations indicate that bisperoxovanadium, or similar compounds, may prove very valuable to obtain and to expand, from committed cells, multipotent cell populations suitable for gene-cell therapy applications and may help to understand the molecular basis of genome reprogramming and "stem-ness."