Estudio del efecto del silenciamiento del receptor de neurotrofinas P75 en la sinapsis neuromuscular y en la fibra muscular durante el envejecimiento.
Loading...
Date
2022
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Universidad de Concepción
Abstract
La unión neuromuscular (UNM) es una sinapsis periférica colinérgica formada entre un axón motor, una fibra muscular esquelética y células de Schwann terminales. La UNM adulta posee una morfología denominada tipo pretzel, que es inervada por un terminal axonal de calibre constante y cubierta por 3 a 5 células de Schwann terminales. Aun cuando esta estructura de la UNM acompaña la vida madura de muchas especies, durante el envejecimiento los tres componentes celulares que conforman esta sinapsis presentan alteraciones en su arquitectura que se acompañan de anormalidades funcionales y morfológicas de las fibras musculares. Creciente evidencia ha señalado que vías de señalización activadas por la unión de neurotrofinas a sus receptores Trks son reguladoras clave de la función, mantención y organización estructural de la UNM. Específicamente, el receptor de neurotrofinas p75, que señaliza junto a las neurotrofinas, pro-neurotrofinas y receptores Trks, se expresa en los tres componentes de la UNM adulta; sin embargo, su función en la UNM envejecida es desconocida. Para determinar el efecto del receptor de neurotrofinas p75 sobre las alteraciones de la UNM y de la fibra muscular durante el envejecimiento, se caracterizó morfológica y molecularmente la sinapsis neuromuscular de ratones nulos para la expresión de este receptor. Los resultados obtenidos a través de análisis mediante microscopía confocal 3D indican que la ausencia del receptor p75 disminuye la inervación del terminal postsináptico y la superposición de las células de Schwann terminales con el terminal axonal. A nivel postsináptico, la ausencia de p75 resultó en un aumento del recambio de receptores de acetilcolina (AChRs) y en músculos de fenotipo envejecido tardío, como el Levator auris longus, la complejidad morfológica de la estructura postsináptica se vio disminuida. A nivel muscular, se observó un aumento en la proporción de fibras musculares rápidas con calibre pequeño sin afectarse las fibras musculares lentas. Tampoco se observaron variaciones en la fibrosis, atrofia o ciclos de daño y regeneración muscular. Estos resultados sugieren que el receptor p75 es requerido para el mantenimiento de la UNM envejecida, permitiendo una mayor superposición de las células de Schwann terminales con el terminal axonal, regulando la inervación de los aparatos postsinápticos y la estabilidad de los AChRs.
The neuromuscular junction (NMJ) is a peripheral cholinergic synapse formed among a motor axon, a skeletal muscle fiber, and terminal Schwann cells. The adult NMJ has a so-called “pretzel-like” morphology which is innervated by an axon terminal with constant caliber and covered by 3 to 5 terminal Schwann cells. Even though the structure of the NMJ accompanies the mature life of many species, during aging the three cellular components that make up this synapse exhibit alterations in their architecture that are accompanied by functional and morphological abnormalities of the muscle fibers. Increasing evidence has indicated that signaling pathways activated by the binding of neurotrophins to their Trk receptors are key regulators of the function, maintenance, and structural organization of the NMJ. Specifically, the p75 neurotrophin receptor, which signals along with neurotrophins, pro-neurotrophins, and Trk receptors, is expressed in all three components of the adult NMJ; however, its function in the aged NMJ is unknown. To determine the effect of this neurotrophin receptor on the NMJ and muscle fiber alterations during aging, the neuromuscular synapse of p75 receptor knockout mice (KOp75) was characterized morphologically and molecularly. The obtained results indicate that the absence of the p75 neurotrophin receptor decreases the innervation of the postsynaptic terminal concomitant with smaller area of the presynaptic terminal. The overlap of terminal Schwann cells with the axon terminal also decreases and is accompanied by a reduction in the area of this cell type. In the postsynaptic structure. The absence of p75 increases the turnover of acetylcholine receptors (AChRs) and in muscles with a late-aging phenotype, such as the Levator auris longus muscle, it decreases the morphological complexity of the postsynaptic structure. At the muscle level, we observed an increase in the proportion of fast muscle fibers with small caliber without affecting the slow muscle fibers or variations in fibrosis, atrophy, or cycles of muscle damage and regeneration. These results suggest that p75 neurotrophin receptor is required for the maintenance of the aged NMJ, allowing a greater overlap of terminal Schwann cells with the axon terminal, regulating the innervation of the postsynaptic apparatus, the stability of AChRs, and likely the functionality of this synaps.
The neuromuscular junction (NMJ) is a peripheral cholinergic synapse formed among a motor axon, a skeletal muscle fiber, and terminal Schwann cells. The adult NMJ has a so-called “pretzel-like” morphology which is innervated by an axon terminal with constant caliber and covered by 3 to 5 terminal Schwann cells. Even though the structure of the NMJ accompanies the mature life of many species, during aging the three cellular components that make up this synapse exhibit alterations in their architecture that are accompanied by functional and morphological abnormalities of the muscle fibers. Increasing evidence has indicated that signaling pathways activated by the binding of neurotrophins to their Trk receptors are key regulators of the function, maintenance, and structural organization of the NMJ. Specifically, the p75 neurotrophin receptor, which signals along with neurotrophins, pro-neurotrophins, and Trk receptors, is expressed in all three components of the adult NMJ; however, its function in the aged NMJ is unknown. To determine the effect of this neurotrophin receptor on the NMJ and muscle fiber alterations during aging, the neuromuscular synapse of p75 receptor knockout mice (KOp75) was characterized morphologically and molecularly. The obtained results indicate that the absence of the p75 neurotrophin receptor decreases the innervation of the postsynaptic terminal concomitant with smaller area of the presynaptic terminal. The overlap of terminal Schwann cells with the axon terminal also decreases and is accompanied by a reduction in the area of this cell type. In the postsynaptic structure. The absence of p75 increases the turnover of acetylcholine receptors (AChRs) and in muscles with a late-aging phenotype, such as the Levator auris longus muscle, it decreases the morphological complexity of the postsynaptic structure. At the muscle level, we observed an increase in the proportion of fast muscle fibers with small caliber without affecting the slow muscle fibers or variations in fibrosis, atrophy, or cycles of muscle damage and regeneration. These results suggest that p75 neurotrophin receptor is required for the maintenance of the aged NMJ, allowing a greater overlap of terminal Schwann cells with the axon terminal, regulating the innervation of the postsynaptic apparatus, the stability of AChRs, and likely the functionality of this synaps.
Description
Tesis presentada para optar al título de Bioquímico/a.
Keywords
Sinapsis, Oxonas, Proteoglicán