Publication: Mecanismos moleculares y diferencias sexuales en enfermedades neurodegenerativas y musculoesqueléticas asociadas al envejecimiento : estudios en modelos animales de parkinson y osteosarcopenia
Authors
Gallo Soljancic, Pablo
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Escuela Internacional de Doctorado
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De Stefano, Maria Egle ; Herrero Ezquerro, María Trinidad
Publisher
Universidad de Murcia
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DOI
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info:eu-repo/semantics/doctoralThesis
Description
Abstract
El capítulo 1 de la tesis doctoral analiza el potencial de Octodon degus como modelo animal para investigar osteoporosis y sarcopenia, dos enfermedades asociadas al envejecimiento. El texto parte de la preocupación global por el envejecimiento de la población y la creciente incidencia de enfermedades crónicas en personas mayores, enfatizando la necesidad urgente de modelos animales adecuados para estudiar estos trastornos.
Se ofrece primero una visión general del envejecimiento y sus consecuencias, centrándose en la osteoporosis, una enfermedad que provoca la disminución de la densidad ósea, especialmente en mujeres mayores, así como en la sarcopenia, que implica la pérdida de masa y fuerza muscular en el adulto mayor. El capítulo repasa brevemente los modelos animales más usados para ambas enfermedades, como la ovariectomía o dietas especiales para osteoporosis, y la inmovilización o manipulación genética para sarcopenia, destacando sus limitaciones.
En este contexto, se presenta a O. degus como un modelo animal prometedor, ya que comparte características fisiológicas y conductuales relevantes con humanos, como su ciclo diurno y vida social compleja. Además, O. degus desarrolla de manera espontánea enfermedades relacionadas con la edad, como la diabetes tipo 2 o patologías neurodegenerativas, lo que añade valor a su uso en investigación geriátrica.
Se plantea la hipótesis de que O. degus experimenta cambios naturales en la masa muscular y en el volumen óseo conforme envejece, de manera análoga a los humanos, con posibles diferencias según sexo y miembro corporal. Los objetivos de la investigación incluyen caracterizar estos cambios relacionados con la edad en músculo y hueso, analizar diferencias entre sexos y comparar extremidades anteriores y posteriores. El propósito final es validar a O. degus como modelo útil para el estudio de osteoporosis y sarcopenia, facilitando así el desarrollo de nuevas estrategias terapéuticas y preventivas para mejorar la calidad de vida en la vejez.
El capítulo 2 de la tesis se centra en los mecanismos moleculares implicados en la enfermedad de Parkinson (EP), enfocándose en la interacción entre el estrés oxidativo y las modificaciones epigenéticas en un modelo murino de EP inducido por MPTP, una neurotoxina que reproduce el daño en las neuronas dopaminérgicas típico de la enfermedad.
Aunque se han realizado progresos en el conocimiento de la EP, persisten interrogantes sobre cómo el estrés oxidativo y los cambios epigenéticos contribuyen a la neurodegeneración. Este estudio emplea dos grupos de ratones (control y tratados con MPTP) para analizar de forma dinámica los niveles de marcadores de daño oxidativo al ADN (8-OHdG) y epigenéticos (5-mC y 5-hmC) en el mesencéfalo ventral y el estriado, áreas clave en la EP, en varios momentos tras la administración de la neurotoxina.
Los objetivos específicos son cuantificar los niveles de 8-OHdG, 5-mC y 5-hmC, comparar los resultados entre grupos y analizar la dinámica temporal de estos procesos, todo ello mediante técnicas avanzadas de cuantificación molecular.
La relevancia de este trabajo radica en varios puntos: explora cómo el estrés oxidativo y la epigenética se relacionan en fases tempranas de la neurodegeneración, examina diferencias regionales en el cerebro y analiza eventos moleculares que podrían convertirse en biomarcadores o futuras dianas terapéuticas para la EP. Los hallazgos podrían abrir nuevas vías para la intervención precoz y el tratamiento de enfermedades neurodegenerativas.
En resumen, la tesis ofrece una visión integral sobre el uso de modelos animales para el estudio del envejecimiento, centrándose tanto en la degeneración ósea y muscular como en los mecanismos moleculares de neurodegeneración, con el objetivo de contribuir a una mejor comprensión y abordaje de estas enfermedades asociadas a la edad.
Chapter 1 of this doctoral thesis analyzes the potential of Octodon degus as an animal model for studying osteoporosis and sarcopenia, two diseases associated with aging. The chapter begins by addressing global concerns about population aging and the growing incidence of chronic diseases among the elderly, highlighting the urgent need for suitable animal models to study these disorders. First, it offers an overview of aging and its consequences, focusing on osteoporosis—a disease that causes a decrease in bone density, especially in older women—and on sarcopenia, which involves the loss of muscle mass and strength in older adults. The chapter briefly reviews the most commonly used animal models for both diseases, such as ovariectomy or special diets for osteoporosis, and immobilization or genetic manipulation for sarcopenia, noting their limitations. In this context, O. degus is introduced as a promising animal model, sharing relevant physiological and behavioral characteristics with humans, such as its diurnal cycle and complex social life. Furthermore, O. degus spontaneously develops age-related diseases, such as type 2 diabetes and neurodegenerative disorders, which enhances its value in geriatric research. The hypothesis proposed is that O. degus experiences natural changes in muscle mass and bone volume as it ages, similarly to humans, with possible differences depending on sex and limb. The research objectives include characterizing these age-related changes in muscle and bone, analyzing sex differences, and comparing forelimbs and hindlimbs. The ultimate goal is to validate O. degus as a useful model for the study of osteoporosis and sarcopenia, thereby facilitating the development of new therapeutic and preventive strategies to improve quality of life in old age. Chapter 2 of the thesis focuses on the molecular mechanisms involved in Parkinson’s disease (PD), specifically on the interaction between oxidative stress and epigenetic modifications in a murine model of PD induced by MPTP, a neurotoxin that reproduces the damage to dopaminergic neurons typical of the disorder. Although progress has been made in understanding PD, questions remain about how oxidative stress and epigenetic changes contribute to neurodegeneration. This study uses two groups of mice (control and MPTP-treated) to dynamically analyze levels of DNA oxidative damage markers (8-OHdG) and epigenetic markers (5-mC and 5-hmC) in the ventral midbrain and striatum—key brain areas in PD—at various times after administration of the neurotoxin. The specific objectives are to quantify levels of 8-OHdG, 5-mC, and 5-hmC, compare results between groups, and analyze the temporal dynamics of these processes, all using advanced molecular quantification techniques. The relevance of this work lies in several points: it explores how oxidative stress and epigenetics are related in the early stages of neurodegeneration, examines regional brain differences, and analyzes molecular events that could become biomarkers or future therapeutic targets for PD. The findings could open new avenues for early intervention and the treatment of neurodegenerative diseases. In summary, the thesis offers a comprehensive view on the use of animal models to study aging—focusing both on bone and muscle degeneration and on the molecular mechanisms of neurodegeneration—with the aim of contributing to a better understanding and management of these age-associated diseases.
Chapter 1 of this doctoral thesis analyzes the potential of Octodon degus as an animal model for studying osteoporosis and sarcopenia, two diseases associated with aging. The chapter begins by addressing global concerns about population aging and the growing incidence of chronic diseases among the elderly, highlighting the urgent need for suitable animal models to study these disorders. First, it offers an overview of aging and its consequences, focusing on osteoporosis—a disease that causes a decrease in bone density, especially in older women—and on sarcopenia, which involves the loss of muscle mass and strength in older adults. The chapter briefly reviews the most commonly used animal models for both diseases, such as ovariectomy or special diets for osteoporosis, and immobilization or genetic manipulation for sarcopenia, noting their limitations. In this context, O. degus is introduced as a promising animal model, sharing relevant physiological and behavioral characteristics with humans, such as its diurnal cycle and complex social life. Furthermore, O. degus spontaneously develops age-related diseases, such as type 2 diabetes and neurodegenerative disorders, which enhances its value in geriatric research. The hypothesis proposed is that O. degus experiences natural changes in muscle mass and bone volume as it ages, similarly to humans, with possible differences depending on sex and limb. The research objectives include characterizing these age-related changes in muscle and bone, analyzing sex differences, and comparing forelimbs and hindlimbs. The ultimate goal is to validate O. degus as a useful model for the study of osteoporosis and sarcopenia, thereby facilitating the development of new therapeutic and preventive strategies to improve quality of life in old age. Chapter 2 of the thesis focuses on the molecular mechanisms involved in Parkinson’s disease (PD), specifically on the interaction between oxidative stress and epigenetic modifications in a murine model of PD induced by MPTP, a neurotoxin that reproduces the damage to dopaminergic neurons typical of the disorder. Although progress has been made in understanding PD, questions remain about how oxidative stress and epigenetic changes contribute to neurodegeneration. This study uses two groups of mice (control and MPTP-treated) to dynamically analyze levels of DNA oxidative damage markers (8-OHdG) and epigenetic markers (5-mC and 5-hmC) in the ventral midbrain and striatum—key brain areas in PD—at various times after administration of the neurotoxin. The specific objectives are to quantify levels of 8-OHdG, 5-mC, and 5-hmC, compare results between groups, and analyze the temporal dynamics of these processes, all using advanced molecular quantification techniques. The relevance of this work lies in several points: it explores how oxidative stress and epigenetics are related in the early stages of neurodegeneration, examines regional brain differences, and analyzes molecular events that could become biomarkers or future therapeutic targets for PD. The findings could open new avenues for early intervention and the treatment of neurodegenerative diseases. In summary, the thesis offers a comprehensive view on the use of animal models to study aging—focusing both on bone and muscle degeneration and on the molecular mechanisms of neurodegeneration—with the aim of contributing to a better understanding and management of these age-associated diseases.
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