Descripción del proyecto
La aptitud muscular: el papel de las proteínas
La contracción muscular es facilitada por complejos proteicos meticulosamente orquestados que incluyen actina y miosina. El mantenimiento dinámico de los niveles de proteínas (proteostasis) es primordial para el tono muscular, así como para la función muscular en el movimiento y el estremecimiento. El equipo del proyecto PROTEOFIT, financiado con fondos europeos, está interesado en comprender cómo el músculo detecta los niveles de proteínas y se adapta en consecuencia. Los investigadores están estudiando los mecanismos moleculares de la adaptación de los músculos a los cambios metabólicos con la esperanza de proporcionar información esencial sobre cómo se perturban estos mecanismos en la obesidad. Se espera que la identificación de los agentes clave del proceso allane el camino a nuevas intervenciones contra la obesidad y los trastornos asociados.
Objetivo
Muscle function is essential for motion, exercise, and shivering, whereas physical inactivity is causally related to reduced metabolic fitness in animal models and humans. A critical requirement for muscle function is that proteins are properly produced and, if necessary, degraded to adapt the proteome to meet metabolic demands. However, there is a fundamental, open gap in understanding how challenges to muscle proteostasis are sensed and how protein fate is subsequently adapted to enhance muscle function in exercise or, conversely, how it is compromised in obesity. I hypothesize that protein fate is highly adaptive and can be fine-tuned to promote proteostasis, the integrity of muscle cells, and metabolic health. Identifying novel key regulators of these mechanisms in muscle may hold great therapeutic promise for targeting metabolic fitness to combat obesity and associated disorders. In this innovative project I want to define new mechanisms of muscle adaptation in humans and preclinical mouse models, with the ultimate goal of using this knowledge to improve muscle function and fitness in obesity. I will identify exercise- and obesity-specific substrates of the proteasome by ubiquitomics in human and mouse muscle and define how the ubiquitination and turnover of these proteins dictates muscle cell function. In a complementary approach, I will use novel loss- and gain-of-function mouse models allowing for precise muscle-specific manipulation of Nfe2l1, an adaptive regulator of proteasomal protein degradation, to define the biological and therapeutic significance of this pathway for muscle function in exercise and obesity. In summary, this novel work will provide a transformative molecular understanding of muscle adaption to metabolic challenges and provide insight into how this translates into metabolic fitness and the development of obesity and associated disorders in humans.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
80539 Muenchen
Alemania