AmyloAge: balancing proteostasis and metabolism in age-related muscular degeneration

Descripción del proyecto

Alteraciones proteínicas en el músculo envejecido

La masa y la fuerza muscular disminuyen con la edad y pueden alcanzar niveles bajos críticos en ancianos, que culminan en una enfermedad llamada sarcopenia (SP). La falta actual de información sobre la heterogeneidad de la SP y sus determinantes genéticos y ambientales obstaculizan el desarrollo de intervenciones efectivas. El proyecto AmyloAge, financiado con fondos europeos, trabaja con la hipótesis de que una dieta rica en grasas genera agregados que contienen amiloides en los músculos envejecidos, lo que provoca fenotipos similares a la miositis por cuerpos de inclusión (MCI). Los científicos del proyecto investigarán la evolución de la composición proteínica del músculo y descubrirán posibles determinantes genéticos del deterioro muscular. Los resultados desvelarán los mecanismos de agregación proteínica y disfunción metabólica en el músculo envejecido con posible importancia terapéutica.

Objetivo

After the age of 30, our muscle strength declines by ~14% per decade. In up to 40% of the elderly, this decline culminates in sarcopenia (SP), critically low muscle mass, causing impaired mobility and longer hospitalizations. Muscle decline rates vary greatly between individuals due to genetic and environmental factors. Yet, our lack of insight into these factors impedes developing effective measures against SP.

SP is clinically similar to inclusion body myositis (IBM), the most common myopathy in the elderly, and their molecular phenotypes are very similar. Preliminary data from my host lab, the Laboratory of Integrative Systems Physiology (LISP), show that high-fat diet induces amyloid-containing aggregates in the muscles of aging mice. Such aggregates are hallmarks of muscle proteinopathies such as IBM. Hence, these diseases may be the pathological extremes of natural protein aggregation in the muscle.

LISP recently described the protective, therapeutic role of activating mitochondrial stress responses in aggregation diseases. Activating these pathways prevents aggregate formation in cells, worms and transgenic Alzheimer’s mice. I thus hypothesize that mitochondrial dysfunction worsens the pathology of muscle aggregation diseases and SP.

My project AmyloAge will explore natural aging in muscle in large, genetically diverse populations of worms, mice and humans. I will use my expertise in proteomics to study the evolution of muscle protein composition and find the genetic determinants associated with unhealthy protein aggregation and muscle decline. With my expertise in biostatistics, I will build an analysis pipeline to find the genes and molecular pathways responsible for protein aggregation and metabolic dysfunction in the muscle.

AmyloAge will increase our knowledge of the molecular and physiological variability in muscle aging. This will lay the groundwork for preventive interventions against SP and protein aggregation diseases like IBM.