Metabolism Core

ABSTRACT Core C – METABOLISM The ability to maintain metabolic and redox homeostasis is at the center of muscle health and degeneration. The Metabolism Core provides access to unique state of the art tools to quantify altered metabolism and mitochondrial function in skeletal muscle. Disruption of energy homeostasis due to mitochondrial dysfunction is a key mechanism controlling diverse cellular processes that can lead to muscle degeneration, including the balance between protein synthesis and degradation, contractile function, E-C coupling, and apoptosis. The Metabolism Core will provide an integrative approach to analyze the role of changes in metabolic and mitochondrial function in skeletal muscle dysfunction to a broad user base. We have developed state of the art tools that include global and targeted metabolomics, magnetic resonance and optical spectroscopy, and biochemical analyses of isolated mitochondria and permeabilized fibers that will provide vastly improved and detailed insights into muscle biology, and an ability to monitor therapeutic approaches at the molecular level. The goal of this core is to expand access to these tools and expertise for experimental design, data collection, analysis, and interpretation to address the role of metabolism in skeletal muscle health and dysfunction. Aim 1 will provide a broad array of targeted and global metabolomic and lipidomic analyses as well as metabolic flux measurements from skeletal muscle biopsy, ligaments and tendons, as well as biofluids and related biological samples. Aim 2 will provide state of the art analyses of in vivo mitochondrial capacity and quality (ATPmax and P/O) and muscle energy state (PCr/ATP and ADP/ATP). Aim 3 will provide detailed biochemical analyses of oxidative phosphorylation and mitochondrial oxidative stress in permeabilized muscle fibers and isolated mitochondria. These measurements will provide an integrated picture of muscle metabolism, mitochondrial function and muscle energetics that can be used to understand the mechanisms leading to protection or pathology in models of skeletal muscle disease. The central role of metabolism connecting all aspects of muscle physiology allows this Core to provide a natural bridge between the Mechanics and Devices and Quantitative Analysis Cores of the CTMR.