MMPC :: MICROMouse Program Application Abstract

MICROMouse Program Application Abstract

MMPC Funded Abstracts

MICROMouse

Funding Programs

In vivo assessment of mouse muscle oxidative capacity by 31P-MRS

Douglas Befroy (New Haven, CT)

MICROMouse Program

Alterations in mitochondrial function have been implicated in the development of obesity, in the pathogenesis of insulin resistance and progression to type 2 diabetes, and as one of the deleterious consequences of a sedentary lifestyle. Numerous strains of transgenic mice are continuously being developed to examine basic physiological mechanisms of mitochondrial metabolism as well as the relationship between mitochondrial function and metabolic disease. Magnetic resonance spectroscopy (MRS) offers a unique strategy to assess metabolism in vivo. The metabolic responses to muscle contraction(s) can be monitored non-invasively using dynamic 31P-MRS and mitochondrial oxidative capacity can be calculated from the kinetics of phosphocreatine (PCr) repletion following a bout of exercise. This methodology has been extensively validated in humans and rat models, and recent studies demonstrate that it can successfully be translated to mouse. This application proposes to implement these techniques and develop a new diagnostic test of muscle mitochondrial capacity to offer to Yale MMPC clients. The method offers several advantages over existing assays of mitochondrial function: 1) the technique complements an existing 31P-MRS methodology available at the Yale MMPC to measure resting muscle Pi to ATP flux; 2) it provides a functionally relevant measurement of in vivo mitochondrial capacity, rather than a theoretical estimate from in vitro analyses of muscle tissue, 3) many transgenic models exhibit no overt metabolic phenotype under normal physiological conditions and require some form of intervention to reveal enhancements or defects in metabolism – this measurement is performed in exercising muscle, enhancing the ability to detect modulations in mitochondrial metabolism; 4) the technique is minimally-invasive, preventing the sacrifice of precious mice which are then available for other analyses, and also permits longitudinal studies. This proposal also includes the development of customized, partially-automated, analysis software to standardize data processing, including the the calculation of metabolite kinetics and oxidative capacity, and enhance experimental throughput.

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