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DESCRIPTION (provided by applicant): AMP activated protein kinase (AMPK) is considered to be a cellular fuel gauge and it is a therapeutic target for disease states such as obesity and type 2 diabetes. Pharmacological activation of AMPK leads to a variety of beneficial effects, including increased insulin sensitivity, reduced glucose production in liver, higher rates of glucose and lipid oxidation in muscle and weight loss. However, chronic activation of AMPK also has potential deleterious effects, such as reduced muscle and whole body growth. This may have severe developmental consequences in children, which are increasingly subject to obesity and type 2 diabetes. For example, the common diabetes drug and AMPK activator, metformin, is prescribed for children as young as 10 years old. However, the chronic pharmacological activation of AMPK in a well-fed, highly anabolic juvenile creates an unusual physiological condition, whereby pathways that are normally reciprocally regulated are simultaneously active. AMPK is activated by energy stress and leads to net protein degradation and reduced growth, while growth factors that are prevalent in juveniles activate the Akt pathway that leads to net protein synthesis. Thus, the balance of protein synthesis and degradation may be differentially affected by AMPK activators in juveniles and adults. In addition, muscle growth in juveniles is associated with a relatively short period of extensive proliferation and fusion of satellite cells o existing muscle fibers, and AMPK has been shown to interfere with this critical process, perhaps further compromising muscle growth. These negative effects may be compounded in obese juveniles, as these conditions interfere with growth factor and nutrient signaling pathways as well as satellite cell function. The proposed work will examine the short- and long-term effects of
AMPK activators on muscle growth, whole-animal growth, and protein turnover and satellite cell function in highly anabolic normal, obese, and AMK knockout juvenile mice. The specific Aims are (1) to determine the influence of short term and chronic AMPK activation on skeletal muscle and whole animal growth, (2) to determine the influence of short term and chronic AMPK activation on protein synthesis and degradation in skeletal muscle, and (3) to characterize the role that AMPK activation plays in regulating satellite cell recruitment and its effect on muscle growth. These studies will entail gross anatomical analyses, microscopic analysis of muscle fiber growth, measurement of protein turnover and analysis of protein expression in the AMPK and Akt pathways, using an in vivo model of obesity as well as AMK knockout mice. These analyses will shed light on basic aspects of the regulation of protein turnover and satellite cell function, while yielding insights on potential consequences or benefits of using AMPK activators in juveniles.
