The Role of the Central Melanocortin System in the Muscle Wasting of Cachexia

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DESCRIPTION (provided by applicant): The goal of this research is to understand the role of the central melanocortin system In the pathogenesis of muscle wasting in cachexia. A patient's ability to maintain lean mass is an important factor in quality of life as well as an important predictor of survival. Currently there are no therapeutic interventions that can improve lean mass retention in chronic disease. The role of the melanocortin system in appetite and basal metabolic rate is well established, but its role in the regulation of the anabolic/catabolic balance of muscle has not been fully examined. Melanocortin 4 receptor (MC4R) knockout mice have an increased lean mass phenotype, and are resistant to loss of lean mass in cachexia. Pharmacologic blockade of melanocortin receptors also ameliorates experimentally-induced cachexia. Critical to the pathogenesis of muscle breakdown are the muscle specific E3 ubiquitin ligases, MAFbx and MuRF-1.1 have shown that pharmacological activation of the central melanocortin system induces expression of these genes in skeletal muscle. The neuroanatomical pathway by which melanocortin signaling influences muscle is likely to be mediated by the sympathetic nervous system, via the signaling mediators AMPK and the FOXO family of transcription factors. Therefore I will investigate whether the transduction of this signal can be altered by the presence of sympathetic blockade. A signaling pathway by which central melanocortins influence muscle mass will be examined in the setting of pharmacologic melanocortin activation. The signaling pathway established will then be examined in an animal model of experimental cachexia in the presence and absence of melanocortin blockade. By comparing pharmacologic activation to the disease model, a common molecular singnaling pathway in muscle will be identified. Finally, the neuronal connectivity of this pathway will be examined by utilizing a retrograde track tracing approach. Pseudorabies virus will be injected into muscle of MC4R-GFP transgenic mice, and infection of MC4R-positive neurons in the hypothalamus will be examined. This work will help develop a clearer understanding of the neural component of muscle wasting in cachexia. A mechanistic understanding of this pathway will provide insight into the care of these patients and provide future targets for rational drug design.