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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DK084646-03
Application #
8113998
Study Section
Special Emphasis Panel (ZDK1-GRB-W (M1))
Program Officer
Castle, Arthur
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
3
Fiscal Year
2011
Total Cost
$44,500
Indirect Cost
Name
Oregon Health and Science University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Braun, Theodore P; Szumowski, Marek; Levasseur, Peter R et al. (2014) Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle. PLoS One 9:e106489
Braun, Theodore P; Grossberg, Aaron J; Krasnow, Stephanie M et al. (2013) Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle. FASEB J 27:3572-82
Braun, Theodore P; Grossberg, Aaron J; Veleva-Rotse, Biliana O et al. (2012) Expression of myeloid differentiation factor 88 in neurons is not requisite for the induction of sickness behavior by interleukin-1?. J Neuroinflammation 9:229
Tan, Benjamin H L; Fladvad, Torill; Braun, Theodore P et al. (2012) P-selectin genotype is associated with the development of cancer cachexia. EMBO Mol Med 4:462-71
Braun, Theodore P; Orwoll, Benjamin; Zhu, Xinxia et al. (2012) Regulation of lean mass, bone mass, and exercise tolerance by the central melanocortin system. PLoS One 7:e42183
Grossberg, Aaron J; Zhu, XinXia; Leinninger, Gina M et al. (2011) Inflammation-induced lethargy is mediated by suppression of orexin neuron activity. J Neurosci 31:11376-86
Braun, Theodore P; Zhu, Xinxia; Szumowski, Marek et al. (2011) Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis. J Exp Med 208:2449-63
Grossberg, Aaron J; Scarlett, Jarrad M; Zhu, XinXia et al. (2010) Arcuate nucleus proopiomelanocortin neurons mediate the acute anorectic actions of leukemia inhibitory factor via gp130. Endocrinology 151:606-16
Braun, Theodore P; Marks, Daniel L (2010) Pathophysiology and treatment of inflammatory anorexia in chronic disease. J Cachexia Sarcopenia Muscle 1:135-145