During the acute stress response, the Sympathetic Nervous System (SNS) induces rapid catabolism of energy reserves through the release of catecholamines and activation of the cAMP/PKA/CREB signaling. However, the molecular mechanism by which catecholamines control skeletal muscle protein balance remains to be elucidated. Diverse stresses conditions induce reduction of protein synthesis in skeletal muscle in part due to upregulation of Redd1 (Regulated in DNA damage and development 1), a protein that functions to repress signaling through the mechanistic target of rapamycin (mTOR) protein kinase complex (mTORC1). We have previously found that a single injection of epinephrine in fed mice increases the protein content and transcriptional activity of Redd1 in skeletal muscle. Conversely, the mRNA levels of Redd1 are decreased in mice muscles that overexpress the dominant negative against CREB. Furthermore, we observed that the addition of forskolin (FSK) in C2C12 cells exposed to serum deprivation exacerbates the CREB transcriptional complex and the expression of Redd1, an effect that can be inhibited by H89, a PKA inhibitor. Thus, the main goal in this project is to determine whether the SNS, and more specifically CREB, can modulate Redd1 expression in response to stress. To that end, we shall use sympathectomyzed and muscle CREB conditioned knockout mice to measure the expression of genes and proteins in response to food deprivation and cold exposure. Furthermore, we shall perform chip and gene reporter assays to investigate the effect of isoproterenol or FSK on Redd1 promoter. To further investigate the role of CREB in the modulation of Redd1, myoblasts will be transfected with CREB dominant negative and exposed to serum deprivation. Understanding these mechanisms could help in the identification of therapeutic strategies to counteract muscle atrophy.
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