Genetic and Pharmacologic Inhibition of Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein Expression Protects Against Denervation-Induced Skeletal Muscle Atrophy In Vivo

Description
Title: Genetic and Pharmacologic Inhibition of Cellular Inhibitor of Apoptosis 1 (cIAP1) Protein Expression Protects Against Denervation-Induced Skeletal Muscle Atrophy In Vivo
Authors: Lejmi Mrad, Rim
Date: 2016
Abstract: Skeletal muscle atrophy is a debilitating condition caused by pathological conditions including cancer cachexia, disuse and denervation. Disuse atrophy is characterized by reduction in fiber size, fiber-type change and induction of markers of atrophy such as MuRF1 and Fn14. Recent studies have focused on understanding the fundamental role of signalling pathways and the proteolytic system in response to muscle atrophy. Unfortunately the exact mechanisms behind atrophy remain poorly understood. I recently demonstrated that cIAP1 and/or cIAP2 proteins are critical regulators of NF-kB activation, which has been shown to be involved in skeletal muscle atrophy. Here, I used genetic and pharmacological means to investigate the role of cIAP1 in a denervation-induced skeletal muscle atrophy model. Interestingly, I found that upon denervation loss of cIAP1 rescues muscle fiber size, prevents fiber-type changing and inhibits the expression of MuRF1 and Fn14. Moreover, treatment of mice with Smac mimetic compounds (SMC), a novel class of small molecule IAP antagonists, showed successful knockdown of cIAP1 in muscle and protects against denervation-induced muscle atrophy. Taken together, these data reveal that cIAP1 is both a novel mediator of skeletal muscle atrophy and an important therapeutic target.
URL: http://hdl.handle.net/10393/34260
http://dx.doi.org/10.20381/ruor-5228
CollectionThèses, 2011 - // Theses, 2011 -
Files