Muscle wasting occurs in many diseases and systematically in older people. It corresponds to the loss of muscle mass that reduces the quality of life and contributes to mortality. In order to fight this major public health concern, it is necessary to identify and to understand its mechanisms of control. One of them is the ubiquitin-mediated degradation of proteins by the proteasome (Hnia et al., 2019). We have identified the Asb2ß protein (Bello et al., 2009), which is an actor of this system and a novel regulator of muscle mass (Davey et al., 2016). Its overexpression is sufficient to induce muscle atrophy in mice (Davey et al., 2016). Our ongoing project is to decipher Asb2ß’s mechanisms of action through the identification of its targets, which are polyubiquitylated and degraded by the proteasome. To reach this aim, we have generated a mouse model that allows the conditional invalidation of ASB2 gene in adult skeletal muscles. By comparing the proteome and the the ubiquitinome of muscles expressing or not Asb2ß, we will identify putative Asb2ß’s targets. The specific aim of the Master project is to perform quantitative proteomic analysis using label free or tag (TMT) tandem mass spectrometry (Tandem Mass Tag) of skeletal mouse muscles expressing or not Asb2ß. The next step will be to validate these substrates using biochemical and cell biology approaches. This project should unravel potential therapeutic target to fight muscle wasting.
Techniques used during the internship:
Bibliography: Bello, N.F., I. Lamsoul, M.L. Heuze, A. Metais, G. Moreaux, D.A. Calderwood, D. Duprez, C. Moog-Lutz, and P.G. Lutz. 2009. The E3 ubiquitin ligase specificity subunit ASB2beta is a novel regulator of muscle differentiation that targets filamin B to proteasomal degradation. Cell death and differentiation. 16:921-932. Davey, J.R., K.I. Watt, B.L. Parker, R. Chaudhuri, J.G. Ryall, L. Cunningham, H. Qian, V. Sartorelli, M. Sandri, J. Chamberlain, D.E. James, and P. Gregorevic. 2016. Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass. JCI insight. 1. Hnia, K., T. Clausen, and C. Moog-Lutz. 2019. Shaping Striated Muscles with Ubiquitin Proteasome System in Health and Disease. Trends Mol Med. 25:760-774.
Supervisors : Dr. Christel MOOG-LUTZ and Dr. Marie-Pierre BOUSQUET IPBS, Toulouse, team “Proteomics and Mass Spectrometry of Biomolecules” http://www.ipbs.fr/proteomics-and-mass-spectrometry-biomolecules
The Proteomics Infrastructure of Toulouse is equiped with up-to-date mass spectrometers and skilled researchers and engineers are able to mentor young and motivated scientists who want to specialize in proteomics.
Contact : Christel.Lutz@ipbs.fr