Project 3.  Satellite cells, cytokine mileau, and regenerative failure in DMD.

Terence Partridge, PhD

The IGF-1 (and IGF-2) pathways have been extensively studied, and the anabolic effect of IGF-1 on muscle is very well established.  Recently, the molecular pathways converging on AKT1 have been found to be perhaps the singular most important pathway in both muscle hypertrophy and atrophy, with AKT1 phosphorylation state dictating the activity of the hypertrophy mTOR pathway, and the atrophic FOXO/atrogenes pathway.   We have recruited Dr. Terence Partridge, a well known myoblast cell biologist from the MRC at Hammersmith Hospital, to lead the research on Project 3.  Dr. Partridge focuses Aim 1 on the influence of the IGF-1 pathway on satellite cell biology.  Current dogma suggests that dystrophic muscle loses its satellite cell populations as a function of age.  To the contrary, Dr. Partridge has used an experimental system of isolated muscle fibers to show that there is no significant reduction in number of satellite cells with age in the normal or dystrophic (mdx) mouse. He also shows a progressive reduction in the proliferative capacity of satellite cells during aging, but again this is similar in dystrophic and normal mice.  Preliminary experiments indicate that this loss of proliferative capacity may be ameliorated by treatment with IGF-1. This, together with the demonstration of beneficial effects of the IGF-1 transgene on muscle pathology in the mdx mouse, suggests that this class of cytokine may help to slow the progress of the dystrophinopathies by enhancing activation of dormant satellite cells.  In parallel, Co-PI of Project 3, Dr. Hoffman, has done characterization of the IGFs and IGF binding proteins, both in dystrophies, and in muscle regeneration, and finds that many of the inhibitory IGFBPs are induced at a later stage of pathology.  Thus, while dystrophic muscle shows very high levels of IGF1 and IGF2, the potential anabolic activity of these cytokines appears abrogated by the equally high induction of multiple inhibitory binding proteins.  One of the best studied binding proteins, IGFBP3, is also a modulator of the TGF-beta cascade, and investigation of IGFBP3 as a modulator of Duchenne dystrophy progression is a focus of Project 2 (Dr. Chen).