Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G(1)/S cell cycle progression viathe activation of phosphatidylinositol 3 '-kinase/Akt signaling pathway

Interest is growing in methods to extend replicative life span of non-immor talized stem cells. Using the insulin-like growth factor I (IGF-I) transgen ic mouse in which the IG;F-I transgene is expressed during skeletal muscle development and maturation prior to isolation and during culture of satelli te cells (the myogenic stem cells of mature skeletal muscle fibers) as a mo del system, we elucidated the underlying molecular mechanisms of IGF-I-medi ated enhancement of proliferative potential of these cells. Satellite cells from IGF-I transgenic muscles achieved at least five additional population doublings above the maximum that was attained by wild type satellite cells . This IGF-I-induced increase in proliferative potential was mediated via a ctivation of the phosphatidylinositol 3'-kinase/Akt pathway, independent of mitogen-activated protein kinase activity, facilitating G(1)/S cell cycle progression via a down-regulation of p27(Kip1). Adenovirally mediated ectop ic overexpression of p27(Kip1) i, exponentially growing IGF-I transgenic sa tellite cells reversed the increase in cyclin E-cdk2 kinase activity, pRb p hosphorylation, and cyclin A protein abundance, thereby implicating an impo rtant role for p27(Kip1) i, promoting satellite cell senescence. These obse rvations provide a more complete dissection of molecular events by which in creased local expression of a growth factor in mature skeletal muscle fiber s extends replicative life span of primary stem cells than previously known .