p75^NTR‐mediated signaling promotes the survival of myoblasts and influences muscle strength

Abstract

During muscle development, the p75(NTR) is expressed transiently on myoblasts. The temporal expression pattern of the receptor raises the possibility that the receptor is influencing muscle development. To test this hypothesis, p75(NTR)-deficient mutant mice were tested for muscle strength by using a standard wire gripe strength test and were found to have significantly decreased strength relative to that of normal mice. When normal mybolasts were examined in vivo for expression of NGF receptors, p75(NTR) was detected on myoblasts but the high affinity NGF receptor, trk A, was not co-expressed with p75(NTR). In vitro, proliferating C2C12 and primary myoblasts co-expressed the p75(NTR) and MyoD, but immunofluorescent analysis of primary myoblasts and RT-PCR analysis of C2C12 mRNA revealed that myoblasts were devoid of trk A. In contrast to the cell death functions that characterize the p75(NTR) in neurons, p75(NTR)-positive primary and C2C12 myoblasts did not differentiate or undergo apoptosis in response to neurotrophins. Rather, myoblasts survived and even proliferated when grown at subconfluent densities in the presence of the neurotrophins. Furthermore, when myoblasts treated with NGF were lysed and immunoprecipitated with antibodies against phosphorylated I-kappaB and AKT, the cells contained increased levels of both phospho-proteins, both of which promote cell survival. By contrast, neurotrophin-treated myoblasts did not induce phosphorylation of Map Kinase p42/44 or p38, indicating the survival was not mediated by the trk A receptor. Taken together, the data indicate that the p75(NTR) mediates survival of myoblasts prior to differentiation and that the activity of this receptor during myogenesis is important for developing muscle.

Small, Nonpeptide p75NTRLigands Induce Survival Signaling and Inhibit proNGF-Induced Death

“…NTR actions include activation of NFB Foehr et al, 2000;Gentry et al, 2000;Mamidipudi et al, 2002;Reddypalli et al, 2005) and PI3K/AKT (Roux et al, 2001;Lachyankar et al, 2003;Reddypalli et al, 2005). These signaling intermediates have been shown to be capable of being independently regulated by Trk and p75 NTR through pathways with varying degrees of overlap and cross-talk and with different kinetics.…”

“…NTR signaling through phosphatidylinositol 3-kinase AKT (PI3K/AKT) or interleukin-1 receptorassociated kinase/nuclear factor B (IRAK/NFB) promotes survival Roux et al, 2001;Mamidipudi et al, 2002;Reddypalli et al, 2005).…”

Functional Role of Sortilin in Myogenesis and Development of Insulin-responsive Glucose Transport System in C2C12 Myocytes

“…Because sortilin expression is up-regulated (Fig. 1), whereas p75NTR and NGF expressions are down-regulated (26), upon differentiation, fine-tuning of the expression levels of these proteins would be required for proper development and maintenance of healthy muscle tissues (28). Although the signaling cascades involved in its myogenic actions have yet to be clarified, several lines of evidence indicate a signaling relationship between p75NTR and the Rho family of small GTPbinding proteins in the process of cellular differentiation (40, 41).…”

Astrocyte and Muscle-Derived Secreted Factors Differentially Regulate Motoneuron Survival

“…Attempts to rectify this resulted in the production of a p75NTR ExonIVϪ/Ϫ mouse, which has subsequently been shown to express a pro-apoptotic fragment, which may reflect a gain-of-function mutation rather than a loss of function (Paul et al, 2004). Because of these technical challenges as well as the constitutive deletion of a protein that is critical for multiple developmental processes (e.g., dendritic development, neurite outgrowth, and myoblast survival), it is difficult to make any strong conclusions regarding the role of p75 NTR in the survival or death of MNs during development (Reddypalli et al, 2005;Salama-Cohen et al, 2005).…”