BackgroundSkeletal muscle displays a marked accumulation of denervated myofibers at advanced age, which coincides with an acceleration of muscle atrophy.MethodsIn this study, we evaluated the hypothesis that the accumulation of denervated myofibers in advanced age is due to failed reinnervation by examining muscle from young adult (YA) and very old (VO) rats and from a murine model of sporadic denervation secondary to neurotrypsin over-expression (Sarco mouse).ResultsBoth aging rat muscle and Sarco mouse muscle exhibited marked fiber-type grouping, consistent with repeating cycles of denervation and reinnervation, yet in VO muscle, rapsyn at the endplate increased and was associated with only a 10 % decline in acetylcholine receptor (AChR) intensity, whereas in Sarco mice, there was a decline in rapsyn and a 25 % decrease in AChR intensity. Transcripts of muscle-specific kinase (21-fold), acetylcholine receptor subunits α (68-fold), ε (threefold) and γ (47-fold), neural cell adhesion molecule (66-fold), and runt-related transcription factor 1 (33-fold) were upregulated in VO muscle of the rat, consistent with the marked persistent denervation evidenced by a large proportion of very small fibers (>20 %). In the Sarco mice, there were much smaller increases in denervation transcripts (0–3.5-fold) and accumulation of very small fibers (2–6 %) compared to the VO rat, suggesting a reduced capacity for reinnervation in aging muscle. Despite the marked persistent denervation in the VO rat muscle, transcripts of neurotrophins involved in promoting axonal sprouting following denervation exhibited no increase, and several miRNAs predicted to suppress neurotrophins were elevated in VO rat.ConclusionsOur results support the hypothesis that the accumulation of denervated fibers with aging is due to failed reinnervation and that this may be affected by a limited neurotrophin response that mediates axonal sprouting following denervation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0101-y) contains supplementary material, which is available to authorized users.

Sepsis triggers more severe and sustained muscle fiber atrophy in limb muscles when compared with respiratory muscle. This response is associated with enhanced proteasomal and autophagic proteolytic pathway activities and is triggered by inhibition of the AKT and complex 1 of the mammalian target of rapamycin pathways and activation of the AMPK pathway.

Objective-Angiopoietin-1 (Ang-1) is an important regulator of angiogenesis in endothelial cells. It promotes migration, proliferation, and differentiation of cells, although the regulating factors involved in these processes remain unclear. In this study, we evaluated the contribution of the transcription factor early growth response-1 (Egr-1) to Ang-1-induced angiogenesis in human umbilical vein endothelial cells (HUVECs). Methods and Results-Expression of Egr-1 was evaluated with real-time PCR and immunoblotting, whereas Egr-1 DNA binding activity was monitored with electrophoretic mobility shift assays. Cell migration was measured with wound healing and Boyden chamber assays, whereas cell proliferation and differentiation of cells into capillary-like tube structures were monitored with cell counting, BrdU incorporation and Matrigels. To selectively inhibit Egr-1 expression, we used both siRNA oligonucleotides and specific DNAzymes. Egr-1 mRNA expression rose approximately 9-fold within 2 hours of Ang-1 exposure and declined thereafter. Upregulation of Egr-1 expression was accompanied by an increase in nuclear mobilization and augmented DNA binding. These processes were mediated through the Erk1/2, PI-3 kinase/AKT, and mTOR pathways. Knockdown of Egr-1 expression completely abrogated Ang-1-induced endothelial migration and significantly reduced proliferation and capillary-like tube formation of HUVECs that overexpress Ang-1. Key Words: endothelial cells Ⅲ angiopoietins Ⅲ angiogenesis Ⅲ transcription factors Ⅲ cell migration T he receptor tyrosine kinase (Tie-2) and its associated ligands, the angiopoietins, have emerged as important regulators of angiogenesis both in adults and in embryos. In adult mice, Ang-1 stimulates in vivo vascular remodeling, vascular enlargement, wound healing, and lymphangiogenesis. 1 In addition, Ang-1 inhibits endothelial cell (EC) apoptosis and stimulates migration, proliferation, and differentiation of these cells. 1 Despite the importance of the Ang-1/Tie-2 receptor pathway to vascular homeostasis and angiogenesis, little is known about transcription factors that are activated downstream from it. Daly et al 2 have reported that Ang-1 inhibits the transcriptional activity of FoxO-1 downstream of the PI-3 kinase/AKT pathway, thereby reducing the expression of several proapoptotic proteins. Elk-1 is activated by Ang-1 downstream from the Erk1/2 pathway and forms a complex by binding serum response factor and serum response element in various promoters. 3 However, neither of these studies addressed the importance of these transcription factors in mediating the biological functions of the Ang-1/Tie-2 pathway. Conclusion-Early growth response-1 (Egr-1) has recently been identified as a transcription factor that is significantly induced downstream from Tie-2 receptors. 4 Egr-1 is an immediateearly gene that is rapidly and transiently induced by many stimuli, including hypoxia, shear stress, and injury. On activation it binds promoter regions of several growth factors, cytokines, recepto...