Age-Associated Methylation Suppresses SPRY1, Leading to a Failure of Re-quiescence and Loss of the Reserve Stem Cell Pool in Elderly Muscle.

The molecular mechanisms by which aging affects stem cell number and function are poorly understood. Murine data have implicated cellular senescence in the loss of muscle stem cells with aging. Here, using human cells and by carrying out experiments within a strictly pre-senescent division count, we demonstrate an impaired capacity for stem cell self-renewal in elderly muscle. We link aging to an increased methylation of the SPRY1 gene, a known regulator of muscle stem cell quiescence. Replenishment of the reserve cell pool was modulated experimentally by demethylation or siRNA knockdown of SPRY1. We propose that suppression of SPRY1 by age-associated methylation in humans inhibits the replenishment of the muscle stem cell pool, contributing to a decreased regenerative response in old age. We further show that aging does not affect muscle stem cell senescence in humans.

HLA-B27 subtype oligomerization and intracellular accumulation patterns correlate with predisposition to spondyloarthritis.

OBJECTIVE: Mechanisms underlying the striking association of spondyloarthritis (SpA) with the class I major histocompatibility complex molecule HLA-B27 remain poorly understood. SpA-like disease develops spontaneously in B*2705-transgenic rats, in conjunction with high HLA-B27 expression levels. This study was undertaken to examine the effects of increased expression of HLA-B27 alleles that are differentially associated with SpA on oligomerization and intracellular redistribution. METHODS: HeLa cells were transfected with complementary DNA encoding for HLA-B proteins fused to yellow fluorescent protein and/or Renilla luciferase and harvested at an early phase and a later phase of expression. We monitored HLA-B intracellular trafficking and localization by means of microscopy and live-cell imaging. Bioluminescence resonance energy transfer (BRET) and Western blotting were used to monitor HLA-B oligomerization. RESULTS: At low expression levels, BRET signals were similarly elevated for all SpA-associated HLA-B27 alleles tested, but were lower for the nonassociated B*2706. Of note, at higher expression levels, HLA-B27 signals remained steady while signal for HLA-B7 decreased sharply, reaching the level observed for B*2706. This was due at least in part to a decreased oligomer proportion without unfolded protein response outbreak. Such differential behavior was not abrogated by proteasome inhibition. With increased expression, all HLA-B proteins accumulated to a high density in cytoplasmic vesicles with labile form and size. The extent of this phenomenon was closely correlated with the level of association with predisposition to SpA. CONCLUSION: To our knowledge, this is the first report of a correlation between the level of predisposition to SpA conferred by HLA-B27 alleles and their biochemical behavior. These findings open new perspectives for understanding the pathogenicity of HLA-B27.

Age-dependent alteration in muscle regeneration: the critical role of tissue niche.

Although adult skeletal muscle is composed of fully differentiated fibers, it retains the capacity to regenerate in response to injury and to modify its contractile and metabolic properties in response to changing demands. The major role in the growth, remodeling and regeneration is played by satellite cells, a quiescent population of myogenic precursor cells that reside between the basal lamina and plasmalemma and that are rapidly activated in response to appropriate stimuli. However, in pathologic conditions or during aging, the complete regenerative program can be precluded by fibrotic tissue formation and resulting in functional impairment of the skeletal muscle. Our study, along with other studies, demonstrated that although the regenerative program can also be impaired by the limited proliferative capacity of satellite cells, this limit is not reached during normal aging, and it is more likely that the restricted muscle repair program in aging is presumably due to missing signals that usually render the damaged muscle a permissive environment for regenerative activity.