Increased activity of canonical NF-kB signaling in muscle fibers alters the satellite cell niche and restrains muscle stem cell function during aging

It has been known for some time that muscle repair potential becomes increasingly compromised with advancing age, and that this age-related defect is associated with reduced activity of muscle satellite cells and with the presence of chronic, low grade inflammation in the muscle. Working from the hypothesis that a heightened inflammatory tone in aged muscle could contribute to poor regenerative capacity, we developed genetic systems to inducibly alter inflammatory gene expression in satellite cells or muscle fibers by modulation of the activity of nuclear factor B (NF-B), a master transcriptional regulator of inflammation whose activity is upregulated in many cell types and tissues with age. These studies revealed that activation of NF-B activity in muscle fibers, but not in satellite cells, drives muscle dysfunction and that lifelong inhibition of NF-B activity in myofibers preserves muscle regenerative potential with aging via cell-non-autonomous effects on satellite cell function. Further analysis of differential gene expression in muscles with varying NF-B activity identified a secreted phospholipase (PLA2G5) as a myofiber-expressed NF-B-regulated gene that governs muscle regenerative capacity with age. Together, these data suggest a model in which NF-B activation in muscle fibers increases PLA2G5 expression and drives the impairment in regenerative function characteristic of aged muscle. Importantly, inhibition of NF-B function reverses this impairment, suggesting that FDA-approved drugs, like salsalate, a prodrug form of sodium salicylate, may provide new therapeutic avenues for elderly patients with reduced capacity to recover effectively from muscle injury.

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Oh J, Sinha I, Tan KY, Rosner B, Dreyfuss JM, Gjata O, Tran P, Shoelson SE, Wagers AJ