title: Age-associated NF-κB signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function.
abstract: Skeletal muscle is a highly regenerative tissue, but muscle repair potential is increasingly compromised with advancing age. In this study, we demonstrate that increased NF-κB activity in aged muscle fibers contributes to diminished myogenic potential of their associated satellite cells. We further examine the impact of genetic modulation of NF-κB signaling in muscle satellite cells or myofibers on recovery after damage. These studies reveal that NF-κB activity in differentiated myofibers is sufficient to drive dysfunction of muscle regenerative cells via cell-non-autonomous mechanisms. Inhibition of NF-κB, or its downstream target Phospholipase A2, in myofibers rescued muscle regenerative potential in aged muscle. Moreover, systemic administration of sodium salicylate, an FDA-approved NF-κB inhibitor, decreased inflammatory gene expression and improved repair in aged muscle. Together, these studies identify a unique NF-κB regulated, non-cell autonomous mechanism by which stem cell function is linked to lipid signaling and homeostasis, and provide important new targets to stimulate muscle repair in aged individuals.
authors.affiliation: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Cambridge, MA 02138, USA.|Joslin Diabetes Center, Boston, MA 02215, USA.|Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Juhyun
authors.initials: J
authors.lastname: Oh
authors.affiliation: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Cambridge, MA 02138, USA.|Joslin Diabetes Center, Boston, MA 02215, USA.|Division of Plastic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Indranil
authors.initials: I
authors.lastname: Sinha
authors.affiliation: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Cambridge, MA 02138, USA.|Joslin Diabetes Center, Boston, MA 02215, USA.
authors.forename: Kah Yong
authors.initials: KY
authors.lastname: Tan
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, MA 02115, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Rosner
authors.affiliation: Joslin Diabetes Center, Boston, MA 02215, USA.|Department of Biomedical Engineering, Boston University, Boston 02215, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Dreyfuss
authors.affiliation: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Ornela
authors.initials: O
authors.lastname: Gjata
authors.affiliation: Joslin Diabetes Center, Boston, MA 02215, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Tran
authors.affiliation: Joslin Diabetes Center, Boston, MA 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Shoelson
authors.affiliation: Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Cambridge, MA 02138, USA.|Joslin Diabetes Center, Boston, MA 02215, USA.|Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
mesh_terms: D000368:Aged; D000375:Aging / Q000502:physiology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016922:Cellular Senescence; D015870:Gene Expression; D006801:Humans; D051379:Mice; D024510:Muscle Development / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000378:metabolism*; D012980:Sodium Salicylate / Q000494:pharmacology; D055153:Stem Cell Niche
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D012980:Sodium Salicylate
keywords: aging; regeneration; satellite cell; skeletal muscle