title: Age-Associated Methylation Suppresses SPRY1, Leading to a Failure of Re-quiescence and Loss of the Reserve Stem Cell Pool in Elderly Muscle.
abstract: 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.
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bigot
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France.
authors.forename: William J
authors.initials: WJ
authors.lastname: Duddy
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France.
authors.forename: Zamalou G
authors.initials: ZG
authors.lastname: Ouandaogo
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Negroni
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Mariot
authors.affiliation: Genomics, Proteomics, and Bioinformatics (GPB) Core of the Intellectual and Developmental Disabilities Research Center (IDDRC), Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ghimbovschi
authors.affiliation: Genomics, Proteomics, and Bioinformatics (GPB) Core of the Intellectual and Developmental Disabilities Research Center (IDDRC), Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Brennan
authors.initials: B
authors.lastname: Harmon
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Wielgosik
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France; Sorbonne Universités, UPMC University of Paris 06, INSERM, UMR-S 1158, Neurophysiologie Respiratoire Expérimentale et Clinique, Paris 13, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Loiseau
authors.affiliation: Genomics, Proteomics, and Bioinformatics (GPB) Core of the Intellectual and Developmental Disabilities Research Center (IDDRC), Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Devaney
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dumonceaux
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France.
authors.forename: Gillian
authors.initials: G
authors.lastname: Butler-Browne
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France. Electronic address: vincent.mouly@upmc.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Mouly
authors.affiliation: Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France. Electronic address: stephanie.duguez@upmc.fr.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Duguez
mesh_terms: D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000066673:Cell Self Renewal; D016922:Cellular Senescence; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D010750:Phosphoproteins; C486055:SPRY1 protein, human
keywords: DNA methylation; aging; human muscle stem cell; myoblast; quiescence; sprouty1