Age-Associated Methylation Suppresses SPRY1, Leading to a Failure of Re-quiescence and Loss of the Reserve Stem Cell Pool in Elderly Muscle
Anne Bigot,
William J. Duddy,
Zamalou G. Ouandaogo,
Elisa Negroni,
Virginie Mariot,
Svetlana Ghimbovschi,
Brennan Harmon,
Aurore Wielgosik,
Camille Loiseau,
Joe Devaney,
Julie Dumonceaux,
Gillian Butler-Browne,
Vincent Mouly,
Stéphanie Duguez
Affiliations
Anne Bigot
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
William J. Duddy
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
Zamalou G. Ouandaogo
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
Elisa Negroni
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
Virginie Mariot
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
Svetlana Ghimbovschi
Genomics, Proteomics, and Bioinformatics (GPB) Core of the Intellectual and Developmental Disabilities Research Center (IDDRC), Children’s National Medical Center, Washington, DC 20010, USA
Brennan Harmon
Genomics, Proteomics, and Bioinformatics (GPB) Core of the Intellectual and Developmental Disabilities Research Center (IDDRC), Children’s National Medical Center, Washington, DC 20010, USA
Aurore Wielgosik
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
Camille Loiseau
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
Joe Devaney
Genomics, Proteomics, and Bioinformatics (GPB) Core of the Intellectual and Developmental Disabilities Research Center (IDDRC), Children’s National Medical Center, Washington, DC 20010, USA
Julie Dumonceaux
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
Gillian Butler-Browne
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
Vincent Mouly
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
Stéphanie Duguez
Sorbonne Universités, UPMC University of Paris 06, INSERM UMRS974, CNRS FRE3617, Centre de Recherche en Myologie (CRM), GH Pitié Salpêtrière, Paris 13, France
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.
