title: Impaired metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes.
abstract: Accumulation of damaged macromolecules, including irreversibly oxidized proteins, is a hallmark of cellular and organismal ageing. Failure of protein homesotasis is a major contributor to the age-related accumulation of damaged proteins. In skeletal muscle, tissue maintenance and regeneration is assured by resident adult stem cells known as satellite cells. During senescence their replication and differentiation is compromised contributing to sarcopenia. In this study we have addressed the impact of oxidatively modified proteins in the impaired metabolism of senescent human satellite cells. By using a targeted proteomics analysis we have found that proteins involved in protein quality control and glycolytic enzymes are the main targets of oxidation (carbonylation) and modification with advanced glycation/lipid peroxidation end products during replicative senescence of satellite cells. Inactivation of the proteasome in aged cells appeared as a key contributor to the accumulation of such damaged proteins. Untargeted metabolomic profiling and functional analyses indicated glucose metabolism impairment in senescent cells, although mitochondrial respiration remained unaffected. A metabolic shift leading to increased mobilization of non-carbohydrate substrates as branched chain amino acids or long chain fatty acids was observed in senescent cells. In addition, phospho-and glycerolipids metabolism was altered. Increased levels of acyl-carnitines indicated augmented turnover of storage and membrane lipids for energy production. Such changes reflect alterations in membrane composition and dysregulation of sphingolipids signaling during senescence. This study establishes a new concept connecting oxidative protein modifications with the altered cellular metabolism associated with the senescent phenotype. In addition, these findings highlight the molecular mechanisms implicated in satellite cells dysfunction during ageing, paving the road for future therapeutic interventions aimed at preventing oxidative modifications of proteins and/or stimulating their elimination.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06 (CNRS UMR 8256, INSERM U1164), Biological adaptation and aging - IBPS, France. Electronic address: martin.baraibar@snv.jussieu.fr.
authors.forename: Martin
authors.initials: M
authors.lastname: Baraibar
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06 (CNRS UMR 8256, INSERM U1164), Biological adaptation and aging - IBPS, France.
authors.forename: Janek
authors.initials: J
authors.lastname: Hyzewicz
authors.affiliation: University of Southern Denmark (University of Southern Denmark), Department of Biochemistry and Molecular Biology, Denmark.
authors.forename: Adelina
authors.initials: A
authors.lastname: Rogowska-Wrzesinska
authors.affiliation: Institut Cochin (INSERM), INSERM, U1016, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Bulteau
authors.affiliation: Institut Cochin (INSERM), INSERM, U1016, France.
authors.forename: Carina
authors.initials: C
authors.lastname: Prip-Buus
authors.affiliation: Institut de Myologie (CHU Pitié-Salpétrière, Sorbonne Universités, UPMC Univ Paris 06), UMRS INSERM U974, CNRS UMR 7215, France.
authors.forename: Gillian
authors.initials: G
authors.lastname: Butler-Browne
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06 (CNRS UMR 8256, INSERM U1164), Biological adaptation and aging - IBPS, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Friguet