title: Attenuation of p38α MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells.
abstract: Functional competence and self-renewal of mammalian skeletal muscle myofibers and progenitor cells declines with age. Progression of the muscle aging phenotype involves the decline of juvenile protective factorsi.e., proteins whose beneficial functions translate directly to the quality of life, and self-renewal of progenitor cells. These characteristics occur simultaneously with the age-associated increase of p38α stress response signaling. This suggests that the maintenance of low levels of p38α activity of juvenile tissues may delay or attenuate aging. We used the dominant negative haploinsufficient p38α mouse (DN-p38α(AF/+)) to demonstrate that in vivo attenuation of p38α activity in the gastrocnemius of the aged mutant delays age-associated processes that include: a) the decline of the juvenile protective factors, BubR1, aldehyde dehydrogenase 1A (ALDH1A1), and aldehyde dehydrogenase 2 (ALDH2); b) attenuated expression of p16(Ink4a) and p19(Arf) tumor suppressor genes of the Cdkn2a locus; c) decreased levels of hydroxynonenal protein adducts, expression of COX2 and iNOS; d) decline of the senescent progenitor cell pool level and d) the loss of gastrocnemius muscle mass. We propose that elevated P-p38α activity promotes skeletal muscle aging and that the homeostasis of p38α impacts the maintenance of a beneficial healthspan.
authors.affiliation: The Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77551-06743, USA.
authors.forename: John
authors.initials: J
authors.lastname: Papaconstantinou
authors.affiliation: The Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77551-06743, USA.
authors.forename: Chen Z
authors.initials: CZ
authors.lastname: Wang
authors.affiliation: The Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77551-06743, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: The Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77551-06743, USA.
authors.forename: San
authors.initials: S
authors.lastname: Yang
authors.affiliation: The Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77551-06743, USA.
authors.forename: James
authors.initials: J
authors.lastname: Deford
authors.affiliation: Institute for Research on Cancer and Ageing of Nice, INSERM, U1081-UMR CNRS 7284, University of Nice - Sophia Antipolis, Centre Antoine Lacassagne, Nice, France.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Bulavin
authors.affiliation: The Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77551-06743, USA.
authors.forename: Naseem H
authors.initials: NH
authors.lastname: Ansari
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology*; D000444:Aldehyde Dehydrogenase / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D018482:Muscle, Skeletal / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D050697:Retinal Dehydrogenase; D015398:Signal Transduction; D013234:Stem Cells / Q000473:pathology*; D013312:Stress, Physiological
chemical_list: C584278:Bub1b protein, mouse; C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000080924:Aldehyde Dehydrogenase 1 Family; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D017346:Protein Serine-Threonine Kinases; D048308:Mitogen-Activated Protein Kinase 14
keywords: aging; gastrocnemius; juvenile protective factors; myofibers; p38α; progenitor cells