title: Aging increases CCN1 expression leading to muscle senescence.
abstract: Using microarray analysis, we found that aging sarcopenia is associated with a sharp increase in the mRNA of the matricellular protein CCN1 (Cyr61/CTGF/Nov). CCN1 mRNA was upregulated 113-fold in muscle of aged vs. young rats. CCN1 protein was increased in aging muscle in both rats (2.8-fold) and mice (3.8-fold). When muscle progenitor cells (MPCs) were treated with recombinant CCN1, cell proliferation was decreased but there was no change in the myogenic marker myoD. However, the CCN1-treated MPCs did express a senescence marker (SA-βgal). Interestingly, we found CCN1 increased p53, p16(Ink4A), and pRP (hypophosphorylated retinoblastoma protein) protein levels, all of which can arrest cell growth in MPCs. When MPCs were treated with aged rodent serum CCN1 mRNA increased by sevenfold and protein increased by threefold suggesting the presence of a circulating regulator. Therefore, we looked for a circulating regulator. Wnt-3a, a stimulator of CCN1 expression, was increased in serum from elderly humans (2.6-fold) and aged rodents (2.0-fold) compared with young controls. We transduced C2C12 myoblasts with wnt-3a and found that CCN1 protein was increased in a time- and dose-dependent manner. We conclude that in aging muscle, the circulating factor wnt-3a acts to increase CCN1 expression, prompting muscle senescence by activating cell arrest proteins.
authors.affiliation: Key Laboratory of Remodeling-Related Cardiovascular Diseases, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China; and.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: Janet D
authors.initials: JD
authors.lastname: Klein
authors.forename: Faten
authors.initials: F
authors.lastname: Hassounah
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiaonan H
authors.initials: XH
authors.lastname: Wang
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D055515:Cysteine-Rich Protein 61 / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000378:metabolism
chemical_list: C491850:CCN1 protein, mouse; C501849:CCN1 protein, rat; D055515:Cysteine-Rich Protein 61; D012333:RNA, Messenger
keywords: Cyr61; RB; p16ink4a; p50; wnt-3a