Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes.
Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Japan.
Atsuhiko T
AT
Naito
Tomokazu
T
Sumida
Seitaro
S
Nomura
Mei-Lan
ML
Liu
Tomoaki
T
Higo
Akito
A
Nakagawa
Katsuki
K
Okada
Taku
T
Sakai
Akihito
A
Hashimoto
Yurina
Y
Hara
Ippei
I
Shimizu
Weidong
W
Zhu
Haruhiro
H
Toko
Akemi
A
Katada
Hiroshi
H
Akazawa
Toru
T
Oka
Jong-Kook
JK
Lee
Tohru
T
Minamino
Toshio
T
Nagai
Kenneth
K
Walsh
Akira
A
Kikuchi
Misako
M
Matsumoto
Marina
M
Botto
Ichiro
I
Shiojima
Issei
I
Komuro
D000375:Aging / Q000378:metabolism*; D000818:Animals; D015922:Complement C1q / Q000378:metabolism*; D003173:Complement C1s / Q000378:metabolism; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D051379:Mice; D044967:Serum / Q000378:metabolism; D060449:Wnt Signaling Pathway
D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D015922:Complement C1q; D003173:Complement C1s