Absence of complement factor H reduces physical performance in C57BL6 mice.
Absence of complement factor H reduces physical performance in C57BL6 mice.
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DOI：
10.1016/j.imbio.2020.152003
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发表时间：
2020-09
期刊：
影响因子：
2.8
通讯作者：
Alexander, Jessy J.
中科院分区：
文献类型：
--
作者：
Seldeen, Kenneth L.;Thiyagarajan, Ramkumar;Redae, Yonas;Jacob, Alexander;Troen, Bruce R.;Quigg, Richard J.;Alexander, Jessy J.
Complement (C) system is a double edge sword acting as the first line of defense on the one hand and causing aggravation of disease on the other. C activation when unregulated affects different organs including muscle regeneration. However, the effect of factor H (FH), a critical regulator of the alternative C pathway in muscle remains to be studied. FH deficiency results in excessive C activation and generates proinflammatory fragments C5a and C3a as byproducts. C3a and C5a signal through their respective receptors, C5aR and C3aR. In this study, we investigated the role of FH and downstream C5a/C5aR signaling in muscle architecture and function. Using the FH knockout (fh−/−) and fh−/−/C5aR−/double knockout mice we explored the role of C, specifically the alternative C pathway in muscle dysfunction. Substantial C3 and C9 deposits occur along the walls of the fh−/− muscle fibers indicative of unrestricted C activation. Physical performance assessments of the fh−/− mice show reduced grip endurance (76 %), grip strength (14 %) and rotarod balance (36 %) compared to controls. Histological analysis revealed a shift in muscle fiber populations indicated by an increase in glycolytic MHC IIB fibers and reduction in oxidative MHC IIA fibers. Consistent with this finding, mitochondrial DNA (mtDNA) and citrate synthase (CS) expression were both reduced indicating possible reduction in mitochondrial biomass. In addition, our results showed a significant increase in TGFβ expression and altered TGFβ localization in this setting. The architecture of cytoskeletal proteins actin and vimentin in the fh−/− muscle was changed that could lead to contractile weakness and loss of skeletal muscle elasticity. The muscle pathology in fh−/− mice was reduced in fh−/−/C5aR−/− double knockout (DKO) mice, highlighting partial C5aR dependence. Our results for the first time demonstrate an important role of FH in physical performance and skeletal muscle health.
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影响因子：
3.7
作者：
Bloemberg D;Quadrilatero J
通讯作者：
Quadrilatero J
DOI：
10.1073/pnas.72.5.1758
发表时间：
1975-01-01
影响因子：
11.1
作者：
CLARKE, M;SCHATTEN, G;SPUDICH, JA
通讯作者：
SPUDICH, JA
影响因子：
15.3
作者：
Hopken, UE;Lu, B;Gerard, C
通讯作者：
Gerard, C
影响因子：
2.8
作者：
Alexander, Jessy J.;Sankaran, Jeyantt S.;Judex, Stefan
通讯作者：
Judex, Stefan
影响因子：
11.2
作者：
CORNELIO, F;DONES, I
通讯作者：
DONES, I