Aim: It has been suggested that the proliferation and early differentiation of myoblasts are impaired in Marfan syndrome (MFS) mice during muscle regeneration. However, the underlying cellular and molecular mechanisms remain poorly understood. Here, we investigated muscle regeneration in MFS mouse models by analyzing the influence of the fibrotic niche on satellite cell function. Methods: In vivo, ex vivo, and in vitro experiments were performed. In addition, we evaluated the effect of the pharmacological inhibition of fibrosis using Ang-(1–7) on regenerating skeletal muscles of MFS mice. Results: The skeletal muscle of MFS mice shows an increased accumulation of collagen fibers (81.2%), number of fibroblasts (157.1%), and Smad2/3 signaling (110.5%), as well as an aberrant number of fibro-adipogenic progenitor cells in response to injury compared with wild-type mice. There was an increased number of proinflammatory and anti-inflammatory macrophages (3.6- and 3.1-fold, respectively) in regenerating muscles of wild-type mice, but not in the regenerating muscles of MFS mice. Our data show that proliferation and differentiation of satellite cells are altered (p ≤ 0.05) in MFS mice. Myoblast transplantation assay revealed that the regenerating muscles from MFS mice have reduced satellite cell self-renewal capacity (74.7%). In addition, we found that treatment with Ang-(1–7) reduces fibrosis (71.6%) and ameliorates satellite cell dysfunction (p ≤ 0.05) and muscle contractile function (p ≤ 0.05) in MFS mice. Conclusion: The fibrotic niche, caused by Fbn1 mutations, reduces the myogenic potential of satellite cells, affecting structural and functional muscle regeneration. In addition, the fibrosis inhibitor Ang-(1–7) partially counteracts satellite cell abnormalities and restores myofiber size and contractile force in regenerating muscles.
|Original language||English (US)|
|State||Published - Jan 2023|
Bibliographical noteFunding Information:
This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (Grant Nos. 14/23391–8, 18/24946–4, 20/15351–7) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Fellowship/Grant No. 314857/2021–4) to E.H.M. M.T.S. received post‐doctoral fellowships from FAPESP and FAPESP/CAPES (Grant Nos. 17/14115–5 and 14/13874–1, respectively). A.R.S., T.E.K., and T.L.N. received Ph.D. fellowships from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES to A.R.S.) and FAPESP (Grant Nos. 17/09069–4 and 13/04783–0 to T.E.K. and T.L.N., respectively).
We thank Gabriel U. Sato for technical assistance and André Cruz and Anselmo S. Moriscot for help with bioinformatics. The monoclonal antibody to MyHC was obtained from the Developmental Studies. Hybridoma Bank was developed under the sponsorships of the NICHD and maintained by the University of Iowa.
© 2022 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
- Marfan syndrome
- satellite cell function
- skeletal muscle regeneration
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't