The fibrotic niche impairs satellite cell function and muscle regeneration in mouse models of Marfan syndrome

Autor(es)

da Silva, Meiricris Tomaz ; Santos, Audrei R. ; Koike, Tatiana E. ; Nascimento, Tabata L. ; Rozanski, Andrei ; Bosnakovski, Darko ; Pereira, Lygia, V ; Kumar, Ashok ; Kyba, Michael ; Miyabara, Elen H.

• Tipo de documento: Artigo Científico
• Fonte: ACTA PHYSIOLOGICA; v. 237, n. 1, p. 19-pg., 2022-10-17.

Resumo

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. (AU)

• Processo FAPESP: 17/14115-5 - Estudo da capacidade regenerativa das células satélite em camundongos com síndrome de Marfan
• Beneficiário: Meiricris Tomaz da Silva
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 20/15351-7 - Papel do adrenoceptor beta 2 na proliferação e diferenciação das células satélite
• Beneficiário: Elen Haruka Miyabara
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/24946-4 - Reabilitação do músculo esquelético de camundongos com síndrome de Marfan: efeito do exercício excêntrico
• Beneficiário: Elen Haruka Miyabara
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/09069-4 - Influência do adrenoceptor beta 2 na função das células satélite
• Beneficiário: Tatiana Emy Koike
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/23391-8 - Resposta regenerativa da musculatura esquelética de camundongos com síndrome de Marfan
• Beneficiário: Elen Haruka Miyabara
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/04783-0 - Influência das proteínas de choque térmico na resposta regenerativa de músculos esqueléticos de camundongos idosos
• Beneficiário: Tábata Leal Nascimento
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/13874-1 - Regeneração muscular esquelética de camundongos com Síndrome de Marfan: estudo do potencial regenerativo das células satélites
• Beneficiário: Meiricris Tomaz da Silva
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado