Regulation of skeletal muscle repair by mesencephalic astrocyte-derived neurotrophic factor

• Autor(a) principal: Sousa, Neuza Sofia Simões de
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/134442
• topic: Inflammation; Regeneration; Aging; Skeletal muscle; MANF; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Aging is characterized by a decline in physiological integrity and increased vulnerability to disease. The field of regenerative medicine aims to develop restorative and rejuvenating interventions using stem cells-based therapies. However, age-related loss of regenerative capability is associated to changes in tissue environment, including immune dysfunction, a roadblock to regenerative interventions. The success of stem cell therapies may depend on its improvement. Skeletal muscle is a paradigmatic model to study age-related loss of repair capacity. Its regenerative success depends on a population of stem cells and the coordination of an immune response, including pro- and anti-inflammatory signaling. Thus, immune modulatory approaches may be necessary to improve stem cell-based therapies in aging. Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is downregulated in aging and has an immune modulatory function, improving immune homeostasis in old animals. Therefore, MANF may impact muscle regeneration. We aimed to investigate the regulation of skeletal muscle repair by MANF and the consequences of age-related MANF-loss to repair efficiency. We show that MANF expression is induced during muscle regeneration in anti-inflammatory macrophages, a response that is blunted in aged animals. Analysis of the regenerative process in old muscles permitted the identification of an age-related decrease in cell recruitment and impaired macrophage’s phenotypic transition, phenotypes recapitulated in a genetic model of conditional MANF ablation in anti-inflammatory macrophages. We further identify cytokines dysregulated in aging and in the MANF-deficient model, suggesting possible candidate factors linking the two phenotypes. Finally, we showed that MANF loss in anti-inflammatory macrophages results in impairments on myofiber formation and reduced stem cell numbers. We propose that MANF produced by anti-inflammatory macrophages regulates macrophage’s phenotypic transition after muscle injury, and that the loss of this mechanism in aging contributes to impaired muscle regeneration. Our work introduces MANF as a new candidate to improve muscle repair in the elderly.