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Advisor(s)
Abstract(s)
O músculo esquelético sofre uma perda progressiva de massa, função e força com a idade, um processo conhecido como Sarcopénia. O estado de inflamação crónica que acompanha este processo de envelhecimento é um condutor potencial mas subexplorado do envelhecimento do músculo. Num estudo recente, o laboratório Neves/Sousa-Victor descobriu que a MANF, uma proteína da resposta de resistência ao stress e expressa pela maioria dos tecidos do corpo humano, tem uma função imunomoduladora autócrina, promovendo a ativação anti-inflamatória e a resolução dos danos dos tecidos, comprovada em estudos no tecido hepático. Desta forma, com este trabalho, testámos a hipótese de que a inflamação causada pela perda de função da proteína MANF poderá levar a um fenótipo de envelhecimento muscular acelerado. Para isso, analisámos tecidos musculares esqueléticos de diferentes modelos de rato: ratos WT em diferentes idades e ratos LysMCre-MANF de meia-idade, que representam um knockout de um alelo de MANF em células mieloides. Para além disso, estudámos ainda o impacto da suplementação da proteína MANF ao nível do envelhecimento muscular e a sua possível reversão fenotípica. Para efetuar estas análises recorremos à sua caracterização histológica e bioquímica. Desta forma, concluímos que a perda de função do MANF nas células mieloides conduz a um fenótipo de envelhecimento muscular acelerado. Foi ainda possível identificar uma citocina, a Osteopontina, comum ao processo de envelhecimento e à perda de MANF. Estatisticamente, a injeção direta de MANF não demonstrou relevância contudo, fenotipicamente, é possível observar alterações inflamatórias locais.
The skeletal muscle suffers a progressive loss of mass and function/strength with age, a process known as Sarcopenia. The state of chronic inflammation that accompanies this aging process is a potential but underexplored driver of muscle aging. In a recent study, the Neves/Sousa-Victor lab discovered that MANF, a stress responsive protein expressed by most tissues of the human body, has an autocrine immunomodulatory function, promoting anti-inflammatory activation and resolution of tissue damage, proved in studies in the liver tissue. In this work, we tested the hypothesis that inflammation driven by MANF loss of function could lead to a phenotype of accelerated muscle aging. We analyzed skeletal muscle tissue from different mouse models including WT mice at different ages and Middle-aged LysMCre-MANF fl mice, representing a tissue-specific conditional knockout allele of MANF in myeloid cells. In addition, we also studied the impact of MANF protein supplementation on muscle aging and its possible phenotypic reversal. To perform these analyses, we resorted to histological and biochemical characterization. In this way, we conclude that the loss of function of MANF in myeloid cells leads to some features of muscle aging, including increased macrophage infiltrates, fibrosis and increased markers of oxidative stress. It was also possible to identify a cytokine, Osteopontin, up regulated both in aging process and in the loss of MANF condition. The analysis of MANF supplementation in aged muscles did not result in significant differences in the parameters analyzed, however, the injury effects produced by the repeated injections precludes a more rigorous analysis of the results.
The skeletal muscle suffers a progressive loss of mass and function/strength with age, a process known as Sarcopenia. The state of chronic inflammation that accompanies this aging process is a potential but underexplored driver of muscle aging. In a recent study, the Neves/Sousa-Victor lab discovered that MANF, a stress responsive protein expressed by most tissues of the human body, has an autocrine immunomodulatory function, promoting anti-inflammatory activation and resolution of tissue damage, proved in studies in the liver tissue. In this work, we tested the hypothesis that inflammation driven by MANF loss of function could lead to a phenotype of accelerated muscle aging. We analyzed skeletal muscle tissue from different mouse models including WT mice at different ages and Middle-aged LysMCre-MANF fl mice, representing a tissue-specific conditional knockout allele of MANF in myeloid cells. In addition, we also studied the impact of MANF protein supplementation on muscle aging and its possible phenotypic reversal. To perform these analyses, we resorted to histological and biochemical characterization. In this way, we conclude that the loss of function of MANF in myeloid cells leads to some features of muscle aging, including increased macrophage infiltrates, fibrosis and increased markers of oxidative stress. It was also possible to identify a cytokine, Osteopontin, up regulated both in aging process and in the loss of MANF condition. The analysis of MANF supplementation in aged muscles did not result in significant differences in the parameters analyzed, however, the injury effects produced by the repeated injections precludes a more rigorous analysis of the results.
Description
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2023
Keywords
Envelhecimento muscular Inflamação Sarcopénia Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) Osteopontina