Marfan syndrome is caused by mutations in an autosomal dominant gene encoding fibrillin-1, which is the key structural glycoprotein for microfibrils and act as scaffolding proteins for formation of elastic fibers and elastin deposition. Skeletal muscle alterations are also found in Marfan syndrome, such as reduction in the number and size of myofibers, combined with fibrosis, deposition of adipose tissue, myofiber splitting and decrease of M-cadherin and myogenin expression in muscles after injury, suggesting an impaired regenerative response of muscles from these individuals. Skeletal muscle regeneration depends on a muscle stem cell pool, the satellite cells. Their ability for life-long muscle regeneration through production of new myoblasts is supported by a remarkable potential for self-renewal. Understanding control of satellite cell self-renewal and maintenance of the satellite cell pool is essential to understanding muscle maintenance and regeneration. Therefore, our strategy was to evaluate the proliferation of satellite cells and the early differentiation of myogenic precursor cells isolated from fibrillin-1-deficient mice and our preliminary results showed that there is an increase in proliferation of satellite cells from these animals compared to those from wild-type and no changes in early differentiation of myogenic precursor cells were observed. Based on these results, we hypothesized that satellite cell pool undergoes cell-autonomous changes in Marfan syndrome, leading to altered self-renewal and/or differentiation potentials. Thus, the aim of this project is to investigate whether the satellite cells from the mouse model of Marfan syndrome suffer from a regeneration defect, either in the ability to self-renew to maintain the satellite cell pool, or to differentiate into myofibers. Transplantation assays that simultaneously measure both the self-renewal and the differentiation potential of a test cell population will be performed (Please, see details in the project).
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