Muscle regeneration unveiled
Endogenous muscle adult stem cells, which are known as satellite stem cells, get activated after skeletal muscle injury and differentiate to form new myofibers. The transcription factors Dach1, Meox2 and Pitx2/3 seem to be involved in the function of satellite cells. The EU-funded 'Roles of Pitx, Dach and Meox genes in adult skeletal muscle stem cells' (SATELLITE CELLS) project set out to delineate the role of these transcription factors in adult skeletal muscle stem cells. Pitx proteins are expressed during development and trigger the onset of myogenesis in the embryo. Expression analysis showed high Pitx2 levels in dormant satellite cells and decreasing levels upon differentiation. On the other hand, Pitx3 continued to be expressed in adult muscle fibres. Knock down of these genes in satellite cells demonstrated unique and overlapping functions in regulating cell behaviour. Pitx3 was essential for maintaining the stem cell pool while Pitx2 triggered the onset of differentiation. In vivo studies in mice lacking Pitx2 showed delayed muscle regeneration upon injury compared to control animals. Pitx3-deficient animals presented a premature differentiation of stem cells while satellite cells lacking both Pitx proteins had a marked deficit in both proliferation and differentiation. This defect in satellite cell functionality hampered muscle regeneration in injured mice, suggesting their involvement in muscle tissue homeostasis. Mutant cells exhibited a strong senescent phenotype due to excessive levels of reactive oxygen species and DNA damage. Treatment of mutant cells or animals with anti-oxidant compounds completely reversed the phenotype and increased their life expectancy. Overall, the results of the SATELLITE CELLS study demonstrated an essential role of Pitx proteins in the maintenance and function of muscle satellite cells. The generated knowledge could find application in the treatment or symptom alleviation of muscular dystrophies.
