Adult vertebrate skeletal muscle has a remarkable capacity for regeneration after injury and for hypertrophy and regrowth after atrophy. In 1961, Alexander Mauro suggested that satellite cells, which lie between the sarcolemma and basement membrane of myofibres, could be adult skeletal muscle stem cells. Subsequent cell transplantation and lineage-tracing studies have shown that satellite cells, which express the Pax7 transcription factor, can repair damaged muscle tissue, but are these cells essential for muscle regeneration and other aspects of muscle adaptability? In this issue, four papers investigate this long-standing question.
On , Chen-Ming Fan and colleagues report that genetic ablation of Pax7+ cells in mice completely blocks regenerative myogenesis after cardiotoxin-induced muscle injury and after transplantation of ablated muscle into a normal muscle bed. Because Pax7 is specifically expressed in satellite cells, the researchers conclude that satellite cells are essential for acute injury-induced muscle regeneration but note that other stem cells might be involved in muscle regeneration in other pathological conditions.
Anne Galy, Shahragim Tajbakhsh and colleagues reach a similar conclusion on . They report that local depletion of satellite cells in a different mouse model leads to marked loss of muscle tissue and failure to regenerate skeletal muscle after myotoxin- or exercise-induced muscle injury. Other endogenous cell types do not compensate for the loss of Pax7+ cells, they report, but muscle regeneration can be rescued by transplantation of adult Pax7+ satellite cells alone, which suggests that Pax7+ cells are the only endogenous adult muscle stem cells that act autonomously.
On , Gabrielle Kardon and colleagues confirm the essential role of satellite cells in muscle regeneration in yet another mouse model. They show that satellite cell ablation results in complete loss of regenerated muscle, misregulation of fibroblasts and a large increase in connective tissue after injury. In addition, they report that ablation of muscle connective tissue (MCT) fibroblasts leads to premature satellite cell differentiation, satellite cell depletion and smaller regenerated myofibres after injury. Thus, they conclude, MCT fibroblasts are a vital component of the satellite cell niche.
Finally, on , Charlotte Peterson and colleagues investigate satellite cell involvement in muscle hypertrophy. By removing the gastrocnemius and soleus muscles in the lower limb of mice, the researchers expose the plantaris muscle to mechanical overload, which induces muscle hypertrophy. After two weeks of overload, muscles genetically depleted of satellite cells show the same increase in muscle mass and similar hypertrophic fibre cross-sectional areas as non-depleted muscles but reduced new fibre formation and fibre regeneration. Thus, muscle fibres can mount a robust hypertrophic response to mechanical overload that is not dependent on satellite cells.
Together, these studies suggest that satellite cells could be a source of stem cells for the treatment of muscular dystrophies but also highlight the potential importance of fibroblasts in such therapies. Importantly, the finding that muscle regeneration and hypertrophy are distinct processes suggests that muscle growth-promoting exercise regimens should aim to minimise muscle damage and maximise intracellular anabolic processes, particularly in populations such as the elderly where satellite activity is compromised.
