Fig. 1: A schematic overview of different steps during muscle repair.

Skeletal muscle tissue comprises multiple cell types and compartments, including multinucleated myofibers, blood vessels, and neuromuscular junctions. Upon injury, this tissue recruits several cell types (represented in the figure) to repair myofibers. The starting phase of muscle regeneration, also known as a proinflammatory response, is characterized by the infiltration of immune cells that will clear the damaged fibers from the injured site. During the first phase, neutrophils^{224,225,226,227,228} and proinflammatory macrophages (also known as M1) are required to clean the muscle cell debris and participate in the recruitment and activation of other cell types^229,230. During the second stage, multiple cell types proliferate, including MuSC. Other immune cells, such as regulatory T cells (known as Treg)²³¹ and eosinophils, also infiltrate the regenerating muscle after injury. Eosinophils stimulate FAPs expansion by forming a transitional niche favorable to clear necrotic debris and prevent FAPs differentiation into adipocytes¹⁹. In order to repair the damaged muscle, MuSC becomes activated, differentiate, and fuse to give rise to multinucleated myotubes. During this time, M1 macrophages are replaced by anti-inflammatory macrophages (also known as M2), which allows the restoration of the tissue. They express anti-inflammatory markers, several ECM-related genes, and growth factors (such as TGF-ß) and contribute to the remodeling of the MuSC niche. While M1 macrophages promote MuSC proliferation and prevent their premature differentiation, M2 macrophages boost MuSC commitment and formation of mature myotubes^{61,232,233,234}. New fibers are thus formed and grow during the last phase, named the restorative phase. MuSC repopulates their stem cell pool at this stage, the injured site is remodeled, and the tissue is recovered and can return to homeostasis.