Figure 3

Inflammatory control of skeletal-muscle regeneration. Replacement of damaged muscle fibers is dependent on satellite cells, resident stem cells that are normally quiescent, and are located under the basal lamina of muscle fibers. Tissue damage leads to their activation, proliferation, differentiation and fusion to form new myofibers. However, their capacity to mediate repair is modified by the extent and type of injury, and consequently by their interaction with various cellular and soluble mediators, most importantly with infiltrating macrophages. The proposed paracrine interaction between macrophages and satellite cells is as follows. During the timely, regulated process of regeneration after acute injury (left), pro-inflammatory cytokines released from M1-macrophages may promote satellite-cell proliferation, whereas cytokines released by anti-inflammatory (M2c) and alternatively activated (M2a) macrophages, respectively, may favor their differentiation and fusion. In particular, interleukin (IL)-4 was shown to regulate fusion of myoblasts in vitro and in vivo [129]. It could be expected that, during chronic damage (right), such as in muscular dystrophies, the increased and persistent presence of the distinct macrophage cell types could modify the relative levels and kinetics of these cytokines, resulting in altered satellite-cell functions and aberrant regeneration, with progressive development of fibrosis and fat accumulation, ultimately leading to non-functional muscle tissue.