(A) Satellite cells (red) residing between the sarcolemma and the basal lamina of multinucleated (green) skeletal muscle fibers (blue). Other cells such as fibroblasts (black) are present outside the lamina. The systemic environment is represented as a grey box surrounding the muscle fiber. Areas highlighted with black boxes are shown in B. (B) Adult (top row) and aged (bottom row) muscle in resting (uninjured, left column) and regenerating (right column) conditions. In adult resting muscle (top left) the Notch ligand Delta1 is expressed in satellite cell microenvironment Notch1 receptor is expressed in quiescent satellite cells. Spry1 the downstream target and intracellular FGF inhibitor is robustly expressed in quiescent satellite cells. The ligands necessary for Spry1 expression in quiescent satellite cells remain unidentified. In response to injury (right column) the muscle fiber degenerates (white) adult (top right) satellite cells signal via Notch to promote progenitor proliferation. Factors from the adult systemic environment are stimulatory to satellite cells (purple arrow). The stimulatory factors remain unidentified. In resting aged muscle (bottom left) Delta1 declines and FGF2 increases in the aged satellite cell microenvironment, leading to diminished levels of Spry1 and Notch signaling. In resting muscle, aged satellite cells are more mitotically active compared to adult satellite cells. The aged systemic environment (purple arrows) contains increased levels of TGFß and Complement 1q (C1q) that hinders satellite cell activation and increases fibrogenic conversion of satellite cells. In injured aged muscle (bottom right), due ß to decreased Notch activation and increased Wnt and TGF signaling aged satellite cells activate poorly. A fraction of satellite cells acquire a fibrogenic fate. Fibroblasts or other cells outside the basal lamina in the microenvironment may also provide signals (black arrows) that influence satellite cell contribution to muscle repair.
