Mechano-biology of resident myogenic stem cells: Molecular mechanism of stretch-induced activation of satellite cells

Satellite cells, resident myogenic stem cells found between the basement membrane and the sarcolemma in postnatal skeletal muscle, are normally quiescent in adult muscles. But when muscle is injured, exercised, overused or mechanically stretched, these cells are activated to enter the cell cycle, divide, differentiate, and fuse with the adjacent muscle fiber. In this way, satellite cells are responsible for regeneration and work-induced hypertrophy of muscle fibers. Therefore, a mechanism must exist to translate mechanical changes in muscle tissue into chemical signals that can activate satellite cells. This mechanism has not been clearly delineated. Recent in vivo studies and studies of satellite cells and single muscle fibers in culture demonstrated the essential role of hepatocyte growth factor (HGF) and nitric oxide (NO) radical in the activation pathway. These experiments also showed that mechanically stretching cultured satellite cells or living skeletal muscles stimulates satellite cell activation. This is achieved by rapid release of HGF from its tethering in the extracellular matrix and its presentation to the c-met receptor. HGF release has been shown to depend on NO radical production by nitric oxide synthase (NOS) in satellite cells and/or muscle fibers, and relies on the subsequent upregulation of matrix metalloproteinase (MMP) activity (possibly achieved by its nitrosylation). These results suggest that the activation mechanism is a cascade of molecular events including calcium-calmodulin formation, NOS activation, NO radical production, MMP activation, HGF release and HGF binding to c-met. An understanding the 'mechano-biology' of satellite cell activation is essential when planning procedures that could enhance muscle growth and repair. This is particularly important for meat-animal agriculture and in human health, disease and aging.