Mechanical loading induces the longitudinal growth of muscle fibers via a rapamycin-insensitive mechanism

Mechanical loading drives skeletal muscle growth, yet the mechanisms that regulate this process remain undefined. Here, we show that an increase in mechanical loading induces muscle fiber growth through two distinct mechanisms. Radial growth, reflected by an increase in fiber cross-sectional area, is mediated through a rapamycin-sensitive signaling pathway, whereas longitudinal growth, marked by the in-series addition of sarcomeres, is mediated through a rapamycin-insensitive signaling pathway. To gain further insight into the events that drive longitudinal growth, we combined BONCAT-based labeling of synthesized proteins with high-resolution imaging and determined that the in-series addition of sarcomeres is mediated by a process that involves transverse splitting at the Z-lines of preexisting sarcomeres. Collectively, our findings not only challenge the long-standing view that mechanically induced growth is uniformly governed by mTORC1 but also lay the framework for a revised understanding of the molecular and structural events that drive this process.