Mechanical Overloading Induced-Activation of mTOR Signaling in Tendon Stem/Progenitor Cells Contributes to Tendinopathy Development.

Despite the importance of mechanical loading in tendon homeostasis and pathophysiology, the molecular responses involved in the mechanotransduction in tendon cells remain unclear. In this study, we found that mechanical loading activated the mammalian target of rapamycin (mTOR) in rat patellar tendon stem/progenitor cells (TSCs) in a stretching magnitude-dependent manner. Application of rapamycin, a specific inhibitor of mTOR, attenuated the phosphorylation of S6 and 4E-BP1 and as such, largely inhibited the mechanical activation of mTOR. Moreover, rapamycin significantly decreased the proliferation and non-tenocyte differentiation of PTSCs as indicated by the reduced expression levels of LPL, PPARγ, SOX-9, collagen II, Runx-2, and osteocalcin genes. In the animal studies, mice subjected to intensive treadmill running (ITR) developed tendon degeneration, as evidenced by the formation of round-shaped cells, accumulation of proteoglycans, and expression of SOX-9 and collagen II proteins. However, daily injections of rapamycin in ITR mice reduced all these tendon degenerative changes. Collectively, these findings suggest that mechanical loading activates the mTOR signaling in TSCs, and rapamycin may be used to prevent tendinopathy development by blocking non-tenocyte differentiation due to mechanical over-activation of mTOR in TSCs.