468319 Novel Role of Cadherin 11 in Extracellular Matrix Synthesis and Muscular Physiology
We demonstrate that CDH11 regulates collagen and elastin synthesis and thereby contributes to tissue integrity both in vivo using a Cdh11-/- mouse model and in vitro using knockdown studies as well as gain of function approaches. We also identified the underlying mechanism and discovered that CDH11 engagement leads to swift and direct activation of both the TGF-β1 and ROCK pathways. This is followed by activation of transcription factors, MRTF-A and MYOCD leading to expression of collagen and elastin genes. In summary, our findings indicate that cell-cell contact by cadherin-11 is a novel regulator of ECM synthesis. Notably, these findings have important implications in skeletal muscle function and overall physical strength of the mice. In tests of physical endurance, Cdh11-/- mice failed to maintain their body position in an inverted grid hanging test, failing in just 10 seconds as compared to WT (1-3 minutes). Furthermore, Cdh11-/- mice have little to no activity wheel usage in contrast to control mice. Finally, our data also indicate that Cdh11-/- mice have significantly higher body fat relative to WT as well as lower lean mass.
Overall, we discovered a novel role for Cadherin-11 in ECM synthesis and tissue structure and identified the underlying mechanism involving direct TGF-β and ROCK activation. Notably, CDH11-mediated molecular events are linked to changes in muscle mass and organization, ultimately affecting neuromuscular function and physiology.