A Muscle is Born

A graphical abstract: anchoring of muscle fibers. Left: proper development of muscle-tendon interface. Right: In this process failure leads to disruption in the formation of the interface

A Technion study sheds light on the embryonic development of the connection between muscles and tendons, which is vital to the organism’s motor activity

A study conducted by Assistant Prof. Peleg Hasson at the Technion’s Rappaport Faculty of Medicine and recently published in Developmental Cell sheds light on the embryonic development of the muscle-tendon interface, the myotendinous junction, which is vital to the organism’s motor activity.

The ability of muscle to move the skeleton is essential to the movement of human beings and other vertebrates. Therefore, defects in the aforementioned junction – i.e. the interaction between muscle fibers and tendon – harm its motor ability. Despite the importance of this interface, and in some cases its impact on degenerative diseases of the muscles, the molecular mechanisms that form it during the embryonic developmental stages have not yet been deciphered.  Hence, the importance of this study, which sheds light on a few essential steps in this process.

The anchoring of muscle fibers in the myotendinous junction depends on various signal transmission routes, one of which is integrin – a receptor that plays a vital role in the connection between the cells and the extra-cellular matrix. One of the main factors that control this receptor’s activity is a protein called fibronectin, which is enriched in tendons. The current study found that an enzyme called LoxL3 modulates fibronectin (via oxidation), and this modulation regulates integrin signaling. LoxL3 is secreted from the tips of developing muscle fibers. During embryonic development, the myofibers grow and reach the tendons, the secreted LoxL3 from the muscle fibers oxidizes the fibronectin molecule, highly enriched in the tendons, which in turn activates the integrin receptor. Following the change, the “anchoring plan” of the muscle fibers is realized at the correct point of interface with the tendon, as you can see on the left side of the diagram below.

In experiments with mice, Assistant Prof. Hasson found that when the enzyme LoxL3 is abnormal, i.e. is when a mutation occurs in it, the whole aforementioned chain of processes is disrupted (LoxL3 → fibronectin → integrin). This disrupts the implementation of the “anchoring plan”; the muscle fibers continue to migrate and become excessively long, thereby “missing” the correct anchoring point. The result: the muscle-tendon interface does not develop properly. The disrupted process can be seen on the right side of the diagram.

Assistant Prof. Hasson stresses that “This is basic research, and it’s still difficult to predict its clinical implications. However, the new revelations concerning the development of the connection between muscle and tendon may lead to further studies that will paint a more accurate picture of this critical process.”