טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKutchuk Liora
SubjectLysyl Oxidase Regulates Muscle-ECM Crosstalk during
Fetal Myogenesis
DepartmentDepartment of Medicine
Supervisor Professor Peleg Hasson
Full Thesis textFull thesis text - English Version


Abstract

The muscle is an integrated tissue composed of distinct cell types and extracellular components. Myogenesis during development is a complex process which involves large scale migration, proliferation and differentiation all taking place in a coordinated fashion. Interactions between all cell types present and crosstalk between developing muscle and the surrounding extra cellular matrix (ECM) are part of this process bringing forth anatomically functioning muscles. These multi cell processes require highly regulated homeostatic regulation and balance.

Muscle connective tissue is of extreme importance to muscle development; it acts as a scaffold for primary muscle development and harbors signaling molecules that have regulatory function on muscle development. Muscle and the surrounding connective tissue are in constant interaction through various regulatory elements. Furthermore, the connective tissue's integrity is of major importance for proper muscle development. For that reason, we focused our attention on Lysyl oxidase (Lox). Lox is an extracellular secreted enzyme with key ECM functions. It was discovered as an ECM modifying enzyme with main functions in maturation and organization of collagen and elastin fibers. Inhibition of Lox's enzymatic activity results in neonatal death primarily due to weakness of the aortic wall's ECM leading to aneurysms. 

Here we find that Lox is a key player in regulating coordinated homeostatic growth of the muscle and its surrounding ECM. Deletion of Lox uncouples the balance between myofibers and the muscle connective tissue (MCT), resulting in reduced muscle content and increased ECM.

We show that Lox which is secreted from the myofibers attenuates TGF-beta (TGFβ) signaling, an inhibitor of myofiber differentiation and promoter of MCT development. We further demonstrate that a TGFβ:Lox feedback loop between the MCT and myofibers maintains the developmental homeostasis between muscle components while tying in MCT organization. Our results allow a better understanding of diseases such as Duchenne Muscular Dystrophy where Lox and TGFβ signaling have been implicated in and balance between muscle constituents.