Muscle composition is regulated by a Lox-TGFβ feedback loop

Abstract

Muscle is an integrated tissue composed of distinct cell types and extracellular matrix. While much emphasis has been placed on the factors required for the specification of the cells that comprise muscle, little is known about the crosstalk between them that enables the development of a patterned and functional tissue. We find in mice that deletion of lysyl oxidase (Lox), an extracellular enzyme regulating collagen maturation and organization, uncouples the balance between the amount of myofibers and that of muscle connective tissue (MCT). We show that Lox secreted from the myofibers attenuates 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 dynamic developmental homeostasis between muscle components while also regulating MCT organization. Our results allow a better understanding of diseases such as Duchenne muscular dystrophy, in which LOX and TGFβ signaling have been implicated and the balance between muscle constituents is disturbed.

Heparanase 2 expression inversely correlates with bladder carcinoma grade and stage

“…Immunohistochemical-grade anti-LOX polyclonal antibody was kindly provided by Dr. Peleg Hasson (Technion, Israel) [13]. Anti-actin monoclonal antibody and Masson's/Trichrome staining kit were purchased from Sigma.…”

Tumor Cell Invasion Can Be Blocked by Modulators of Collagen Fibril Alignment That Control Assembly of the Extracellular Matrix

“…Loss-of-function animal models for LOX and LOXL2 demonstrated differential tissue dysfunctions indicating the enzymes' different roles in development and homeostasis (22)(23)(24). In addition, overexpression of these enzymes in cancer has been correlated with distinct events during tumor progression.…”

Axial and limb muscle development: dialogue with the neighbourhood

“…3e) [123,124]. A recent study has shown that developing muscle cells secrete the lysyl oxidase enzyme (Lox, Table 1) which is important for the formation of collagen fibres [125]. Strikingly, if this enzyme is missing, as in Lox -/-mutant embryos, secondary myogenesis is impaired due to an excessive number of muscle connective tissue fibroblasts, including their associated extracellular matrix, at the expense of myofibres.…”

“…Strikingly, if this enzyme is missing, as in Lox -/-mutant embryos, secondary myogenesis is impaired due to an excessive number of muscle connective tissue fibroblasts, including their associated extracellular matrix, at the expense of myofibres. It was further shown that Lox is able to regulate TGFb signalling in the fibroblasts and this way, ensures the right balance between myofibres and muscle connective tissue [125]. Thus, reciprocal communication between these two tissues is necessary for their normal development and for synchronous assembly of the musculoskeletal system at all stages of muscle development.…”