Fibroblast fusion to the muscle fiber regulates myotendinous junction formation

Wesal Yaseen,Ortal Kraft-Sheleg,Douglas P Millay,Peleg Hasson,Shay Melamed,Chengyi Sun,Shelly Zaffryar-Eilot

doi:10.1038/s41467-021-24159-9

Abstract

Vertebrate muscles and tendons are derived from distinct embryonic origins yet they must interact in order to facilitate muscle contraction and body movements. How robust muscle tendon junctions (MTJs) form to be able to withstand contraction forces is still not understood. Using techniques at a single cell resolution we reexamine the classical view of distinct identities for the tissues composing the musculoskeletal system. We identify fibroblasts that have switched on a myogenic program and demonstrate these dual identity cells fuse into the developing muscle fibers along the MTJs facilitating the introduction of fibroblast-specific transcripts into the elongating myofibers. We suggest this mechanism resulting in a hybrid muscle fiber, primarily along the fiber tips, enables a smooth transition from muscle fiber characteristics towards tendon features essential for forming robust MTJs. We propose that dual characteristics of junctional cells could be a common mechanism for generating stable interactions between tissues throughout the musculoskeletal system.

Highlights

Vertebrate muscles and tendons are derived from distinct embryonic origins yet they must interact in order to facilitate muscle contraction and body movements
This analysis further identifies that the secreted extracellular matrix (ECM) modifying enzyme Lysyl oxidase-Like 3 (LoxL3), an essential enzyme required for muscle tendon junctions (MTJs) formation, that is secreted from myofiber tips[12] is transcribed by fibroblasts and not by myogenic cells
Using fluorescent in situ hybridization (FISH) analyses and tracing of fibroblast nuclei in vitro and in vivo within the developing muscle, we identify a mechanism of horizontal RNA transfer by which lateral plate mesoderm (LPM)-derived fibroblasts transdifferentiate, switch on myogenic characteristics and fuse into the myofibers along the MTJs

Summary

Introduction

Vertebrate muscles and tendons are derived from distinct embryonic origins yet they must interact in order to facilitate muscle contraction and body movements. We identify fibroblasts that have switched on a myogenic program and demonstrate these dual identity cells fuse into the developing muscle fibers along the MTJs facilitating the introduction of fibroblast-specific transcripts into the elongating myofibers. We suggest this mechanism resulting in a hybrid muscle fiber, primarily along the fiber tips, enables a smooth transition from muscle fiber characteristics towards tendon features essential for forming robust MTJs. We propose that dual characteristics of junctional cells could be a common mechanism for generating stable interactions between tissues throughout the musculoskeletal system. Derived cells from muscle boundaries and their fusion into the myofibers is essential for normal MTJ development ensuring proper localization of proteins along these junctions

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Conclusion