Saptaparna Pal, Amity University Kolkata
Vertebrate muscles and tendons must interact to facilitate muscle contraction and body movements. These are derived from distinct embryonic origins. The robust muscle-tendon junctions (MTJS) form to be able to withstand contraction forces and the reason behind this is still not understood. The classical view of distinct identities for the tissue composing the musculoskeletal system was examined using a technique at a single-cell resolution. Fibroblasts were identified that have switched on a myogenic program and illustrate this dual identity. These cells fuse into the developing muscle fibers along the MTJS facilitating the beginning of fibroblast-specific transcripts into the elongating myofibers. It has been suggested that this mechanism results in a hybrid fiber transfer firstly along with the fiber tips, enabling a smooth transformation from muscle fiber characteristics towards tendon aspects essential for forming robust MTJS. It has been proposed that dual characteristics of junctional cells could be a common mechanism for developing stable connections between tissues throughout the musculoskeletal system.
Over the last few decades, transplantation experiments in avian embryos, as well as genetic investigation in mice, were performed that identified the lineages that make up the vertebrate limb musculoskeletal skeleton. These experiments demonstrated that while myogenic precursor cells are somite-derived, the tendons, bones, and connective tissues are obtained from the lateral plate mesoderm (LPM). These early observations can be revisited by using single-cell resolution. It focuses on specific regions, such as the interaction sites between the distinct tissues to resolve their cellular contributions. One such focal point includes the myotendinous junction (MTJS).
The force generated by the muscle to the tendons and skeletal elements were transmitted by the critical functioning of muscles. However, an understanding of the mechanisms that underlie MTJ development and maintenance is still relatively unclear. The myofiber tips along with the MTJS serves as the site of interactions with tendons during neonatal and embryonic growth and development. When myofibers strengthen and elongate via myoblasts fusion, the majority of fusion events also take place in these regions. Multiple signaling pathways such as BMP and FGP signaling are tightly coordinated together along the fiber tips. Still, their proper contribution to myofiber elongation, fusion, and MTJ maintenance and development is unclear.
Single-cell transcriptome analysis of the MTJ region was carried out that reveals the presence of a unique cluster of cells expressing both fibroblastic as well as myogenic characteristics. The secreted extracellular matrix (ECM) modifying enzyme Lysyl oxidase-Like3 (LOXL3) was identified. This analysis further identified an essential enzyme required for MTJ formation, which is released from myofiber tips and is transcribed by fibroblasts and not by myogenic cells. Recruitment of LPM- derived cells from muscle boundaries and their fusion into the myofibers were suggested and is essential for normal MTJ development promising proper localization of proteins along these junctions.
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Reference:
- Yaseen, W., Kraft-Sheleg, O., Zaffryar-Eilot, S. et al. Fibroblast fusion to the muscle fiber regulates myotendinous junction formation. Nat Commun 12, 3852 (2021). https://doi.org/10.1038/s41467-021-24159-9
- The in-text image and the thumbnail have been extracted from Servier Medical Art.
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