Myotendinous Junction development and repair

Abstract

The myotendinous junction (MTJ) is the critical interface connecting muscle to tendon, enabling force transmission for movement and serving as the primary site of muscle injuries. Despite research into MTJ repair, treatment outcomes are suboptimal, partly due to the absence of a comprehensive synthesis of its structural components, cellular diversity, and developmental mechanisms, which impedes the rational selection of materials, cells, and regulatory factors for effective regeneration. This review synthesizes current knowledge on the cytoskeletal and extracellular matrix (ECM) architecture of the MTJ, the cell types involved in its development and repair, and the key molecular regulators governing its formation. We describe the hierarchical architecture of the MTJ and the key molecular complexes that mediate the mechanical connection between the muscle and the tendon. We also describe the roles of Col22a1-expressing muscle nuclei and various resident stem/progenitor cells in MTJ maintenance and healing. We discuss essential regulatory signaling pathways, including Slit, LRT, and BMP4. Furthermore, we evaluate existing MTJ repair strategies. Based on a review of MTJ development and injury repair, we observe that current treatment approaches largely fail to incorporate key insights from MTJ development, particularly regarding stem/progenitor cells and regulatory signals. Therefore, we propose that tissue engineering techniques, by integrating MTJ-resident stem/progenitor cells such as CD106⁺CD24⁻muscle-tendon progenitors (MTPs) and Hic1⁺Col22a1⁺ progenitors, key MTJ developmental regulatory signals like Slit, Lrt, and BMP4, as well as MTJ decellularized ECM scaffolds or biomimetic 3D-printed scaffolds, will substantially enhance the efficacy of MTJ repair therapies.

The Translational Potential of this Article

This review summarizes MTJ development across molecular linkages, signaling regulation, cellular composition, and tissue architecture, while assessing MTJ injury repair in terms of efficacy, mechanisms, limitations, and translational paths. Key barriers of MTJ repair include: conventional treatments (conservative and surgical) lacking high-quality data, RCTs, and unified guidelines for diverse patients; emerging approaches (bioactive factors, cell therapies, decellularized ECM scaffolds, tissue engineering) stuck at proof-of-concept or small-animal stages, without large-animal validation. It proposes establishing standardized cohorts, protocols, and parameters for conventional methods; accelerating large-animal safety/efficacy testing for emerging approaches to speed translation; constructing MTJ organoids based on key developmental cells and cues to provide a rapid drug testing platform for MTJ injury, thereby accelerating clinical translation; and integrating MTJ regulatory signals and stem/progenitor cells to enhance emerging therapy outcomes.