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. 2012 Sep 10;2(2):53-63.
Print 2012 Apr.

The development of the myotendinous junction. A review

Benjamin Charvet  1 , Florence Ruggiero, Dominique Le Guellec
Affiliations

The development of the myotendinous junction. A review

Benjamin Charvet et al. Muscles Ligaments Tendons J. .

Abstract

The myotendinous junction (MTJ) is a complex specialized region located at the muscle-tendon interface that represents the primary site of force transmission. Despite their different embryologic origins, muscle and tendon morphogenesis occurs in close spatial and temporal association. After muscle attachment, muscle and tendon constitute a dynamic and functional integrated unit that transduces muscle contraction force to the skeletal system. We review here the current understanding of MTJ formation describing changes during morphogenesis and focusing on the crosstalk between muscle and tendon cells that leads to the development of a functional MTJ. Molecules involved in the formation of the linkage, both at the tendon side and at the muscle side of the junction are described. Much of this knowledge comes from studies using different animal models such as mice, zebrafish and Drosophila where powerful methods for in vivo imaging and genetic manipulations can be used to enlighten this developmental process.

Keywords: DGC; basement membrane; collagen; development; integrin; myotendinous junction.

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Figures

Figure 1
Figure 1
Schematic representation (parasagittal section) of adult muscle/tendon interface. The collagen fibers, produced by tenocytes, are anchored perpendicularly to the sarcolemma of the finger-like processes. The sub-sarcolemmal densities present at the tips of finger-like processes correspond to the muscle side of MTJ. These densities result from the massive recruitment of protein linkage-complexes that connect actin filaments from the last Z-band to the tendinous extracellular matrix. actF: Actin filament from last Z-band; Bm: Basement membrane; C: Collagen fibers; Flp: Finger-like process; M: Muscle; Sm: Sar-comer; Ssd: Sub-sarolemmal density; StC: Satellite cell; T: Tendon; Tc: Tenocyte; Zb: Z-band.
Figure 2
Figure 2
Schematic representation of the MTJ at the molecular level. Two types of linkage complexes are described so far: the dystrophin-associated protein complex (DAPC) also called dystrophin-associated glycoprotein complex (DGC) (proteins 4 to 17) and the protein complex containing the transmembrane α7β1 integrin (proteins 21–37 and 30–32). Both complexes connect the sarcomeric actin to the tendinous extracellular matrix (ECM) via the basement membrane laminin α2, most likely assembled into the laminin 211 trimer. These complexes are enriched at the MTJ and correspond to the sub-sarcolemmal densities observable in the finger-like processes with transmission electron microscopy. Both systems are interconnected via the intracellular proteins α-actinin or desmin.
Figure 3
Figure 3
Schematic representation of MTJ formation during development. In developing somites, the myotome compartment that contains myoblasts is juxtaposed to the syndetome containing tenoblasts. In limb buds, myoblasts and tenoblasts are somite-derived cells. (A) Tenoblasts secrete a sparse fibrillar ECM adjacent to myoblasts. (B) Myoblasts fuse in contractile myotubes and a nascent basement membrane appears at the interface between myotubes and tendon. The first random contractions organize collagen fibers in parallel array. In the same time, the ECM provides a solid support, which constraints the thick and thin filaments of sarcomere to organize into parallel arrangement. (C) Sarcolemma resistance to the increasing contractile forces augments correlatively with the progressive formation of sarcomeres and stretching results in the progressive parallel alignment of collagen fibers. This process suggests a mechanical crosstalk between muscle and tendon. The size of collagen fibers increase and the finger-like processes begin to form. The deposition and assembly of a continuous basement membrane is finished. The myotubes that are not anchored to ECM are eliminated by apoptosis. Satellite cells are observed associated with myotubes and tenocytes are aligned along the collagen fibers. MTJ development ceases after birth. As shows the Figure 1, formation of finger-like processes and the recruitment of linkage complexes at the tips of sarcolemmal protrusions (corresponding to the sub-sarcolemmal densities observed with transmission electron microscopy), align sarcomeres parallel to collagen fiber axis and permit the transmission of muscle forces to skeleton through tendons.
Figure 4
Figure 4
Cross-talk between muscle (pink) and tendon (dark grey) cells in Drosophila. The MTJ (light grey) is formed through muscle-specific αPS2βPS integrin interaction with the tendon-secreted ECM component TSP and its regulator Slow. Laminin binds the αPS1βPS tendon-specific integrin via the molecular adaptator TSP. The αPS2βPS integrin intracellular signal is mediated by FAK and induced the expression of vein gene in muscle cell. Vein protein is deposited in intercellular space and links the tendinous EGF-receptor. Vein expression and deposition of the corresponding protein are regulated by moleskin. Interaction of Vein on EGF-R leads to the stripe gene expression via MAPK signaling. Stripe, which expression is also induced by wingless (wg) hedgehog (hh) pathway activation, is a central actor of tendon cell differentiation. This transcription factor induces the expression of tsp and slit genes. Slit binds ROBO at the muscle cell surface and LTR at the tendon cell surface. Wnt5 also provides a structural link between the muscular receptor ryk and the frizzled/LRP co-receptors.
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