Abstract
Mechanical forces between cells and extracellular matrix (ECM) influence cell shape and function. Tendons are ECM-rich tissues connecting muscles with bones that bear extreme tensional force. Analysis of transgenic zebrafish expressing mCherry driven by the tendon determinant scleraxis reveals that tendon fibroblasts (tenocytes) extend arrays of microtubule-rich projections at the onset of muscle contraction. In the trunk, these form a dense curtain along the myotendinous junctions at somite boundaries, perpendicular to myofibers, suggesting a role as force sensors to control ECM production and tendon strength. Paralysis or destabilization of microtubules reduces projection length and surrounding ECM, both of which are rescued by muscle stimulation. Paralysis also reduces SMAD3 phosphorylation in tenocytes and chemical inhibition of TGFβ signaling shortens tenocyte projections. These results suggest that TGFβ, released in response to force, acts on tenocytes to alter their morphology and ECM production, revealing a feedback mechanism by which tendons adapt to tension.
Highlights
Cells in all multicellular organisms are exposed to mechanical forces through adhesions to neighboring cells and to the extracellular matrix (ECM), as well as the ebb and flow of the environment
Using a bacterial artificial chromosome (BAC) transgenic line that expresses mCherry under the control of regulatory elements for scxa, Tg(scxa:mCherry), we examined the morphogenesis of tenocytes during embryonic (20 hr post fertilization to 72 hpf) and early larval (72 hpf to 5 dpf) zebrafish development
During the period in which axial muscles in the trunk begin to contract and embryos become motile, tenocytes align along future myotendinous junction (MTJ) and undergo dramatic changes in cell shape that correlate with the establishment and strengthening of muscle attachments
Summary
Cells in all multicellular organisms are exposed to mechanical forces through adhesions to neighboring cells and to the extracellular matrix (ECM), as well as the ebb and flow of the environment. Despite their prevalence, little is known about how tendon fibroblasts (tenocytes) respond in vivo to tensional force at muscle attachments, or how they adapt to changes in mechanical load. While extensive research has been conducted to evaluate the effects of exercise on size and strength of muscle fibers, less is known about how it effects tendon morphology and function Understanding this is key to gaining insights into the causes of tendon defects and developing new treatments for tendon injuries or atrophy. We show that the force of muscle contraction regulates the growth and branching of tenocyte projections via TGFb signaling Such feedback between tenocytes and ECM may be a common mechanism for force adaptation within the musculoskeletal system
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