Researchers publishing in Matrix Biology Plus have discovered that cochlin, a protein that decreases with age, is vital for the health of tendons.
Tendons require a healthy extracellular matrix
Previous work has found that tendon tissues, which link muscle to bone, require a healthy extracellular matrix (ECM) to function; if the ECM is degraded, the tendon has problems with handling the forces put on it and in healing from injury [1]. Tenocytes, cells that maintain tendon tissue, respond to external pressures when building and removing the ECM and thus maintain tendon homeostasis [2].
These researchers have previously found that aging depletes the amount of Scleraxis-lineage tenocytes and that this depletion is directly responsible for the loss of tendon function, as demonstrated in a mouse model [3]. That work found that cochlin appears to be a crucial part of regulating tendon health.
While cochlin is found in the ECM, it is not part of structural collagen, and previous literature discussing it mostly focused on its effects in the inner ear. Its effects on tendon development have not been well documented. Therefore, this paper follows the team’s previous line of experiments, this time focusing specifically on cochlin.
Cochlin impacts how tendons mature
For their first experiment, the researchers created a strain of mice that do not produce cochlin and analyzed their tendons at 3, 6, and 9 months of age. At all three ages, the cochlin-less mice had significantly wider collagen fibrils than wild-type controls. While there were trends, there did not appear to be significant effects on how these tendons matured, except for a substantially reduced stiffness at 6 months. Peak load, however, was significantly affected: the tendons of 6-month-old cochlin-less mice could not withstand as much load as their wild-type counterparts, and this difference was only increased at 9 months.
There were also substantial alterations to tendon homeostasis, as revealed by a gene expression analysis. In line with previous research, the cochlin-less mice had signs of hearing damage, but they also had significant alterations to genes involved in protein conversion, RNA metabolism, lysosomal function, and cellular proliferation. The researchers hold that the loss of this single protein creates a broad impact to many aspects of cellular biology.
While the loss of cochlin impaired the tendons’ ability to handle stress, it did not seem to affect their ability to heal. One month after the researchers had surgically injured the flexor tendons of wild-type and cochlin-less mice at 10 to 12 weeks of age, the mice had healed in the same way. While there were trends towards decreased stiffness and decreased loading ability in the cochlin-less mice, it is unlikely that they were due to differences in how they healed. The researchers, therefore, posit that cochlin is necessary for proper tendon maturation but not healing.
Important but one of many
The researchers use the discussion section of this paper to analyze why this protein might have such wide-ranging effects. They note that it binds to collagen [4] and may have direct impacts on how its structure functions. Clearly, cochlin has impacts on maturation, but they did not attempt to analyze its effects on aging per se; as they also note, this would be particularly difficult to isolate in naturally aging animals, as a great many other things are going wrong with the ECM as well.
This work primarily notes the differences between young and middle-aged animals. Tendons, in mice, take a while to mature properly, and this paper concluded its work at almost half the animals’ natural lifespan; future work that analyzes changes with aging must therefore differentiate the positive effects of maturation versus the negative effects of age-related degeneration.
Further work that upregulates cochlin, and perhaps other ECM-related proteins that are downregulated with age, would be necessary to isolate their effects and determine whether the depletion of this protein with age is a cause or a consequence of other forms of age-related degeneration.
Collectively, these data identify Cochlin as a critical regulatory component of proper tendon structure and future work will define the therapeutic potential of conservation or restoration of Cochlin to facilitate continued tendon health through the lifespan.
Literature
[1] Di, X., Gao, X., Peng, L., Ai, J., Jin, X., Qi, S., … & Luo, D. (2023). Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets. Signal transduction and targeted therapy, 8(1), 282.
[2] Galloway, M. T., Lalley, A. L., & Shearn, J. T. (2013). The role of mechanical loading in tendon development, maintenance, injury, and repair. JBJS, 95(17), 1620-1628.
[3] Korcari, A., Nichols, A. E., Buckley, M. R., & Loiselle, A. E. (2023). Scleraxis-lineage cells are required for tendon homeostasis and their depletion induces an accelerated extracellular matrix aging phenotype. Elife, 12, e84194.
[4] Verdoodt, D., Van Camp, G., Ponsaerts, P., & Van Rompaey, V. (2021). On the pathophysiology of DFNA9: Effect of pathogenic variants in the COCH gene on inner ear functioning in human and transgenic mice. Hearing research, 401, 108162.
View the article at lifespan.io
