Tenomodulin is Required for Tendon Endurance Running and Collagen I Fibril Adaptation to Mechanical Load

Abstract

Tendons are dense connective tissues that attach muscles to bone with an indispensable role in locomotion because of their intrinsic properties of storing and releasing muscle- generated elastic energy. Tenomodulin (Tnmd) is a well-accepted gene marker for the mature tendon/ligament lineage and its loss-of -function in mice leads to a phenotype with distinct signs of premature aging on tissue and stem/progenitor cell levels. Based on these findings, we hypothesized that Tnmd might be an important factor in the functional performance of tendons. Firstly, we revealed that Tnmd is a mechanosensitive gene and that the C-terminus of the protein co-localize with collagen I-type fibers in the extracellular matrix. Secondly, using an endurance training protocol, we compared Tnmd knockout mice with wild types and showed that Tnmd deficiency leads to significantly inferior running performance that further worsens with training. In these mice, endurance running was hindered due to abnormal response of collagen I cross-linking and proteoglycan genes leading to an inadequate collagen I fiber thickness and elasticity. In sum, our study demonstrates that Tnmd is required for proper tendon tissue adaptation to endurance running and aids in better understanding of the structural-functional relationships of tendon tissues.

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

“…In contrast to our previous results, we found out that Tnmd −/− OAF contain collagen fibrils with smaller calibers and lower compressive stiffness, which cannot provide enough strength and proper load distribution over large parts of the OAF. According to these results and our previous finding that Tnmd is a mechanosensitive and mechanoregulated gene (Dex et al, ), we propose that the above‐described phenotypic differences between tendon and IVD tissues are the consequence of the different biomechanical environments, namely IVDs are subjected mainly to compressive stress while tendons to tensile forces.…”

“…In our previous studies, we compared Tnmd knockout ( Tnmd − / − ) mice with their wild‐type (WT) littermates and showed that the absence of Tnmd causes reduced tendon cell proliferation and density in vivo (Docheva et al, ), coupled with significantly lower self‐renewal and augmented senescence of tendon‐derived stem/progenitor cells (TSPCs) in vitro (Alberton et al, ). Furthermore, we observed the pathological thickening and stiffening of collagen I (Col I) fibers in Tnmd − / − Achilles tendons resulting in running distance and time failure in Tnmd − / − mice challenged by running tests (Dex et al, ). Interestingly, the local absence of Tnmd in the cardiac chordae tendineae cordis (CTC) promoted angiogenesis and matrix metalloproteinases (MMPs) activation (Kimura et al, ), a phenomenon also observed when Tnmd − / − mice were subjected to surgically induced Achilles tendon rupture.…”

The Power of Experimental Models for Understanding the Genetic Basis for Superior Endurance Running

“…The role of integrin-linked kinase (ILK) in skeletal muscles and tenomodulin (TNMD/Tnmd) in tendons was assessed using a conditional KO model 3 and a constitutive KO mouse model, respectively. 4 Integrin-linked kinase is a protein highly expressed in skeletal muscle, more precisely at myotendinous junctions (MTJs). The principal function of MTJs is to bind myofibers to tendons and therefore it is relevant for proper force transmission.…”

“…It has been recently reported that Tnmd is needed for optimal running performance. 4 Mice lacking Tnmd failed in forced endurance running tests (daily treadmill exercise for 60min. at 10m/min with a declination of 10°).…”

“…This evidence strongly suggests that Tnmd is an important gene required for proper tendon tissue adaptation and there for epivotal for superior endurance running. 4 …”