Katja M Heinemeier (1) & Jens L Olesen (2)

1: Institute of Sports Medicine, Bispebjerg Hospital, Copenhagen, Denmark
2: Department of Rheumatology, Aalborg Hospital, Aalborg, Denmark

https://doi.org/10.36866/pn.70.25

It is well known that regular exercise can lead to hypertrophy of skeletal muscle, and there is a relatively good understanding of the mechanisms involved in this adaptive process. But what happens with the tissues that support the skeletal muscle when strength is increased as a result of training? Tendons, which connect muscle to bone, are essential for transmission of force and storage of elastic energy during muscle contraction, and it seems logical that they should adapt along with the muscle tissue, to keep the muscle-tendon unit functioning.

It is clear that tendon tissue responds to loading, but while the adaptive response in muscle tissue relates closely to the loading stimulus, the tendon’s response appears far less sensitive.

Long-term training does seem to induce changes in both the mechanical and biochemical characteristics of tendon tissue. Several studies indicate that the tendon becomes stiffer (so that it elongates less at a certain amount of applied force) (Magnusson et al. 2007), and in animals a greater maximal load can be sustained by the tendons (Wang, 2006). Changes in the mechanical tendon properties can be related both to an increase in cross sectional area and to changes in the tendon tissue ‘quality’. In line with this, training-induced tendon hypertrophy has been shown in animals, and in humans the cross sectional area of Achilles tendons in individuals who regularly perform weight-bearing exercise is larger than in sedentary individuals (Magnusson et al. 2007). The loading-induced hypertrophy of the tendon tissue is presumably based on an increase in the local synthesis of type I collagen – the main ‘building-block’ of tendon tissue –as both acute exercise and long-term training appear to induce the production of this protein (Langberg et al. 1999; Langberg et al. 2001).

Possible role of collagen inducing growth factors

One of many unanswered questions is how exercise/training can lead to increased production of collagen in the loaded tendon tissue.

In vitro studies indicate that certain collagen-inducing growth factors, including transforming growth factor-β-1 (TGF-β-1), connective tissue growth factor (CTGF), and insulin like growth factor-I (IGF-I), are candidates to act as mediators of mechanically induced collagen synthesis in connective tissue (Chiquet et al. 2003). These growth factors are produced by fibroblasts in vitro in response to mechanical stimuli, and they can subsequently induce the expression of collagen in the mechanically stimulated cells (by autocrine stimulation) (Fig. 1). This mediator role is especially well documented for TGF-β-1, and a recent study shows that mechanically induced collagen synthesis in cultured patella tendon fibroblasts is directly dependent on TGF-β-1 function (Yang et al. 2004).

In a recent study we aimed to investigate whether TGF-β-1, CTGF and the IGF-I isoforms – IGF-IEa and mechano growth factor (MGF) –could be involved in the loading-induced changes in collagen production in tendon tissue in vivo. We found that the level of mRNA for type I collagen was substantially increased in rat Achilles tendons after a 4-day plantar-flexor strength training programme (Fig. 2). At the same time the expression of TGF-β-1 and IGF-I isoforms (IGF-IEa and MGF) were increased, while no change was found in the level of CTGF mRNA (Fig. 2 & 3). These results underline that loading of tendon structures can induce the expression of collagen and suggest a potential role for TGF-β-1 and the IGF-I isoforms in mediating this effect (Heinemeier et al. 2007a; Heinemeier et al. 2007b).

Tendon ‘quality’ and collagen cross-linking

Changes in tendon mechanical properties do not necessarily depend on changes in tendon size. Several studies have shown a markedly increased tendon stiffness without any increase in tendon cross sectional area (e.g. Reeves et al. 2003), and although these results are still debated, it is likely that repeated loading can lead to changes in the properties of the tendon tissue matrix. In line with this, it has been suggested that an increase in the number of cross-links between collagen molecules could be part of the tendon response to mechanical loading. This would lead to stabilization and strengthening of the fibrillar collagen structures and thus to increased stiffness of the tendon matrix.

Lysyl oxidase is essential for the formation of cross-links between newly formed collagen molecules, and we have found that the expression of this enzyme is induced more than 35 fold in rat Achilles tendons in response to 4 days of resistance training (Heinemeier et al. 2007a). This finding definitely supports that an increase in cross-link formation could be an important part of the adaptive process in loaded tendons. In fact, it may be speculated that collagen turnover is increased in response to loading (Langberg et al. 2001) to give the opportunity to assemble new collagen fibres with a higher content of cross-links. Such a response could explain a training-induced increase in stiffness without changes in cross sectional area.

Can tendons keep up with muscle?

There is no doubt that tendons respond to repeated loading. But how well does the tendon response correspond with the response of the skeletal muscle tissue?

In the rat training study discussed above, three different types of muscle contractions – shortening, lengthening and static contractions – were applied. With this setup the lengthening contractions led to a substantially greater force production than the shortening contractions, while the static loading led to an intermediate force production. We found that the expression of growth regulatory factors, IGF-IEa, MGF and myostatin, in the trained muscle tissue was highly reflective of the force production (Fig. 3). Surprisingly however, in tendon the expression of both collagen, growth factors, and lysyl oxidase was equally induced with all training types and thus unrelated to force production (Figs. 2 & 3) (Heinemeier et al. 2007a;Heinemeier et al. 2007b). In other words it appears that tendons, compared to muscles, are relatively insensitive to the degree of mechanical stimulus, and it could be speculated that the tendon adaptation will not ‘keep up’ with the muscle adaptation if muscle contractions with high loads are performed repeatedly. This may help explain the high incidence of tendon overload injuries in sports.

In summary, repeated loading appears to change the mechanical characteristics of tendons. These changes could be explained by an increased tendon cross sectional area – possibly relating to a growth factor-induced collagen production –but also by changes in the tendon tissue matrix, such as increased levels of cross-linking between collagen molecules. Importantly, the tendon tissue seems less sensitive than skeletal muscle to changes in mechanical stimulus.

References

Chiquet M, Renedo AS, Huber F & Fluck M (2003). How do fibroblasts translate mechanical signals into changes in extracellular matrix production? Matrix Biol 22, 73–80.

Heinemeier KM, Olesen JL, Haddad F, Langberg H, Kjaer M, Baldwin KM & Schjerling P (2007a). Expression of collagen and related growth factors in rat tendon and skeletal muscle in response to specific contraction types. J Physiol 582, 1303–1316.

Heinemeier KM, Olesen JL, Schjerling P, Haddad F, Langberg H, Baldwin KM, & Kjaer M (2007b). Short-term strength training and the expression of myostatin and IGF-I isoforms in rat muscle and tendon: differential effects of specific contraction types. J Appl Physiol 102, 573–581.

Langberg H, Rosendal L, & Kjaer M (2001). Training-induced changes in peritendinous type I collagen turnover determined by microdialysis in humans. J Physiol 534, 297–302.

Langberg H, Skovgaard D, Petersen LJ, Bulow J, & Kjaer M (1999). Type I collagen synthesis and degradation in peritendinous tissue after exercise determined by microdialysis in humans. J Physiol 521, 299–306.

Magnusson SP, Narici MV, Maganaris CN & Kjaer M . Human tendon behaviour and adaptation, in vivo. 10.1113/jphysiol.2007.139105.

Reeves N, Maganaris CN & Narici MV (2003). Effect of strength training on human patella tendon mechanical properties of older individuals. J Physiol 548, 971–981.

Wang JH (2006). Mechanobiology of tendon. J Biomech 39, 1563–1582.

Yang G, Crawford RC & Wang JH (2004). Proliferation and collagen production of human patellar tendon fibroblasts in response to cyclic uniaxial stretching in serum-free conditions. J Biomech 37, 1543–1550.