**6.3 Matrix metalloproteinases**

The ECM surrounding tendon provides structural support, protection, and maintenance of the functional integrity. The modulation of ECM function is controlled by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The MMPs constitute a large family of endopeptidase zinc dependent that modulates ECM functions, degrading their constituents, such as proteoglycans, collagen, fibronectin, laminin, and other proteins during normal and pathological tissue remodeling. It has been reported that gelatinases (MMP-2 and MMP-9) play an important role in the ECM turnover induced by tissue injury and exercise training [84].

In order to compare exercise types (concentric, eccentric, or isometric) over gene expression of MMPs, a previous study noticed that MMP-2 mRNA expression increases moderately in the tendon in concentric and isometric exercises. On the other hand, MMP inhibitor, TIMP-1, and TIMP-2 increased gene expressions in response to all training types [77]. These data suggest a self-regulatory mechanism in attempt to protect the ECM against a high degradation of ECM compounds. In humans, it was found that MMP-2 mRNA decreased significantly 4 hours posteriorly to resistance training but returned to resting levels 24 hours after exercise. The mRNA expression of TIMP-1 did not change 24 hours post-acute exercise.

Interestingly in rodent models, previous data has already shown that acute or chronic exercises upregulate MMP-2 activity in the tendon, which is considered substantial mechanisms to tendon adaptation [85]. In contrast, anabolic-androgenic steroid treatment strongly inhibited this activity. Thus, anabolic-androgenic steroid treatment (AAS) can impair tissue remodeling in animal's tendons undergoing physical exercise by downregulating MMP activity, thus increasing the potential for tendon injury [86].

In the same research line, it has been demonstrated that the effects of exercise training on tendon repair are not the same for different tendon types and tendon regions (distal, proximal, and intermediary). For example, Marqueti et al. [87], showed that the intermediate region of the trained animals with AAS supplementation differed from the proximal and distal regions. Moreover, trained animals with AAS supplementation decreased MMP-2 activity form in three regions of the calcaneal tendon (distal, proximal, and intermediary) but not on the deep flexor tendons. The results suggest that the differences in the response to exercise and AAS treatment are a result of distinct metabolism and recruitment of these tendon regions in the exercise program. In another study, Pereira et al. [85] investigated MMP-2 activity in different regions of the calcaneal tendon after RT in ovariectomized rats. The authors demonstrated that ovarian hormones modulate MMP-2 activity differently in proximal region when compared to distal region; however, acute and chronic RT promote sufficient local stimuli to increase total and active MMP-2. Furthermore, proximal region of the calcaneus tendon seems to be more sensitive than the distal region to both acute and chronic RT due to greater MMP-2 activity increase, even in the ovariectomy condition.
