Abstract
The study was conducted to define the biomechanical response of rat Achilles tendon after a single bout of exercise and a short or long duration of daily exercise. We hypothesized that a single bout or a short duration of exercise would cause a transient decrease in Achilles tendon mechanical properties and a long duration of daily exercise would improve these properties. One hundred and thirty-six Sprague-Dawley rats were divided into cage activity (CA) or exercise (EX) groups for a single bout, short-term, or long-term exercise. Animals in single bout EX groups were euthanized, 3, 12, 24, or 48 h upon completion of a single bout of exercise (10 m/min, 1 h) on a flat treadmill. Animals in short-term EX groups ran on a flat treadmill for 3 days, 1, or 2 weeks while animals in long-term EX groups ran for 8 weeks. Tendon quasi-static and viscoelastic response was evaluated for all Achilles tendons. A single bout of exercise increased tendon stiffness after 48 h of recovery. Short-term exercise up to 1 week decreased cross-sectional area, stiffness, modulus, and dynamic modulus of the Achilles tendon. In contrast, 8 weeks of daily exercise increased stiffness, modulus, and dynamic modulus of the tendon. This study highlights the response of Achilles tendons to single and sustained bouts of exercise. Adequate time intervals are important to allow for tendon adaptations when initiating a new training regimen and overall beneficial effects to the Achilles tendon.
Introduction
It is universally acknowledged that physical exercise benefits all components of the body, including tendons [1]. Numerous studies have described tendon adaptations with improved mechanical properties following appropriate exercise protocols [1–3]. Despite the ability of tendons to adapt to beneficial exercise, mal-adaptations stemming from improper loading patterns can negatively affect tendon properties and result in tendinopathy or even tendon rupture [4,5]. The Achilles tendon can experience substantial loads during repetitive activities such as walking and running, sometimes reaching loads six times the body weight [6]. Such high load activities also result in the Achilles tendon bearing stresses well into the linear region. However, Achilles tendon injuries, commonly referred to as tendonitis or tendinopathy, have been identified as the most common overuse injuries in running athletes and are one of the most severe injuries in terms of the amount of training and racing time lost as a result of the injury [7,8]. Furthermore, Achilles tendon ruptures affect 15–55 per 100,000 people each year, and the majority of these tendon injuries are sports-related [9]. It is important to develop suitable exercise regimens to evoke beneficial exercise adaptations and avoid detrimental tendinopathic injuries.
Achilles tendons respond differently to various patterns of exercise, and exercise affects tendon properties both acutely and chronically [2,3,10,11]. Most studies using in vivo ultrasound scanning indicated unchanged or decreased Achilles tendon stiffness immediately after one bout of exercise [12]. Literature indicated that additional eccentric exercise might not be beneficial without removing the athlete from regular training and competition during the treatment period, and might be detrimental to a fundamentally intact tendon, but with reactive tendon cells or sensitized tendon matrix in the early stage of tendinopathy [13]. However, other studies have reported superior structural and material properties of the tendon after chronic or long-term exercise regimens [3,11]. Continuous eccentric training, used clinically as a rehabilitation protocol in patients with chronic Achilles tendinopathy or after tendon repair, has also been shown to reduce pain, improve function, and expedite return to activity [14,15]. In general, sufficient time between loadings is critical to allow for gradual adaptions of a tendon to the applied load to prevent injury [6]. There is a paucity of studies clarifying the mechanical response of the Achilles tendon at different time intervals after initiation of loading and how the tendon mechanical adaptations progress from a single bout of exercise to sustained exercise. Previous studies have indicated a loading-induced collagen synthesis after a 4-day exercise in rat Achilles tendon, while another study focusing on rat supraspinatus tendon indicated reduced matrix metalloproteinase activity in the tendon up to 48 h after one single bout of exercise [1,16]; however, these changes have not yet been described at the mechanical level. In order to develop suitable exercise time schedules to improve tendon health while avoiding tissue damage, it is important to delineate how tendons mechanically respond to one bout of exercise, and how the initiation of short-term exercise translates to tendon adaptations during sustained long-term exercise.
Therefore, the objective of this study was to define the biomechanical responses of rat Achilles tendon to one bout, continuous short-term, and long-term noninjurious exercise. We hypothesized that one bout of exercise and the short-term of exercise would cause a transient decrease in Achilles tendon mechanical properties and long-term exercise would improve these properties.
Materials and Methods
Study Design.
A hundred and 36 Sprague-Dawley rats (400–450 g, IACUC approved at University of Pennsylvania, Philadelphia, PA) were divided into exercise (EX) or cage activity (CA) groups for one bout, short-, or long-term exercise as shown in Fig. 1 and as utilized in a previous shoulder study [1]. The rats were randomly divided in different CA or EX groups and housed in an American Association for Laboratory Animal Care-accredited facility. All animals were euthanized with controlled, flowrate carbon dioxide and frozen for mechanical testing following a previously published protocol, and the right Achilles tendons were involved in this study.[1].
Fig. 1.
Single (a) and multiple (b) bouts of exercise study designs. (a) All rats in single bout of exercise (EX) groups underwent 2 weeks of treadmill training, followed by 72 h of rest. These rats were euthanized, 3–48 h after completion of a single bout of exercise (EX3 h, EX12 h, EX24 h, and EX48h) and were compared with a control, treadmill-trained group (CA-T). (b) Rats in multiple bouts of exercise groups underwent 2 weeks of treadmill training, followed by repeated exercise sessions for 3 days or 1, 2, or 8 weeks (EX3d, EX1w, EX2w, EX8w) and were compared with either an early time point CA group (CA2) or a later time point CA group (CA8). Mechanical testing was performed on Achilles tendons.
To investigate the acute effects of a single bout of exercise, animals in the acute EX groups first underwent 2 weeks of progressive, downhill treadmill training for acclimation to the equipment, running speed, and environment. A downhill acclimation regime was chosen to minimize any possible confounding effects of this training period. Following 72 h of rest, EX animals underwent a single treadmill exercise session at a constant speed of 10 m/min for 1 h on a flat treadmill [1,17,18]. These animals were then euthanized, 3, 12, 24, or 48 h upon completion of their single bout of exercise (EX3h, EX12h, EX24h, EX48h). A control, treadmill-trained cage activity group (CA-T) was euthanized at 72 h after its last bout of treadmill training and did not undergo any treadmill exercise sessions.
To investigate the adaptations of the Achilles tendon to short-term and long-term exercise, the EX animals ran on a flat treadmill (10 m/min, 60 min) for 3 days (n = 9), 1 week (n = 12) and 2 weeks (n = 14) for the short-term groups, and 8 weeks (n = 19) for the long-term groups, after a treadmill training period of 2 weeks [1]. Rats were euthanized 72 h after their final exercise session to avoid potentially confounding acute effects of exercise. One control group maintained normal CA for 2 weeks (CA2w, n = 13) as the control group for short-term exercise (EX3d, EX1w, and EX2w), while the other group were kept normal CA 8 weeks (CA8w, n = 13) as the control group for long-term exercise (EX8w) to diminish the effects of significant animal growth during testing.
Mechanical Testing.
Right Achilles tendons of the rats were uni-axially tested in a tensile-loading frame [1]. Stain dots were used to track optical strain. Cross-sectional area (CSA) was measured using a custom laser device [19]. Briefly, a CCD laser was used in combination with two linear variable displacement transducers (LVDTs) to acquire thickness and x- and y- displacements (system's accuracy is 0.05 mm2). Four passes across the tendon width were taken at the insertion site, and 2 mm, 4 mm, and 8 mm from the insertion site of the tendon. A custom program in matlab (The Mathworks, Inc., Natick, MA) was then utilized to calculate the average tendon area in each location. This code first calculated cross-sectional areas from each of the four passes utilizing displacement values from the laser and the two LVDTs. These four area values were then used to linearly interpolate area values between them at 0.05 mm intervals. The interpolated area values were then averaged to obtain the mean cross-sectional area of each tendon specimen [20].
After measuring cross-sectional area, the calcaneus was rigidly affixed in an acrylic cylinder with poly (methyl methacrylate). The tendon end was sandwiched between two pieces of sandpaper (400 grit) with cyanoacrylate glue. This construct was loaded on a materials testing machine (Instron E3000 Electropuls, Instron, Inc., Norwood, MA) and the following testing protocol was used: (1) preconditioning (ten triangle cycles from 1 to 1.5% strain at 0.25 Hz and then held at gage length for 300 s), (2) stress relaxation to 6% strain, held for 300 s, (3) frequency sweep (0.1, 1, 5, 10 Hz) of 10 sine cycles at 0.125% strain amplitude, (4) return to gage length and hold for 60 s, and (5) ramp to failure at 0.3%/s.
The stiffness was calculated as the slope of the linear region from the load–displacement curve during a ramp to failure at a ramp rate 0.3%/s. Strain within the tendon was tracked optically using the previously applied stain dots, and tissue modulus was calculated as the slope of the resulting stress–strain curve. Percent stress relaxation was calculated from a 300 s stress-relaxation test initiated with a fast ramp to 6% strain assuming a starting gage length of 12 mm. Tendon viscoelastic properties including dynamic modulus (Dyn. Mod.) and tangent of the phase angle (tan(δ)) between the stress and strain response were calculated from frequency sweeps at 0.1, 1, 5, 10 Hz for ten sinusoidal cycles (with parameters evaluated from the tenth cycle) at 6% strain magnitude and 0.125% strain amplitude [17].
Statistics.
To determine the acute effects of a single bout of exercise on tendon mechanical properties, a one-way analysis of variance (ANOVA) was performed for the EX3 h, EX12, EX24, EX48, and CA-T groups. If the ANOVA was significant (P ≤ 0.05) or a trend (P ≤ 0.1), then a Sidak's multiple comparison test was used to compare each EX group and CA-T group individually with significance (P ≤ 0.05) or trends (P ≤ 0.1). To determine the effects of short-term, sustained exercise on tendon mechanical properties, a one-way ANOVA was performed for the EX3d, EX1w, EX2w, and CA2w groups. If the ANOVA was significant (P ≤ 0.05) or a trend (P ≤ 0.1), then a Sidak's multiple comparison test was used to compare each EX group and CA-T group individually with significance (P ≤ 0.05) or trends (P ≤ 0.1). To determine the effects of long-term, sustained exercise on tendon mechanical properties, a Student's t-test was used to compare EX8w and CA8w groups with significance (P ≤ 0.05) or trends (P ≤ 0.1). All analyses were performed in graphpad prism 5 (GraphPad Software, San Diego, CA), and all data are presented as mean ± standard deviation.
Results
One-Bout of Exercise.
No change in CSA, stress relaxation, or modulus was noted at any time points after one bout of exercise (Figs. 2(a), 2(b), and 2(d)). Increased stiffness was observed at 48 h after exercise compared to the control CA-T group; no difference was noted at any other time points (Fig. 2(c)). For dynamic mechanical properties, trends of increased dynamic modulus along with trends of decreased tan(δ) were noted 48 h after the exercise (Fig. 3).
Fig. 2.
Quasi-static mechanical properties after single bout of exercise. Fifty-five male SD rats were included in this section and a one-way ANOVA was performed followed by a Sidak's multiple comparison test with significance (P ≤ 0.05) or trends (P ≤ 0.1). Increased stiffness was noted only at 48 h after one bout of exercise. No change of CSA, stress-relaxation, and modulus were noted at any time points. Solid line indicates significance (P ≤ 0.05).
Fig. 3.
Dynamic mechanical properties after single bout of exercise. Fifty-five male SD rats were included in this section and a one-way ANOVA was performed followed by a Sidak's multiple comparison test with significance (P ≤ 0.05) or trends (P ≤ 0.1). Trends of increased dynamic modulus and decreased tan(δ) were only noted at 48 h after one bout of exercise (Data of 0.1 Hz and 10 Hz were similar, not shown). Solid line indicates significance (P ≤ 0.05) and dashed line indicates trends (P ≤ 0.1).
Short-Term Exercise.
Consistent decrease in CSA was noted in all groups after different periods of short-term repeated exercise (Fig. 4(a)). Increased stress relaxation was noted only after 3 days of exercise (Fig. 4(b)). Decreased stiffness was noted in all groups after short-term exercise (Fig. 4(c)), whereas decreased modulus was only observed after 3 days and 1 week after exercise (Fig. 4(d)). For dynamic mechanical properties, decreased dynamic modulus and increased tan(δ) were observed after 3 days and 1 week of exercise (Fig. 5).
Fig. 4.
Quasi-static mechanical properties after short-term exercise. Forty-seven male SD rats were included in this section and a one-way ANOVA was performed followed by a Sidak's multiple comparison test with significance (P ≤ 0.05) or trends (P ≤ 0.1). Decrease in CSA was noted in all EX groups. Increased stress-relaxation was observed after 3 days of exercise. Trends and significant decrease in stiffness and modulus were observed after short-term exercise. Solid line indicates significance (P ≤ 0.05) and dashed line indicates trends (P ≤ 0.1).
Fig. 5.
Dynamic mechanical properties after short-term exercise. Forty-seven male SD rats were included in this section and a one-way ANOVA was performed followed by a Sidak's multiple comparison test with significance (P ≤ 0.05) or trends (P ≤ 0.1). Decrease in dynamic modulus and increase in tan(δ) were noted after 3 days and 1 week of repeated exercise (Data of 0.1 Hz and 10 Hz were similar, not shown). Solid line indicates significance (P ≤ 0.05) and dashed line indicates trends (P ≤ 0.1).
Long-Term Exercise.
After 8 weeks of exercise, quasi-static mechanical properties showed no changes in CSA or stress relaxation (Figs. 6(a) and 6(b)). A trend of increased stiffness and significantly increased modulus were observed after 8 weeks of exercise (Figs. 6(c) and 6(d)). For dynamic mechanical properties, increased dynamic modulus and decreased tan(δ) were observed after 8 weeks of exercise (Fig. 7).
Fig. 6.
Quasi-static mechanical properties after long-term exercise. Thirty-two male SD rats were included in this section and a Student's t-test was performed with significance (P ≤ 0.05) or trends (P ≤ 0.1). Increase in stiffness and modulus with no change in CSA or stress relaxation was identified. Solid line indicates significance (P ≤ 0.05) and dashed line indicates trends (P ≤ 0.1).
Fig. 7.
Dynamic mechanical properties after long-term exercise. Thirty-two male SD rats were included in this section and a Student's t-test was performed with significance (P ≤ 0.05) or trends (P ≤ 0.1). Trends of increase in dynamic modulus and decrease in tan(δ) were observed (Data of 0.1 Hz and 10 Hz were similar, not shown). Solid line indicates significance (P ≤ 0.05) and dashed line indicates trends (P ≤ 0.1).
Discussion
Tendon is a dynamic tissue that actively responds to mechanical loading and adapts differentially to varying levels of activity [21]. To develop beneficial exercise regimens and avoid detrimental overuse injuries, this study investigated the acute effect of one bout of exercise on tendon mechanics, as well as how the short-term and long-term of noninjurious exercise affected the mechanical response of rat Achilles tendons.
Surprisingly, increased tendon stiffness and trends of improved dynamic mechanical properties were identified 48 h after a single bout of exercise. This transient increase of tendon mechanical properties after 48 h of one bout of exercise could indicate an acute protective biological response to sudden loading, which may happen due to either a transient positive net balance of collagens synthesis or the formation augmented cross-linking induced by the sudden loading. Our previous study on supraspinatus tendons utilizing the same exercising protocol as described here did observe rounder cell shape and decreased matrix metalloproteinase activity in the supraspinatus tendon at 48 h after one bout of exercise, indicating altered metabolic activity [1]. Additionally, an increase in type I collagen in peri-tendinous tissue was observed at 72 h of recovery after 3 h of running (36 km) [22] and a rapid increase in collagen synthesis after strenuous exercise in human tendon and muscle within 6 h and lasting up to 72 h after 1 h of one-legged kicking exercise at 67% of maximum workload was also demonstrated [23]. Although a direct relationship between this positive net balance of collagen synthesis and mechanical properties has not yet been established, collagen is the most abundant structural protein and a major component of tendons and its biological function lies predominantly in bearing mechanical load [24]. In addition to the positive net balance of collagen synthesis, the increase in stiffness could also happen in the absence of collagen accrual if cross-linking of the existing matrix was augmented by loading [25], as was a substantial increase in mRNA expression of the collagen cross-linking enzyme lysyl oxidase in response to 4 days of strength training [16].
In contrast to our findings, most clinical in vivo measurements of the mechanical properties of Achilles tendon after one bout of exercise have reported unchanged [26,27] or decreased stiffness [12]. However, these previous assessments were performed immediately after the exercise while no study has assessed these properties 48 h after the exercise regimen. Interestingly, two recent studies have also reported increased stiffness after static stretching or 10 sets of 15-repetition heel drop exercise [28,29]. It is likely that different exercise modes, leg dominance, and pre-exercise daily physical activity are important factors that may influence tendon mechanical responses to one bout of exercise in the human population. Further, it has been shown that habitual loading (which may correspond to the treadmill-training here) may result in a higher basal rate of collagen synthesis [28]. Future studies could focus on longer observation time after one single bout of exercise and a “training” before the real test.
The decrease in CSA observed during the short-term exercise regimens could be postulated as the initiation of tendon adaptation via extracellular matrix reorganization or realignment. However, we also observed a decrease in tendon stiffness, modulus, and dynamic modulus up to 1 week of exercise, while there was no difference in modulus, tan (δ), and dynamic modulus was observed at 2 weeks of exercise. It was postulated that a positive net balance of collagen synthesis requires a sufficient period of rest without which the tendon will undergo continuous loss of collagen and thus result in inferior mechanical properties [25], so the transient decrease of mechanical properties up to 1 week of exercise might be due to continuous bouts of exercise, which may render the tendon at a higher risk of injury during this time period. Furthermore, these changes could also be a result of tendon microdamage or material fatigue after initiation of a continuous exercise protocol. The initial loss of tissue integrity due to tendon microdamage and the mechanobiological under-stimulation of tendon cells secondary to the microtrauma of the collagen fibrils could lead to inferior tendon mechanical properties [25,30]. However, these mechanical properties are recovered at 2 weeks after exercise and might indicate adaption to the new external loading regimen, potentially due to the initiation a healing response to the “microdamage,” which led to a positive net balance in collagen synthesis and ultimately beneficial adaptations to exercise [25,30].
Consistent with previous observations [31,32], no changes were found in the CSA of Achilles tendons between the long-term EX and CA groups; however, enhanced tendon structural and material properties were exhibited after long-term exercise, further supporting the known health benefits of sustained moderate exercise. Clinically, it has been shown that habitual loading can result in tendon hypertrophy and increased stiffness of the human patellar tendon [33], while Achilles tendons appear to be capable of increasing their stiffness in response to 14 weeks of exercise by adapting both material and dimensional properties [10]. Additionally, increased tissue modulus was observed in rat Achilles tendons after 12 weeks of uphill running [3].
Our previous study that employed the same exercise protocol as described here reported more significant mechanical changes after 2 weeks of exercise than after 8 weeks of exercise in supraspinatus tendons [1]. However, we observed more evident mechanical alternations after 8 weeks of exercise in rat Achilles tendons. This could be due to differential adaptions patterns of different loading environments, including different joint anatomical structure, muscular contracture orientation, and tendon functional capabilities. Additionally, this could be further supported by the fact that our well-established overuse protocol for supraspinatus tendons [32] did not result in damage to the Achilles tendons [3,34].
This study is not without its limitations. Although the rat Achilles model has been used extensively to investigate various Achilles tendon pathologies, the use of a quadruped animal does not exactly replicate the human. Furthermore, although the changes found in this study are mild, this is likely expected as they are consistent with the adaptations often seen in human tendons following mild exercise. Only a single moderate running protocol was employed in this study. This protocol was chosen based on previous studies investigating relations between running speed and maximal oxygen uptake and correlated to an exertion of approximately 40–50% of a rat's maximum rate of oxygen consumption [35]. Further, this protocol was milder than that used in Heinemeier et al. [3], and thus, it was ensured to not cause any deleterious adaptations to the Achilles tendon [1]. The time points used in this study were chosen to represent the effects of one single bout, the initiation of a new protocol of continuous bouts, and the adaption of tendon after sustained bouts of exercise. Although the exact timing of responses may not be directly translatable to humans, the overall concepts and findings in this study can be valuable for clinical references. Finally, while animals in the acute EX groups underwent 2 weeks of progressive downhill treadmill training, which may have impacted the acute tendon response to exercise versus an untrained group, our comparisons are still valid since we used a trained CA group as a control instead of a naïve CA group. Additionally, in our experience, 2 weeks of treadmill training is required to minimize animal stress and reduce the number of excluded animals [1]. Despite these limitations, our results clearly demonstrate that the rat Achilles tendon responds acutely and chronically to exercise. Further studies will investigate tendon histologic, metabolic, and genetic responses to identify the biological markers and clarify the substantial mechanisms of these mechanical adaptations.
Overall, our findings suggest that one bout of exercise may lead to a transient increase of mechanical properties; however, initiation of a new exercise routine with repeated loading causes a short-term decrease in Achilles tendon mechanical properties, and continuous long-term moderate exercise improves the overall mechanical health of tendons. This study highlights the dynamic temporal response of tendons to one bout of exercise, the importance of avoiding strenuous exercise while initiating a new training regimen in order to allow for natural tendon adaptations, and the overall beneficial of moderate exercise to the Achilles tendon.
Acknowledgment
This study was funded by the Penn Center for Musculoskeletal Disorders (National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases P30 AR0696192).
Footnotes
Funding Data
Penn Center for Musculoskeletal Disorders (NIH, P30 AR069619; Funder ID: 10.13039/100000002).
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