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CLINICAL SCIENCES

Is Exercise the Right Medicine for Dystrophic Muscle?

SPAULDING, HANNAH R.; SELSBY, JOSHUA T.

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Medicine & Science in Sports & Exercise: September 2018 - Volume 50 - Issue 9 - p 1723-1732
doi: 10.1249/MSS.0000000000001639

Abstract

Duchenne muscular dystrophy (DMD) affects 1 in every 5000 boys (1) and is caused by a deficiency of the protein, dystrophin. It is a muscle-wasting disease that leads to impaired mobility and wheel chair confinement, and ultimately, patients succumb to respiratory or cardiac failure. Diagnoses of DMD typically occur around 4–5 yr of age, driven largely by parental concerns about missed or delayed achievement of developmental milestones, frequent falls, and, in some instances, a distinct gait. Dystrophin is a 2.3-Mb gene with 79 exons that is translated into a 427-kDa protein (2). Mutations to the dystrophin gene resulting in a frame shift or nonsense mutation cause a deficiency of functional dystrophin protein. Dystrophin acts as the anchor for the dystrophin–glycoprotein complex, functions in related signaling, and serves a critical role in membrane stability during muscle contraction and eccentric contractions, in particular. In the absence of dystrophin, muscle cells are sensitive to eccentric injury resulting in physical disruption of the sarcolemma, loss of Ca2+ homeostasis, increased proteolysis, free radical injury, and widespread cellular dysfunction, among other maladies (3–6). DMD is most commonly modeled by the mdx mouse, which has a nonsense mutation in exon 23. On the whole, the disease phenotype is relatively mild with only slight reductions in longevity (7) and impaired cardiac function only apparent after approximately 8 months (8,9) likely due to increased utrophin protein abundance (10), increased capacity for repair (11), and differences in locomotion (12). Limb muscles experience an acute necrotic bout from approximately 3–8 wk of age followed by relative stability before declining again after 12 months of age (13). The diaphragm undergoes a progressive disease and most accurately recapitulates many aspects of disease progression including impaired function, fibrosis, and necrosis, among others (14).

The absence of functional dystrophin affects not only the skeletal and cardiac muscle cells but also the skeletal, endocrine, and central nervous systems (15). Kyphosis, due in part to osteoporosis, is prevalent in DMD patients. Indeed, vertebral and leg fractures are common in DMD patients and resultant immobilization from leg fractures can lead to permanent loss of ambulation (16). The use of glucocorticoids, which is the standard of care for DMD patients, may exacerbate bone loss and contribute to fractures directly and indirectly, and it prolongs ambulation, which increases the opportunity for fractures due to falls (17). DMD patients tend to be obese, with excess weight gain beginning early in disease progression due to decreased mobility, and weight gain is further driven by increased appetite with steroid treatments (18). Obesity and increased weight gain result in increased rate of hyperinsulinemia and insulin resistance leading to increased occurrence of type 2 diabetes and cardiovascular disease for DMD patients (19). In addition, and perhaps due, at least in part, to these physical effects, DMD patients suffer from increased risk of depression and anxiety (20). Importantly, in healthy populations, exercise has been widely shown to counter many of these DMD-associated effects. At the very core of endurance training is increased cardiorespiratory function, whereas overload training increases hypertrophy serving to combat two significant problems encountered by DMD patients. In addition, exercise has been shown to decrease the severity of depression, maintain bone density, and increase overall muscle health, among other benefits (21). Thus, exercise would seem to be a well-suited intervention for DMD patients. Indeed, exercise serves as the basis of physical therapy and uses multiple exercise modalities to maintain muscle flexibility and health in DMD patients.

As a premise of this review, it is assumed that patients are receiving appropriate nutritional support and effective physical therapy. This review will focus on exercise beyond that what is generally performed during physical therapy. The role of exercise on DMD has been previously reviewed, e.g., Gianola et al. (22), Grange and Call (23), and Markert et al. (24), although in many of these previous studies, exercise was broadly considered. Here, we will independently explore exercise modality and consider independent muscle groups, with a particular focus on functional and histological outcomes, with the intention that this more refined approach will allow us to better identify emerging patterns of exercise benefits for dystrophic muscle (see Glossary, Supplemental Digital Content 1, description of functional measures, https://links.lww.com/MSS/B265).

ENDURANCE EXERCISE

Researchers have investigated the effects of a variety of exercise modalities in mouse and human studies. The breadth of exercise regimens, measures, durations, and disease states makes comparisons between these investigations difficult. To better elucidate the effects of low-intensity exercise in dystrophic muscle, data were collected from studies using swimming, voluntary wheel running, and treadmill running interventions (Fig. 1). To visualize these data, we plotted exercise modality, age of intervention initiation, duration of treatment, and effect of exercise on a single set of axes. The effect of exercise on a dependent variable was estimated from published investigations to calculate a percent change caused by exercise compared with sedentary dystrophic controls. In this manner, values less than 100% indicate a detrimental effect of exercise, whereas values larger than 100% indicate that a dependent variable was improved with exercise. To appropriately report and plot measurements such as fibrosis, necrosis, and creatine kinase (CK) activity, in which an increase indicates a negative effect, an inverse calculation was used to appropriately place these data on the figures. Hind limb muscles were divided into two categories defined as anterior (i.e., tibialis anterior (TA) and extensor digitorum longus (EDL)) and posterior compartments (i.e., gastrocnemius, soleus, and plantaris). In total, the literature provides contradictory information on the effect of exercise on disease severity (Fig. 1; see also Tables, Supplemental Digital Content 2, all data reviewed, https://links.lww.com/MSS/B266). Duration, intensity, and modality of exercise complicate interpretation of data supporting the use of or contraindication of exercise as an intervention for DMD patients. To better identify the effect of exercise modality on disease severity, the effects of voluntary wheel running, swimming, and treadmill/rota-rod exercises were considered in more depth.

F1
FIGURE 1:
Effect of low-intensity exercise on health outcomes in dystrophic mice. Low-intensity exercise provides both beneficial and detrimental health outcomes. The breadth of initiation age, duration, and modality complicate an appreciation for the effects of exercise on disease severity. Data were obtained from the literature, and the effect of exercise was normalized to sedentary mdx mice. Additional statistical analyses were not performed. For any given variable, age of initiation is shown at 100% (y axis), and the deviation from 100% and the duration of the intervention can be determined. The figure is constructed such that beneficial changes are more than 100% and detrimental changes are less than 100%, including those where an elevation would indicate increased pathology. Nonsignificant findings were not plotted. Data point shapes represent activities as indicated. Colors represent muscles as follows: black, whole body; gray, forelimb; purple, anterior hind limb; blue, posterior hind limb; red, heart; and green, diaphragm.

Voluntary wheel running

In the investigations considered, voluntary wheel running maintained or positively affected all measures of relative tension and fatigue resistance in muscles of the forelimb and in anterior and posterior compartments of the hind limb in dystrophic mice regardless of age and duration of wheel running (Fig. 2). Forelimb strength increased by more than 25% after 4 wk of exercise starting at 12 wk of age (25). Fatigue resistance of the EDL in vitro and TA in situ was improved by 45% and 48% after 16 and 18 wk of exercise, respectively, starting at 4 wk of age (26,27). In addition, relative tension in the EDL improved, whereas other measures of EDL function were preserved (28) and maximum torque in the plantarflexor muscles were increased with voluntary wheel running (29). Similarly, EDL fatigability decreased by 65% after 48 wk of exercise started at 24-wk-old mice (30). After 9 wk of exercise, 12-wk-old mice maintained soleus function and fatigue resistance was significantly increased (31). Relative tension and specific eccentric force of the soleus in 16-wk-old mice also increased 25% after 12 wk of exercise and tetanic force was increased 45% after 16 wk of exercise, whereas other measures of soleus and EDL function were maintained (25,26). After 1 yr of voluntary wheel running, EDL relative tension and soleus function, such as relative tension, fatigue resistance, and half relaxation time, were maintained compared with unexercised controls (31–33). Although these data seem to provide compelling evidence supporting the use of exercise to maintain limb muscle health, conflicting results were reported in the diaphragm (Fig. 2). In three independent studies, 3- to 4-wk-old mice ran on a wheel for 1 yr. In one investigation, diaphragm relative tension was impaired by nearly threefold (33); however, a 30% increase in active tension, a 14% increase in fatigue resistance, and preservation of a variety of respiratory function and fatigue measures were reported in the other investigations (31,32). In a shorter experiment, mice exercised for 9 wk starting at 3 wk of age had increased diaphragm contraction time, while maintaining other measures of diaphragm function (31). The effect of voluntary wheel running on cardiac function is also unclear (Fig. 2). After just 4 wk of exercise, 11-wk-old mice had greater than 25% thinning of the left ventricle wall thickness and increased left ventricle dilation similar to dystrophin-related cardiomyopathy (34). In one investigation, left ventricle ejection fraction decreased by 30% after 14 wk of exercise (27), but in another, after 1 yr of exercise, left ventricle ejection fraction was similar between sedentary and exercised mice, whereas cardiac output was increased twofold and stroke volume increased by 80% with exercise training (33).

F2
FIGURE 2:
Effect of voluntary wheel running on health outcomes in mdx mice. All measures of hind limb muscle function were maintained or improved by voluntary wheel running. Conflicting results emerged concerning the effect of voluntary wheel running on cardiac and respiratory function. Values greater than 100% are measures positively affected by exercise. Nonsignificant data were omitted from the figure. Data point shapes/colors represent measures as indicated.

The integrity of the skeletal system is also compromised in DMD patients both as a function of dystrophin deficiency and as a common use of glucocorticoids. Kyphosis is a spinal deformity that is a hallmark of dystrophin deficiency and negatively affects respiratory function (35). Brereton et al. (36) indicated that after 1 month of voluntary wheel running, kyphosis increased by 25% in 4-month-old mice. In addition to increased kyphosis, and perhaps contributing to it, fibrosis of the erector spinae increased by 40% (36). Kyphosis and injury to the erector spinae are not routinely reported in the dystrophic literature, making comparisons difficult. Notably, these findings are in contrast to the bulk of data showing that younger mice after a similar duration of exercise and 4-month-old mice after a longer duration of exercise have improved limb muscle function (25,28,29). However, given its function, the erector spinae may experience increased, damaging stress during exercise.

Swimming

Swimming interventions were beneficial for most skeletal muscles in mdx mice (Fig. 3). Forelimb strength increased by 30% at 8 wk of age after 4 wk of exercise training (37). Similarly, EDL half relaxation time decreased in 20-wk-old mice after 15 wk of swimming, indicating that Ca2+ sequestration was improved, fatigability was decreased by greater than 20% in EDL, and EDL relative tension was sustained (38). In addition, soleus half relaxation time was maintained and relative tension increased by 60% after 15 wk of swimming (38). In older animals, 8 wk of exercise begun at 44 wk of age increased relative tension in the soleus and EDL and sustained half relaxation time suggesting improved limb muscle health with exercise in age animals (39). Importantly, however, cardiac and respiratory muscle had increased fibrosis in exercised mdx mice compared with sedentary mdx mice after 10 wk of swimming in 19-wk-old mice (Fig. 3). In addition, inflammation was increased twofold as was the heart wall to lumen ratio (40).

F3
FIGURE 3:
Effect of swimming on health outcomes in mdx mice. Exercise improved forelimb function and hindlimb muscle function but was detrimental to cardiac muscle function. Values greater than 100% are measures positively affected by exercise. Nonsignificant data were omitted from the figure. Data point shapes/colors represent measures as indicated.

The intensity of exercise in these studies and how this may affect interpretation of the findings mentioned previously make the effect of swimming unclear. Playing in a swimming pool is a low-intensity exercise recommended by physical therapists for a variety of muscle dysfunctions including DMD. It is likely that the intensity of exercise, as a percent V˙O2max, in mice from these studies greatly exceeded that of DMD patients playing in a pool.

Forced running

Unlike voluntary wheel running, treadmill and rota-rod running are forced exercises that generally led to increased muscle damage and impaired function (Fig. 4). After 4 wk of training, 8-wk-old mice had a 20%–50% reduction in forelimb strength (41–45), increased plasma CK activity, increased fibrosis in the quadriceps and heart, and increased oxidative stress in the quadriceps and abdominal muscles (44,46,47). In the TA, the abundance of necrotic muscle cells and inflammatory cells increased twofold, further supporting increased damage and decreased muscle function with treadmill training (41). Interestingly, damage and muscle regeneration were similar in TA, gastrocnemius, and diaphragm muscles after 4 wk of treadmill running compared with unexercised controls. Also, diaphragm relative tension was maintained (44). Animals that began training at 8 wk of age also had reduced forelimb strength after 4 wk of training (48) and decreased force production in the gastrocnemius after 24 wk (49). Twelve weeks of training starting at 12 wk of age decreased tetanic force and increased fibrosis twofold in the gastrocnemius (50). Similarly, after 6 wk of rota-rod training, forelimbs fatigue was similar between exercised and sedentary age-matched controls, but the gastrocnemius and quadriceps of 14-wk-old mdx mice had more than twofold more necrosis than sedentary age-matched controls (51), further supporting increased muscle damage and decreased muscle function caused by forced training. In some contrast, training for 10 wk starting at 10 wk of age decreased soleus and gastrocnemius necrosis by more than 40% but, consistent with previous findings, dramatically increased plantaris necrosis (52). The authors suggest (52) that the degree of fiber loss may be related to the increased contractile activity, although it seems likely that the increased relative activity of the plantaris in combination with the fast fiber type is accountable for increased plantaris necrosis, whereas the soleus and gastrocnemius are protected. Finally, after 4 wk of treadmill training, oxidative stress was increased in the quadriceps and abdominal muscles, but not the heart (47). In the same animals, fibrosis was increased in the heart and quadriceps, but the abdominal muscles were protected.

F4
FIGURE 4:
Effect of treadmill running/rota-rod on health outcomes in mdx mice. Forced running caused a variety of responses in dependent variables. Values greater than 100% are measures positively affected by exercise. Nonsignificant data were omitted from the figure. Data point shapes/colors represent measures as indicated.

In most studies, mice were forced to run for 30 min at 12 m·min−1 (360 m·d−1) 2–3 times per week, and in one investigation, mice ran at 9 m·min−1 for 60 min 5 times per week. By comparison, with volitional wheel running, young mdx mice ran an estimated peak of 14 km·d−1 (100 km·wk−1), 28-wk-old mice ran nearly 3 km·d−1 (20 km·wk−1), and 52-wk-old mice ran approximately 2 km·d−1 (14 km·wk−1) (33). The role of distance (daily or weekly) is unclear, although data suggest that these shorter, forced bouts with treadmill running are not as efficacious as larger daily running volumes seen during wheel running. This interpretation is complicated, however, by the intermittent nature of mouse wheel running, which has typical bouts of 1–10 min in mdx mice (53).

Downhill running

Downhill running has been used as a method for deliberate induction of contraction-induced injury in dystrophic muscle (54,55). Our analysis of these investigations strongly supports this conclusion (Fig. 5). For example, after only 3 d of downhill running, there was a 40% increase in damage to the biceps brachii, triceps brachii, soleus, gastrocnemius, and diaphragm in 2-month-old mice (55). Interestingly, damage was not increased in the TA or EDL (55). After 7 wk of training, fibrosis increased threefold in the TA of 31-wk-old mice. In addition, plasma CK activity and fibrosis of the biceps increased more than twofold, further supporting increased damage (56). Forelimb strength also decreased by 15% in these same animals (56). Fibrosis of the diaphragm and heart after 2 wk of downhill running were similar to sedentary controls (56), but after 10 wk of downhill running, dystrophic lesions increased in the heart by threefold with a 17% increase in heart mass (57). The only improvement was the soleus in which twitch tension increased 50% after 3 wk of downhill running, although half relaxation time increased (58).

F5
FIGURE 5:
Effect of downhill running on health outcomes in mdx mice. Downhill running was largely detrimental to the hind limb (anterior and posterior compartments), forelimb, and cardiac muscles. Values greater than 100% are measures positively affected by exercise. Nonsignificant data were omitted from the figure. Data point shapes/colors represent measures as indicated.

HUMAN STUDIES

Conservative exercise protocols have been investigated in the context of both ambulatory and nonambulatory DMD patients. Despite the advent of mechanical respiratory support, respiratory failure remains a significant cause of death in DMD patients. Given this, inspiratory and expiratory muscle training as well as resistive training protocols have been used in ambulatory patients. Generally, these interventions increased respiratory endurance by 46% with training after 6 wk (59) and increased respiratory pressure and markers of respiratory strength after 24, 36, 40, and 96 wk of training (60–63) (Fig. 6). In nonambulatory patients, 6.5 wk of respiratory exercise increased vital capacity and airway pressure greater than 70%, making clear that nonambulatory patients can respond favorably to a therapeutic intervention (64).

F6
FIGURE 6:
Effect of exercise on DMD patients. Exercises designed to improve range of motion and respiratory endurance improved health outcome measure in DMD patients. Starting ages were not provided in this figure because the range of starting ages within a study varied, as did ambulatory status. Values greater than 100% are measures positively affected by exercise. Nonsignificant data were omitted from the figure. Data point shapes/colors represent exercises as indicated.

In addition to respiratory function, range of motion and ability to complete tasks of daily living are important to the quality of life of DMD patients. To identify exercise protocols to prolong independence, nonambulatory patients were provided jaw stretching and strengthening interventions (65,66). Collectively, Nozaki et al. (65) and Kawazoe et al. (66) discovered that masticatory performance and occlusal force and the degree of mouth opening were improved after 24 wk of jaw exercises. In ambulatory patients, training by an assisted cycle or arm ergometer resulted in increased or maintained endurance and range of motion in targeted muscles (67,68). These data suggest that stretching and exercise increased range of motion and maintain strength of skeletal muscles. However, given the concerning respiratory and cardiac data presented earlier, more information on the interplay between limb muscle exercise and effect on respiratory and cardiac function is necessary.

ACUTE EXERCISE

Performance of activities of daily living in DMD patients requires consideration of acute bouts of exercise. This seems particularly urgent considering that few patients are part of regular exercise training regimens and regular play, not to mention occasional, high-intensity activities, such as the violent forces experienced on inflatable playground equipment (i.e., a bouncy castle or the like), which could certainly be considered an acute exercise bout. Indeed, activities like this can lead to agonizing decisions because competing parental roles are in conflict. Despite its importance, the literature does not provide fertile ground or necessary nuance for a rich discussion of acute exercise and we recognize this as an important gap in the literature. Nevertheless, summation of limited available evidence points to increased susceptibility to acute injury in dystrophic muscle.

In mdx mice, less than 30 min of swimming seemed damaging, despite being a non–weight-bearing activity, as the number of damaged fibers in the TA were increased by up to fivefold (69). Furthermore, Evan’s blue dye penetration into dystrophic muscle was dramatically elevated compared with healthy after a single 20-min swimming bout (70). Of interest, in this investigation, fibers expressing a microdystrophin construct were also resistant to swimming-induced injury, whereas fibers from within the same section lacking microdystrophin expression had robust penetration of Evan’s blue dye (70). These sections are particularly important because they clearly demonstrate increased damage in dystrophin-deficient muscle compared with dystrophin-expressing muscle when subjected to the same acute exercise bout. In addition, a single bout of treadmill running increased serum CK activity sevenfold (71), whereas in healthy mice, only a twofold to threefold change might be expected after either treadmill running or even eccentric exercises (72,73). In the quadriceps, necrosis was increased more than twofold after 30 min of treadmill running (71), and in the EDL, force was decreased 2.5-fold and membrane permeability was increased after 45 min of downhill running in mdx mice (74). Although direct comparison to injury in healthy muscle is rare, our expectation, based on the sensitivity of dystrophic muscle to contraction-induced injury, demonstrated elevations in serum CK activity, and increased Evan’s blue dye penetration, is that this degree of damage in dystrophic muscle surpasses that anticipated in healthy muscle after performance of the same activity. To that point and although not a single acute running bout, 3 d of downhill running increased membrane permeability in dystrophic limb muscle by 10%, whereas in healthy muscle, no permeability was noted (55). Lastly, when mdx mice ran voluntarily for 24 h, damaged fibers in the gastrocnemius were increased 18% and sixfold in the TA and quadriceps (75). This latter study is of note because long-term volitional wheel running generally improved outcomes, whereas shorter treadmill bouts exacerbated markers of injury. Collectively, these data suggest that dystrophic skeletal muscle is capable of exercise-mediated adaptations despite increased damage early in a training regimen (i.e., acute exercise), although the degree to which it may be trained and how closely the training response of dystrophic muscle follows that of healthy muscle is unclear.

Importantly and consistent with the animal literature, acute or single bouts of exercise result in increased serum CK activity in DMD patients (76). Although certainly increased serum CK activity can occur as a result of exercise in healthy patients, the effect, and thus presumptive underlying muscle injury, is greater in DMD patients after similar activities. For example, 8 h after a 15-min bout of physical therapy in the water, serum CK activity increased nearly 1000 U·L−1 from baseline in DMD patients compared with an increase of less than 10 U·L−1 in healthy subjects (76). Supporting this notion of increased susceptibility to acute injury, circulating myoglobin increased 1114.8 ng·mL−1 from baseline in DMD patients but only 46.2 ng·mL−1 in healthy controls 8 h after exercise (76).

Although dystrophic muscle seems capable of exercise-mediated adaptations under the right training conditions (25,26,28–31,39), it is associated with increased injury after acute exercise, which may suppress exercise-mediated adaptations compared with healthy. Furthermore, despite these data seeming to make clear that an acute bout of exercise is more damaging to dystrophic muscle compared with healthy muscle, we cannot rule out the possibility that because DMD patients ostensibly have a lower V˙O2max than healthy controls, dystrophic muscle was operating at a higher relative workload and therefore may be expected to have a greater degree of muscle injury. Moreover, because injury after acute exercise may be necessary for adaptation in healthy muscle, we cannot rule out the possibility that increased damage after acute exercise is necessary for a training adaptation in dystrophic muscle, although the degree to which disease and disease-related injury may alter this process, either directly or indirectly, is unknown.

EXERCISE MIMETICS

Exercise has the potential to provide a robust therapeutic effect to dystrophic muscle; however, the forces produced during exercise and its multisystemic involvement make its use tenuous. To harness the effects of exercise without associated complications, several groups have used pharmaceutical and nutraceutical approaches to mimic the effects of exercise. For example, myostatin inhibition has repeatedly resulted in increased muscle mass and function in a dystrophic muscle (77,78), which ostensibly would translate into improved tasks of daily living. Indeed, several clinical trials are currently making use of myostatin inhibition as a therapy for muscular dystrophy (NCT02310763, NCT02515669, NCT02907619); however, the effect on cardiac function will need to be carefully monitored. In addition, induction of oxidative metabolism and the oxidative muscle phenotype has been successfully accomplished using the AMPK activator, AICAR (79,80), and activation of mitochondrial biogenesis pathways has been attempted via PGC-1α overexpression and gene transfer (6,81,82) and supplementation with resveratrol and quercetin (83–87). Although generally further testing is needed, including long-term investigations and clinical trials, these approaches have the promise to afford DMD patients with some benefits of exercise while minimizing risk.

CONCLUSIONS

When considering exercise as a therapy for DMD patients, it is essential to consider the totality of effects on patients and particularly to vital muscles. DMD patients typically succumb to respiratory or cardiac failure; thus, exercises that protect or improve limb muscle function while impairing respiratory or cardiac function provide little benefit to the patient. In mouse studies, swimming generally improved limb muscle function but caused histopathological damage in cardiac and respiratory muscles, suggesting that caution should be used when considering swimming as an exercise for DMD patients until the role of exercise intensity is made clearer. Similarly, voluntary wheel running provided contradictory information on the effect on cardiac and respiratory function, but was consistently beneficial to limb muscles. The multisystemic nature of DMD and the effects of exercise on these systems are also of interest for DMD patients. Increased kyphosis (36) paired with conflicting diaphragm (31,33) and heart function data in mice (27,33,34) brings to light the need to further investigate and balance the benefits of exercise while minimizing detrimental side effects. Concurrent investigation of respiratory and cardiac function as well as other systems is necessary to effectively prescribe exercise as a therapy for DMD.

The authors have no conflicts of interest. Partial support for H. R. S. was provided by Project Parent Muscular Dystrophy, Ryan’s Quest, and Michael’s Cause. The results of the study do not constitute and endorsement by the American College of Sports Medicine.

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Keywords:

MDX; DMD; DYSTROPHIN; RUNNING; SWIMMING

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