Exercise and duchenne muscular dystrophy - Distrofia Muscular

ISSUES AND OPINIONS

EXERCISE AND DUCHENNE MUSCULAR DYSTROPHY: WHERE WE HAVE BEEN AND WHERE WE NEED TO GO CHAD D. MARKERT, PhD,1 LAURA E. CASE, DPT, PCS,2 GREGORY T. CARTER, MD, MS,3 PATRICIA A. FURLONG, RN, BSN, MS,4 and ROBERT W. GRANGE, PhD5 1

Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, USA Division of Physical Therapy, Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA 3 Department of Clinical Neurosciences, Providence Medical Group, Olympia, Washington, USA 4 Parent Project Muscular Dystrophy, Middletown, Ohio, USA 5 Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, Virginia, USA Accepted 14 November 2011 2

The Parents’ Perspective on Exercise Families and boys/men with DMD, as well as physical therapists and educators, often inquire as to how much and what types of exercise are appropriate to help alleviate signs of the disease and possibly improve function. For all of us, life is a continuous balancing act filled with cautious modifications and adjustments. We look to health care professionals and researchers for better guidelines and treatments and remain hopeful that evidence-based exercise prescriptions will be developed for the Duchenne community. (Paraphrased from introductory statements made by Pat Furlong, President and CEO of Parent Project Muscular Dystrophy.) Duchenne muscular dystrophy (DMD) is a devastating and ultimately fatal disease characterized by progressive muscle wasting and weakness. It is caused by the absence of a functional dystrophin protein, which in turn leads to reduced expression and mislocalization of dystrophin-associated proteins. Fibrosis is a pathologic feature observed in patients with Duchenne muscular dystrophy (DMD) and in mdx mice, an experimental model of DMD. The effects of exercise in individuals with Duchenne muscular dystrophy (DMD) have not yet been adequately studied.1,2 To address this clinically critical gap in knowledge and to obtain opinions of professionals in the field, an exercise and DMD working group was formed, and a roundtable session was convened at the New Directions in

Biology and Disease of Skeletal Muscle Conference, New Orleans, Louisiana, May 1, 2008. The purpose of the roundtable was to initiate dialogue among physical therapists, physicians, and basic scientists to craft an action plan to study exercise in DMD. Members of the working group are listed in Table 1. There were three goals for the roundtable: (1) to initiate a working relationship among colleagues from various scientific disciplines and the Parent Project Muscular Dystrophy (PPMD); (2) to discuss the current findings related to exercise and DMD from animal and human studies and, from these, identify research questions within the clinical, physiological, and translational arenas; and (3) to generate key recommendations as the basis for the action plan (see later). OVERVIEW OF ROUNDTABLE DISCUSSION

The motivation for the roundtable was the view that parents and health care professionals believe it is important to keep individuals with DMD active as long as possible in a physiologically beneficial way. To achieve this goal, it was noted that previous work has addressed exercise prescription in the context of neuromuscular disease, but definitive parameters regarding the risks/benefits of exercise for DMD are not yet known. Consequently, definitive physical activity or exercise guidelines for DMD do not exist.1–9 WHAT HAVE WE LEARNED FROM ANIMAL STUDIES?

Abbreviations: ACSM, American College of Sports Medicine; DMD, Duchenne muscular dystrophy; GRMD, golden retriever muscular dystrophy; MET, metabolic equivalent; MMT, manual muscle testing; PPMD, Parent Project Muscular Dystrophy Key words: DMD; dystrophic; mdx; mechanisms; muscle; physical activity This study is an overview of the recommendations that emerged from an Exercise and Duchenne Muscular Dystrophy Roundtable held on May 1, 2008 as part of the New Directions in Biology and Disease of Skeletal Muscle Conference, New Orleans, Louisiana, April 27 to May 1, 2008. Contributors to the roundtable included physicians, therapists, basic scientists, and societal stakeholders. Correspondence to: C. D. Markert; e-mail: [email protected] C 2011 Wiley Periodicals, Inc. V

Published online 18 November 2011 in (wileyonlinelibrary.com). DOI 10.1002/mus.23244

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Issues & Opinions: Exercise and DMD Roundtable

The three major animal models of DMD that have been used to study pathogenesis and therapeutic strategies are the mdx mouse, the canine X-linked muscular dystrophy (CXMD), and the golden retriever muscular dystrophy (GRMD) model. In some older murine studies, evidence indicated that eccentric and high-intensity exercise may result in decreases in muscle strength.7,10,11 Conversely, submaximal exercise may have potential benefit in the mdx mouse model, although it differs phenotypically from human DMD.12–15 CXMD is the best MUSCLE & NERVE

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Table 1. Contributors to the exercise and DMD roundtable.

Pat Furlong—President and CEO of Parent Project MD Dr. Kristen Baltgalvis—mouse models/basic; Department of Biochemistry, University of Minnesota Medical School Dr. Katie Bushby—basic/physician; Institute of Human Genetics, Newcastle University Dr. Greg Carter—physician/mouse models; MDA/ALS Center, University of Washington School of Medicine Dr. Laura Case—physical therapist; Division of Physical Therapy, Department of Community and Family Medicine, Duke University Medical Center Dr. Casey Childers—physician/GRMD dog model; Department of Neurology, Wake Forest University and Wake Forest Institute for Regenerative Medicine Dr. Annamaria De Luca—mouse models/basic; Unit of Pharmacology, Department of Pharmaco-Biology, University of Bari Ms. Tina Duong, physical therapist—mouse models/clinical; Research Center for Genetic Medicine, Children’s National Medical Center Dr. Robert Grange—mouse models/basic; Dept. of Human Nutrition, Foods and Exercise, Virginia TechMs. Ms. Wendy King—physical therapist; Department of Neurology, College of Medicine, Ohio State University Dr. Joe Kornegay—veterinarian/GRMD dog model; School of Medicine, University of North Carolina-Chapel Hill Dr. Rich Lovering—basic/physical therapist; Department of Physiology, School of Medicine, University of Maryland Dr. Dawn Lowe—mouse models/basic; Program in Physical Therapy and Rehabilitation Sciences, University of Minnesota Medical School Dr. Chad Markert—GRMD dog model, translational and integrative skeletal muscle physiology; Wake Forest Institute for Regenerative Medicine Dr. Craig McDonald—physician, human/applied; Department of Physical Medicine and Rehabilitation, University of California, Davis Ms. Shree Pandya—physical therapist; School of Medicine and Dentistry, University of Rochester Ms. Helen Posselt—physical therapist; Queensland, Australia Dr. Chris Ward—mouse models/basic; School of Nursing, University of Maryland

representation of DMD, but the phenotype of the most widely used GRMD model is variable, thus functional endpoints are difficult to ascertain. Canine studies suggested vulnerability to even mild forms of exercise.16 In non-mammalian models (Caenorhabditis elegans, a nematode), when dystrophin-deficient muscles were experimentally denervated, they did not degenerate, suggesting that an absence of contraction is protective.17 Studies performed in both normal and dystrophic animals have shown that unaccustomed eccentric exercise may injure the contractile and cytoskeletal components of the muscle fibers.12,18– 23 Concentric exercise, which involves shortening of the muscle during contraction, does not have the deleterious effects observed in eccentric exercise.19,21 During eccentric exercise, sarcomeres are stretched, and the actin and myosin filaments are pulled apart. This leads to disruption of the thick and thin filament array and damage to cytoskeletal proteins.20,24,25 Structural damage is observed by the appearance of Z-line streaming and myofibrillar disruptions. Mechanical strain, the contributing factor that induces muscle injury, causes an immediate loss of force-generating capacity and initiates a cascade of processes that result in skeletal muscle damage. The inability to quickly repair a disruption of the membrane causes an elevation in intracellular calcium concentration, which triggers calcium-activated degradation pathways and further ultrastructural damage.20,24,25 This damage results in fiber degeneration followed by inflammation and, eventually, fiber regeneration. A majority of studies reported that dystrophic muscles have an increased susceptibility to high Issues & Opinions: Exercise and DMD Roundtable

mechanical forces. Eccentric exercise reduces the force-generating capacity of dystrophic muscles to a greater extent than in normal muscles.18,19,26 There is also evidence of greater mechanical disruption of the sarcolemma, increased fiber degeneration, and necrosis. However, the muscles of young dystrophic mdx mice have a more rapid rate of recovery of force production than those of normal mice.27,28 Histological and contractile studies suggest that this more rapid recovery is due to an increased regenerative capacity, which is lost in older mice. The severity of disease in mice lacking both dystrophin and utrophin is similar to DMD, but one has to account for the discrete functions of utrophin.28 Adaptations of diseased muscle to exercise occur at many levels, starting with the extracellular matrix, but they also involve cytoskeletal architecture, muscle contractility, repair mechanisms, and gene regulation.29–32 The majority of exercise injury investigations have attempted to determine the susceptibility of dystrophin-deficient muscles to contraction-induced injury. There is some evidence in animal models that diseased muscle can adapt and respond to mechanical stress. However, exercise injury studies showed that dystrophic muscles have an increased susceptibility to high mechanical forces.19,23,26 Most of the studies involving exercise training have shown that muscle adaptations in dystrophic animals were qualitatively similar to the adaptations observed in control muscle. Deleterious effects of the dystrophy usually occur only in older animals with advanced muscle fiber degeneration or after high-resistive eccentric training.10,11,19,23 MUSCLE & NERVE

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HUMAN STUDIES

The main limitations in applying the conclusions from animal studies to humans are the differences in phenotype between humans and genetically homologous animal models, the significant biomechanical differences between humans and animal models, and age spans.33,34 For clarification, physical activity may encompass the movements of daily living (e.g., dressing, walking) as well as participation in highly structured (e.g., youth sports) or unstructured (e.g., playing with friends in the yard) physical activities. Exercise is a structured physical activity because it can be defined by an exercise prescription that considers type of exercise, intensity, duration, and frequency. There is a need to define safe parameters to define the exercise prescription, as well as safe modes of muscle activation, in both structured and unstructured environments. The problem of exercise training and contraction-induced muscle injury remains the biggest clinical concern.35 Muscle pain, particularly after activity, is a prominent complaint in boys with DMD.35 Older studies in humans with DMD have suggested that submaximal exercise may be beneficial, especially early in the course of the disease36–39 Knowledge of the natural history of DMD helps us understand how and when physical exercise might be beneficial. The weakness progresses steadily, but the rate may be variable during the disease course. Quantitative strength testing showed greater than 40–50% loss of strength by 6 years of age.40–42 With manual muscle testing, DMD subjects exhibit loss of strength in a linear fashion from ages 5–13 years, and measurements obtained several years apart show steady disease progression. Variability may be noted when individuals are analyzed over a shorter time course.43 Previous investigators have noted a change in the rate of strength loss at approximately 14–15 years of age.43 This change did not appear to be associated with achievement of a particular score on the manual muscle test (MMT) scale but rather consistently occurred in various muscle groups in the early second decade. Thus, the investigators recommended that natural history control trials that evaluate therapies in DMD should be cautious about including subjects transitioning to the teenage years because of the flattening of the MMT strength curve with increasing age.43 Quantitative strength measures have been shown to be more sensitive for demonstrating strength loss than MMT when strength is graded 4–5.41 Exercise prescriptions and recommendations in DMD need to consider a multitude of issues. The muscle groups that perform the most eccen748


tric activity, including hip extensors, knee extensors, and ankle dorsiflexors in the lower extremities, tend to undergo the greatest mechanical loads.41 This has been proposed as the main reason lower extremity weakness predates loss of strength in the upper extremities. Edwards and colleagues proposed that routine eccentric contractions during gait are a likely source of the pattern of weakness typically seen in myopathies.44,45 Studies of strengthening interventions in DMD subjects have shown maintenance of strength or even mild improvement over the period of investigation. However, these studies are limited by use of primarily non-quantitative measures, lack of control groups, and use of the opposite limb as a control without considering the effects of cross-training.36–39,46 What is clear and agreed upon by this working group is that boys with DMD are increasingly sedentary with age because of weakness and progressive loss of muscle function, complicated by cardiorespiratory comorbidity and progressive joint contractures and deformity. The primary muscle pathology, contraction-induced injury, and secondary disuse atrophy may all contribute to weakness, and increased fat mass may contribute to functional losses and difficulty moving in individuals who gain excessive amounts of weight as function declines. There were a number of broad study themes suggested to improve our understanding of the role of exercise as a potential therapeutic treatment for DMD (Table 2). These included: practical studies (a physical activity survey; functional endpoint measures); translational studies (how best to apply exercise findings in animals to DMD patients; development of new assays in animal models to reflect the physical limitations observed in patients); and basic studies (identify and define both the positive and negative physiological adaptations in response to exercise). It was also suggested that physical activity guidelines could be established and expressed in metabolic equivalents (MET ¼ 3.5 ml oxygen/kg body mass/minute) similar to those described by the American College of Sports Medicine (ACSM) for cardiac rehabilitation patients.47 METs can be used to describe the energy cost of activities from dressing to walking to jogging.47 Knowledge of these energy costs, together with assessment of other physical capabilities (e.g., muscle strength and flexibility), could contribute to development of appropriate treatment plans. Another outcome of our discussion was preparation of a series of research questions (by no means exhaustive) that could address the key overarching purpose of identification of the parameters of potentially beneficial vs. potentially MUSCLE & NERVE

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Table 2. Broad study themes. Study theme Physical activity survey

Exercise paradigms (animal to human)

Physiological adaptation

New assays

Functional endpoint measures

Energy costs of physical activities

Brief description and purpose Develop a brief (5 or 6 questions) survey to obtain information from parents, physicians, and physical therapists about DMD patients’ participation in activities, and observations about this participation; answers could be used to guide the design of proposals to study the activities more rigorously. Use established exercise paradigms in animal models to develop a conceptual framework on how to proceed with therapeutic exercise in humans with DMD. In addition, explore and define new animal exercise protocols to evaluate the threshold of possible benefit. Parameters should include intensity, duration, and frequency. Exercise is known to elicit multiple positive adaptations in many physiological systems and tissues and is also known to have detrimental effects in fragile muscles and in disease states, but further study is needed. What positive adaptations can be safely achieved in individuals with DMD? What activities will facilitate positive adaptation? What types of exercise or activities, in addition to eccentric exercise, can cause potentially negative adaptations or damage and should be avoided? Develop and validate new assays of physical function in DMD animal models that reflect the DMD phenotype observed in patients; for example, gait analysis, joint range of motion, and other measures to provide surrogate markers of clinical disability observed in DMD. Standardize methods for acquiring data that describe quality of life and functional outcomes specific to the DMD patient population, for more readily comparable study results; for example, see refs. 54 and 55. Daily activity levels of DMD boys have only been partially studied49,50,42; use of the COSMED (mobile breath-by-breath VO2) system to obtain metabolic measurements and the METs for various activities (e.g., dressing, walking, wheelchair movement).

detrimental types and levels of activity and exercise for individuals with DMD. KEY UNANSWERED QUESTIONS

1. What is the appropriate amount and type of physical activity or exercise? 2. How long and how often should children be physically active? (What type, intensity, and duration of exercise and/or activity?) 3. What are the contributions of fatigue, and how should it be best defined and measured? 4. What is the role of muscle stretching? For example, will flexibility exercises assist/maintain flexibility and therefore increase ease of movement and decrease the resistance against which weak muscles contract? Would maintenance of flexibility decrease intramuscular fibrosis? Will flexibility prevent contractures and improve biomechanics for movement? 5. With appropriate exercise, can the progression of muscle atrophy and weakness be mitigated? Table 3 expands further upon these questions. RECOMMENDATIONS FOR RESEARCH ACTION PLAN

The consensus from members of the roundtable was that exercise may have beneficial or detrimental effects for DMD patients; however, the balance of these effects has not been determined rigorously in the literature. The parameters of potentially beneficial vs. detrimental activities/exercises, including type, intensity, frequency, and duration Issues & Opinions: Exercise and DMD Roundtable

have not yet been established for DMD. There is a need for further detailed studies on the effects of exercise, to identify safe and potentially beneficial types and amounts of activity and exercise as well as to identify potentially harmful types and amounts of activity and exercise. Toward this goal, a framework of standard operating procedures focused on the mdx model has been developed.48–51 The goal would be to define these potentially beneficial or detrimental activities/exercises for type, intensity, frequency, and duration (i.e., an activity/exercise prescription). To determine these parameters, directed research should be undertaken with a distinct translational emphasis. The establishment of a model(s) to study exercise safely and effectively in DMD will be increasingly important. An appropriate model(s) will facilitate the assessment of exercise interventions. In addition to safety and efficacy, ideal models would also permit longitudinal assessment of the dynamic variables related to exercise. These variables may change with time as the disease progresses and as therapies emerge that modify disease pathophysiology. 1. Future studies, both animal and human, need to use standardized, reliable, systematic methods to assess muscle performance. This approach will allow for cross-study comparison. 2. It is critical to quantitatively determine the exercise loads that are beneficial and to determine the thresholds at which injury may occur. This could be done first in animals and then in humans. 3. Alternative exercise approaches, such as aquaticbased therapy, should be studied, particularly in MUSCLE & NERVE

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Table 3. Key research questions. Setting

Key research questions

Clinical

What role does exercise/physical activity play in either lessening or exacerbating muscle loss and contractures in DMD patients? Are there periods of disease progression, particularly related to the age of the DMD patient, when exercise is more prone to give benefit or cause further injury? What is the role of appropriate exercise as an adjunct to other treatment modalities (e.g., drugs, gene therapy, etc.)? How much of the loss in strength and function is due to the natural history of disease progression and how much is due to contraction-induced injury or disuse atrophy? What effects do strength/endurance activities have on muscle function in the short term (e.g., initial days or weeks), the intermediate term (e.g., several weeks to months), and the long term (e.g., many months to years)? What should the primary outcomes/endpoints be to assess the effects of exercise? For instance, if one primary outcome/endpoint is to prolong ambulation, what are the appropriate activities and exercise prescriptions? How does exercise impact other variables (e.g., weakness, increased body mass relative to strength, contractures) that might confound using length of ambulation as an endpoint? What outcome parameters (biomarkers), that is, strength, severity of contractures, MRI, etc., best predict/confirm benefits and/or deleterious effects of exercise? Can non-invasive imaging methods be used to determine whether exercise increases or decreases damage? What prospective clinical study design would best address these and other questions in DMD patients? Is the decrease in myocardial contractility correctable? Why does heart rate does not respond to exercise as it does in normal boys41,56,57? What is the capability of the peripheral tissues to extract oxygen from the blood? How does physical activity affect progressive cycles of degeneration/ regeneration? How does absence of dystrophin from smooth muscle affect vascular responses to exercise? How does it affect other smooth muscle tissues (e.g., intestinal tract)? To what extent does exercise influence tissue reorganization (e.g., fibroblast proliferation)? What similarities/differences exist if exercise and DMD microarray data are compared (i.e., do genes upregulated with exercise counter the downregulation of the same genes in DMD, or vice versa)? What role can/should animal models such as the mdx mouse and GRMD dog play in addressing these and other questions? How can we best determine the predictive value of animal exercise models and determine which model is the most relevant? What criteria must be satisfied before translating animal work to humans?

Physiological

Translational

4.

5.

6.

7.

8.

boys with DMD who are non-ambulatory and have less than antigravity muscle strength. Functional activities and quality of life should be included in study endpoints, as well quantitative strength testing.52 Granting agencies should target funding and request proposals to determine the role of therapeutic exercise in DMD. An initial request for proposals could target MET generation and daily movement activity guidelines for DMD boys and their parents; parental involvement with registries is critical.5,49,50 A cornerstone for exercise and DMD studies should be ‘‘translational research teams,’’ including clinicians and basic scientists. Identify grant reviewers who have specific expertise in evaluating the potential therapeutic benefits of exercise in DMD. Education and dissemination of research findings as they emerge must be prioritized.

FUTURE DIRECTIONS

The No Use is Disuse (NUD) study,53 from The Netherlands, will be the first comprehensive study 750


in human subjects with DMD to address whether low-intensity physical training is beneficial in terms of preservation of muscle endurance and functional abilities. The study consists of two training intervention studies: dynamic leg and arm training for ambulatory boys with DMD and functional training with arm support for wheelchair-dependent boys with DMD. This study should help fill some gaps in our knowledge of the effects of exercise training in boys with DMD and also provide more insight into the types of exercise that should be recommended for these boys. REFERENCES 1. Grange RW, Call JA. Recommendations to define exercise prescription for Duchenne muscular dystrophy. Exerc Sport Sci Rev 2007;35: 12–17. 2. Markert CD, Ambrosio F, Call JA, Grange RW. Exercise and Duchenne muscular dystrophy: toward evidence-based exercise prescription. Muscle Nerve 2011;43:464–478. 3. Ansved T. Muscle training in muscular dystrophies. Acta Physiol Scand 2001;171:359–366. 4. Ansved T. Muscular dystrophies: influence of physical conditioning on the disease evolution. Curr Opin Clin Nutr Metab Care 2003;6: 435–439. 5. Cup EH, Pieterse AJ, Ten Broek-Pastoor JM, Munneke M, van Engelen BG, Hendricks HT, et al. Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review. Arch Phys Med Rehabil 2007;88:1452–1464.

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