Exercise and duchenne muscular dystrophy: Where we have been and where we need to go

ISSUES AND OPINIONS

EXERCISE AND DUCHENNE MUSCULAR DYSTROPHY: WHERE WEHAVE BEEN AND WHERE WE NEED TO GOCHAD 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

1Wake Forest Institute for Regenerative Medicine, Wake Forest University, Winston-Salem, North Carolina 27157, USA2Division of Physical Therapy, Department of Community and Family Medicine, Duke University Medical Center,Durham, North Carolina, USA

3Department of Clinical Neurosciences, Providence Medical Group, Olympia, Washington, USA4 Parent Project Muscular Dystrophy, Middletown, Ohio, USA5Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, Virginia, USA

Accepted 14 November 2011

The Parents’ Perspective on Exercise

Families and boys/men with DMD, as well as physi-cal therapists and educators, often inquire as to howmuch and what types of exercise are appropriate to helpalleviate signs of the disease and possibly improve func-tion. For all of us, life is a continuous balancing actfilled with cautious modifications and adjustments. Welook to health care professionals and researchers for betterguidelines and treatments and remain hopeful that evi-dence-based exercise prescriptions will be developed for theDuchenne community. (Paraphrased from introduc-tory statements made by Pat Furlong, Presidentand CEO of Parent Project Muscular Dystrophy.)

Duchenne muscular dystrophy (DMD) is a dev-astating and ultimately fatal disease characterizedby progressive muscle wasting and weakness. It iscaused by the absence of a functional dystrophinprotein, which in turn leads to reduced expressionand mislocalization of dystrophin-associated pro-teins. Fibrosis is a pathologic feature observed inpatients with Duchenne muscular dystrophy(DMD) and in mdx mice, an experimental modelof DMD. The effects of exercise in individuals withDuchenne muscular dystrophy (DMD) have notyet been adequately studied.1,2 To address this clin-ically critical gap in knowledge and to obtain opin-ions of professionals in the field, an exercise andDMD working group was formed, and a roundtablesession was convened at the New Directions in

Biology and Disease of Skeletal Muscle Confer-ence, New Orleans, Louisiana, May 1, 2008. Thepurpose of the roundtable was to initiate dialogueamong physical therapists, physicians, and basic sci-entists to craft an action plan to study exercise inDMD. Members of the working group are listed inTable 1. There were three goals for the roundta-ble: (1) to initiate a working relationship amongcolleagues from various scientific disciplines andthe Parent Project Muscular Dystrophy (PPMD);(2) to discuss the current findings related to exer-cise and DMD from animal and human studiesand, from these, identify research questions withinthe clinical, physiological, and translational arenas;and (3) to generate key recommendations as thebasis for the action plan (see later).

OVERVIEW OF ROUNDTABLE DISCUSSION

The motivation for the roundtable was the viewthat parents and health care professionals believeit is important to keep individuals with DMD activeas long as possible in a physiologically beneficialway. To achieve this goal, it was noted that previ-ous work has addressed exercise prescription inthe context of neuromuscular disease, but defini-tive parameters regarding the risks/benefits ofexercise for DMD are not yet known. Conse-quently, definitive physical activity or exerciseguidelines for DMD do not exist.1–9

WHAT HAVE WE LEARNED FROM ANIMAL STUDIES?

The three major animal models of DMD that havebeen used to study pathogenesis and therapeuticstrategies are the mdx mouse, the canine X-linkedmuscular dystrophy (CXMD), and the golden re-triever muscular dystrophy (GRMD) model. Insome older murine studies, evidence indicated thateccentric and high-intensity exercise may result indecreases in muscle strength.7,10,11 Conversely, sub-maximal exercise may have potential benefit in themdx mouse model, although it differs phenotypi-cally from human DMD.12–15 CXMD is the best

Abbreviations: ACSM, American College of Sports Medicine; DMD,Duchenne muscular dystrophy; GRMD, golden retriever muscular dystro-phy; MET, metabolic equivalent; MMT, manual muscle testing; PPMD,Parent Project Muscular Dystrophy

This study is an overview of the recommendations that emerged from anExercise and Duchenne Muscular Dystrophy Roundtable held on May 1,2008 as part of the New Directions in Biology and Disease of SkeletalMuscle Conference, New Orleans, Louisiana, April 27 to May 1, 2008.Contributors to the roundtable included physicians, therapists, basicscientists, and societal stakeholders.Correspondence to: C. D. Markert; e-mail: [email protected]

VC 2011 Wiley Periodicals, Inc.Published online 18 November 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI 10.1002/mus.23244

Key words: DMD; dystrophic; mdx; mechanisms; muscle; physical activity

746 Issues & Opinions: Exercise and DMD Roundtable MUSCLE & NERVE May 2012

representation of DMD, but the phenotype of themost widely used GRMD model is variable, thusfunctional endpoints are difficult to ascertain. Ca-nine studies suggested vulnerability to even mildforms of exercise.16 In non-mammalian models(Caenorhabditis elegans, a nematode), when dystro-phin-deficient muscles were experimentally dener-vated, they did not degenerate, suggesting that anabsence of contraction is protective.17

Studies performed in both normal and dystro-phic animals have shown that unaccustomedeccentric exercise may injure the contractile andcytoskeletal components of the muscle fibers.12,18–23 Concentric exercise, which involves shorteningof the muscle during contraction, does not havethe deleterious effects observed in eccentric exer-cise.19,21 During eccentric exercise, sarcomeres arestretched, and the actin and myosin filaments arepulled apart. This leads to disruption of the thickand thin filament array and damage to cytoskeletalproteins.20,24,25 Structural damage is observed bythe appearance of Z-line streaming and myofibril-lar disruptions. Mechanical strain, the contributingfactor that induces muscle injury, causes an imme-diate loss of force-generating capacity and initiatesa cascade of processes that result in skeletal muscledamage. The inability to quickly repair a disrup-tion of the membrane causes an elevation in intra-cellular calcium concentration, which triggers cal-cium-activated degradation pathways and furtherultrastructural damage.20,24,25 This damage resultsin fiber degeneration followed by inflammationand, eventually, fiber regeneration.

A majority of studies reported that dystrophicmuscles have an increased susceptibility to high

mechanical forces. Eccentric exercise reduces theforce-generating capacity of dystrophic muscles toa greater extent than in normal muscles.18,19,26

There is also evidence of greater mechanical dis-ruption of the sarcolemma, increased fiber degen-eration, and necrosis. However, the muscles ofyoung dystrophic mdx mice have a more rapid rateof recovery of force production than those of nor-mal mice.27,28 Histological and contractile studiessuggest that this more rapid recovery is due to anincreased regenerative capacity, which is lost inolder mice. The severity of disease in mice lackingboth dystrophin and utrophin is similar to DMD,but one has to account for the discrete functionsof utrophin.28

Adaptations of diseased muscle to exerciseoccur at many levels, starting with the extracellularmatrix, but they also involve cytoskeletal architec-ture, muscle contractility, repair mechanisms, andgene regulation.29–32 The majority of exerciseinjury investigations have attempted to determinethe susceptibility of dystrophin-deficient muscles tocontraction-induced injury. There is some evidencein animal models that diseased muscle can adaptand respond to mechanical stress. However,exercise injury studies showed that dystrophicmuscles have an increased susceptibility to highmechanical forces.19,23,26 Most of the studies involv-ing exercise training have shown that muscleadaptations in dystrophic animals were qualitativelysimilar to the adaptations observed in control mus-cle. Deleterious effects of the dystrophy usuallyoccur only in older animals with advanced musclefiber degeneration or after high-resistive eccentrictraining.10,11,19,23

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 Med-

ical Center� Dr. Casey Childers—physician/GRMD dog model; Department of Neurology, Wake Forest University and Wake Forest Institute for Re-

generative 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

Issues & Opinions: Exercise and DMD Roundtable MUSCLE & NERVE May 2012 747

HUMAN STUDIES

The main limitations in applying the conclusionsfrom animal studies to humans are the differencesin phenotype between humans and genetically ho-mologous animal models, the significant biome-chanical differences between humans and animalmodels, and age spans.33,34 For clarification, physi-cal activity may encompass the movements of dailyliving (e.g., dressing, walking) as well as participa-tion in highly structured (e.g., youth sports) orunstructured (e.g., playing with friends in theyard) physical activities. Exercise is a structuredphysical activity because it can be defined by anexercise prescription that considers type of exer-cise, intensity, duration, and frequency. There is aneed to define safe parameters to define the exer-cise prescription, as well as safe modes of muscleactivation, in both structured and unstructuredenvironments.

The problem of exercise training and contrac-tion-induced muscle injury remains the biggestclinical concern.35 Muscle pain, particularly afteractivity, is a prominent complaint in boys withDMD.35 Older studies in humans with DMDhave suggested that submaximal exercise may bebeneficial, especially early in the course of thedisease36–39 Knowledge of the natural history ofDMD helps us understand how and when physicalexercise might be beneficial. The weakness pro-gresses steadily, but the rate may be variable dur-ing the disease course. Quantitative strength test-ing showed greater than 40–50% loss of strengthby 6 years of age.40–42 With manual muscle test-ing, DMD subjects exhibit loss of strength in a lin-ear fashion from ages 5–13 years, and measure-ments obtained several years apart show steadydisease progression. Variability may be notedwhen individuals are analyzed over a shorter timecourse.43 Previous investigators have noted achange in the rate of strength loss at approxi-mately 14–15 years of age.43 This change did notappear to be associated with achievement of aparticular score on the manual muscle test(MMT) scale but rather consistently occurred invarious muscle groups in the early second decade.Thus, the investigators recommended that naturalhistory control trials that evaluate therapies inDMD should be cautious about including subjectstransitioning to the teenage years because of theflattening of the MMT strength curve withincreasing age.43 Quantitative strength measureshave been shown to be more sensitive for demon-strating strength loss than MMT when strength isgraded 4–5.41

Exercise prescriptions and recommendationsin DMD need to consider a multitude of issues.The muscle groups that perform the most eccen-

tric activity, including hip extensors, knee exten-sors, and ankle dorsiflexors in the lower extrem-ities, tend to undergo the greatest mechanicalloads.41 This has been proposed as the main rea-son lower extremity weakness predates loss ofstrength in the upper extremities. Edwards andcolleagues proposed that routine eccentric con-tractions during gait are a likely source ofthe pattern of weakness typically seen inmyopathies.44,45

Studies of strengthening interventions in DMDsubjects have shown maintenance of strength oreven mild improvement over the period of investi-gation. However, these studies are limited by useof primarily non-quantitative measures, lack of con-trol groups, and use of the opposite limb as a con-trol without considering the effects of cross-train-ing.36–39,46 What is clear and agreed upon by thisworking group is that boys with DMD are increas-ingly sedentary with age because of weakness andprogressive loss of muscle function, complicated bycardiorespiratory comorbidity and progressive jointcontractures and deformity. The primary musclepathology, contraction-induced injury, and second-ary disuse atrophy may all contribute to weakness,and increased fat mass may contribute to func-tional losses and difficulty moving in individualswho gain excessive amounts of weight as functiondeclines.

There were a number of broad study themessuggested to improve our understanding of therole of exercise as a potential therapeutic treat-ment for DMD (Table 2). These included: practi-cal studies (a physical activity survey; functionalendpoint measures); translational studies (howbest to apply exercise findings in animals to DMDpatients; development of new assays in animalmodels to reflect the physical limitations observedin patients); and basic studies (identify and defineboth the positive and negative physiological adap-tations in response to exercise). It was also sug-gested that physical activity guidelines could beestablished and expressed in metabolic equivalents(MET ¼ 3.5 ml oxygen/kg body mass/minute)similar to those described by the American Collegeof Sports Medicine (ACSM) for cardiac rehabilita-tion patients.47 METs can be used to describe theenergy cost of activities from dressing to walking tojogging.47 Knowledge of these energy costs, to-gether with assessment of other physical capabil-ities (e.g., muscle strength and flexibility), couldcontribute to development of appropriate treat-ment plans. Another outcome of our discussionwas preparation of a series of research questions(by no means exhaustive) that could address thekey overarching purpose of identification of theparameters of potentially beneficial vs. potentially


detrimental types and levels of activity and exercisefor individuals with DMD.

KEY UNANSWERED QUESTIONS

1. What is the appropriate amount and type ofphysical activity or exercise?

2. How long and how often should children bephysically active? (What type, intensity, and du-ration of exercise and/or activity?)

3. What are the contributions of fatigue, and howshould it be best defined and measured?

4. What is the role of muscle stretching? For exam-ple, will flexibility exercises assist/maintain flexi-bility and therefore increase ease of movementand decrease the resistance against which weakmuscles contract? Would maintenance of flexi-bility decrease intramuscular fibrosis? Will flexi-bility prevent contractures and improvebiomechanics for movement?

5. With appropriate exercise, can the progressionof muscle atrophy and weakness be mitigated?

Table 3 expands further upon these questions.

RECOMMENDATIONS FOR RESEARCH ACTION PLAN

The consensus from members of the roundtablewas that exercise may have beneficial or detrimen-tal effects for DMD patients; however, the balanceof these effects has not been determined rigor-ously in the literature. The parameters of poten-tially beneficial vs. detrimental activities/exercises,including type, intensity, frequency, and duration

have not yet been established for DMD. There is aneed for further detailed studies on the effects ofexercise, to identify safe and potentially beneficialtypes and amounts of activity and exercise as well asto identify potentially harmful types and amounts ofactivity and exercise. Toward this goal, a frameworkof standard operating procedures focused on themdx model has been developed.48–51 The goal wouldbe to define these potentially beneficial or detrimen-tal activities/exercises for type, intensity, frequency,and duration (i.e., an activity/exercise prescription).To determine these parameters, directed researchshould be undertaken with a distinct translationalemphasis. The establishment of a model(s) to studyexercise safely and effectively in DMD will be increas-ingly important. An appropriate model(s) will facili-tate the assessment of exercise interventions. In addi-tion to safety and efficacy, ideal models would alsopermit longitudinal assessment of the dynamic varia-bles related to exercise. These variables may changewith time as the disease progresses and as therapiesemerge that modify disease pathophysiology.

1. Future studies, both animal and human, needto use standardized, reliable, systematic methodsto assess muscle performance. This approachwill allow for cross-study comparison.

2. It is critical to quantitatively determine the exerciseloads that are beneficial and to determine thethresholds at which injury may occur. This couldbe done first in animals and then in humans.

3. Alternative exercise approaches, such as aquatic-based therapy, should be studied, particularly in

Table 2. Broad study themes.

Study theme Brief description and purpose

Physical activity survey Develop a brief (5 or 6 questions) survey to obtain information from parents, physicians, and physicaltherapists 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.

Exercise paradigms (animal tohuman)

Use established exercise paradigms in animal models to develop a conceptual framework onhow to proceed with therapeutic exercise in humans with DMD. In addition, explore and define newanimal exercise protocols to evaluate the threshold of possible benefit. Parameters should includeintensity, duration, and frequency.

Physiological adaptation Exercise is known to elicit multiple positive adaptations in many physiological systems and tissuesand is also known to have detrimental effects in fragile muscles and in disease states, butfurther 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 toeccentric exercise, can cause potentially negative adaptations or damage and should be avoided?

New assays Develop and validate new assays of physical function in DMD animal models that reflect the DMDphenotype observed in patients; for example, gait analysis, joint range of motion, and othermeasures to provide surrogate markers of clinical disability observed in DMD.

Functional endpoint measures Standardize methods for acquiring data that describe quality of life and functional outcomesspecific to the DMD patient population, for more readily comparable study results; for example,see refs. 54 and 55.

Energy costs of physicalactivities

Daily activity levels of DMD boys have only been partially studied49,50,42; use of the COSMED (mobilebreath-by-breath VO2) system to obtain metabolic measurements and the METs for variousactivities (e.g., dressing, walking, wheelchair movement).


boys with DMD who are non-ambulatory andhave less than antigravity muscle strength.

4. Functional activities and quality of life shouldbe included in study endpoints, as well quantita-tive strength testing.52

5. Granting agencies should target funding andrequest proposals to determine the role of ther-apeutic exercise in DMD. An initial request forproposals could target MET generation anddaily movement activity guidelines for DMDboys and their parents; parental involvementwith registries is critical.5,49,50

6. A cornerstone for exercise and DMD studiesshould be ‘‘translational research teams,’’ in-cluding clinicians and basic scientists.

7. Identify grant reviewers who have specific exper-tise in evaluating the potential therapeutic bene-fits of exercise in DMD.

8. Education and dissemination of research find-ings as they emerge must be prioritized.

FUTURE DIRECTIONS

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

in human subjects with DMD to address whetherlow-intensity physical training is beneficial in termsof preservation of muscle endurance and func-tional abilities. The study consists of two trainingintervention studies: dynamic leg and arm trainingfor ambulatory boys with DMD and functionaltraining with arm support for wheelchair-depend-ent boys with DMD. This study should help fillsome gaps in our knowledge of the effects of exer-cise training in boys with DMD and also providemore insight into the types of exercise that shouldbe recommended for these boys.

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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 contracturesin DMD patients?

Are there periods of disease progression, particularly related to the age of the DMD patient, when exercise ismore 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 monthsto years)?

What should the primary outcomes/endpoints be to assess the effects of exercise? For instance, if one primaryoutcome/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/confirmbenefits 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?

Physiological 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)?Translational 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?


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Exercise and duchenne muscular dystrophy: Where we have been and where we need to go