Endurance training - Neurology

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Jan 2, 2007 - Abstract—We studied the effect of aerobic training on conditioning in patients with limb-girdle muscular dystrophy type. 2I (LGMD2I).
Endurance training An effective and safe treatment for patients with LGMD2I M.-L. Sveen, MD; T.D. Jeppesen, MD; S. Hauerslev, BSc; T.O. Krag, PhD; and J. Vissing, MD, PhD

Abstract—We studied the effect of aerobic training on conditioning in patients with limb-girdle muscular dystrophy type 2I (LGMD2I). Nine patients with LGMD2I cycled fifty 30-minute sessions at 65% of their maximal oxygen uptake over 12 weeks. Training significantly improved work capacity, paralleled by self-reported improvements. Creatine kinase levels did not increase significantly, and muscle morphology was unaffected. Moderate-intensity endurance training is a safe method to increase exercise performance and daily function in patients with LGMD2I. NEUROLOGY 2007;68:59–61

Limb-girdle muscular dystrophy type 2I (LGMD2I) is a recessively inherited muscle disease that constitutes 38% of patients with LGMD2 in Denmark.1 LGMD2I is caused by mutations in the fukutinrelated protein gene. Fukutin-related protein is a cytosolic protein that glycosylates ␣-dystroglycan.2 ␣-Dystroglycan and integrin ␣7␤1D are the two main laminin receptors in skeletal muscle3 and are believed to play a major role for the integrity of the sarcolemma. Patients with LGMD2I lead a sedentary lifestyle and are often advised to avoid physical exertion. Aerobic exercise is safe and beneficial in a number of muscle diseases.4 The effect of endurance training on disorders like LGMD2I with defects of the dystrophin-associated glycoprotein complex, which may be mechanically sensitive, has not been studied. Because of the importance of ␣-dystroglycan in linking the sarcolemma to the extracellular matrix, exercise could be deleterious in patients with LGMD2I. In this study, we studied the effect of 12-week aerobic exercise training on work performance, selfassessed well-being, and muscle regeneration and degeneration in nine patients with LGMD2I. Methods. Subjects. We studied three women and six men with LGMD2I (age 48 ⫾ 5 years, weight 81 ⫾ 4 kg, height 180 ⫾ 3 cm) homozygous for the 826C⬎A mutation. Nine healthy, sedentary, matched subjects (age 43 ⫾ 4 years, weight 80 ⫾ 6 kg, height 174 ⫾ 4 cm), completed the same training program. Half of the patients participated in low-impact physiotherapy sessions once a

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week before inclusion but conducted no other form of exercise. All patients with LGMD2I were ambulant, with onset of symptoms at age 20 ⫾ 4 years. One patient had macroglossia, and seven had calf hypertrophy. Three patients had asymptomatic dilated cardiomyopathy (ejection fraction [EF]; 30% to 40%). Two patients had marginally decreased EF (45% and 55%) without dilatation. Vital capacity was 3.9 ⫾ 0.3 L. Four patients had experienced repeated episodes of exertional myoglobinuria. Muscle dynamometry1 showed that hip flexion strength was decreased by 82%, adduction was decreased by 72%, and abduction was decreased by 36% (p ⬍ 0.05 vs healthy). Static strength measures were not repeated after training because dynamic, aerobic variables are the most relevant efficacy measures to test after endurance training. Patients with LGMD2I, homozygous for the 826C⬎A mutation, represent a mild LGMD2 phenotype. Thirty such patients followed up in our clinic showed no significant deterioration of manual muscle strength at half-yearly visits. For this reason, untreated control patients were not studied. Training program. Subjects trained at home on a stationary cycle ergometer for 12 weeks at a heart rate corresponding to 65% of their maximal oxygen uptake (VO2max). A total of fifty 30minute training sessions were completed. Weekly sessions increased progressively during the first 4 weeks, reaching five sessions the final 8 weeks. Establishing training intensity, monitoring compliance, performance of cycle tests, and processing of muscle biopsies are described in the methods in appendix E-1 on the Neurology Web site at www.neurology.org. Muscle histology is illustrated in figure E-1. As a marker of exercise-induced muscle damage, plasma creatine kinase (CK) was measured before and after the 12-week training period, 24 to 48 hours after the final training session.5 Plasma lactate and heart rate were used to validate the degree of exhaustion during cycle tests before and after training.6 Self-reported changes in activities of daily living. After the 12-week training program, patients completed a modified questionnaire, grading changes in physical endurance, leg muscle strength, and walking distance. Statistics. Values are mean ⫾ standard error. P ⬍ 0.05 (twotailed testing) was considered significant. Within-group changes with training were assessed by a paired Student t test. Differences between groups were assessed by an unpaired Student t test. The significance of self-reported changes was assessed by a Mann– Whitney test.

From the Neuromuscular Research Unit, Department of Neurology and the Copenhagen Muscle Research Center, National University Hospital, Rigshospitalet, Copenhagen, Denmark. This project was supported by grants from the Danish Medical Research Council (nos. 22-00-1056 and 22-03-0474), the Novo Nordisk Foundation, the University of Copenhagen, the Copenhagen Hospital Corporation (H:S). Disclosure: The authors report no conflicts of interest. Received May 1, 2006. Accepted in final form September 20, 2006. Address correspondence and reprint requests to Dr. Marie-Louise Sveen, Department of Neurology 2082, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; e-mail: [email protected] Copyright © 2007 by AAN Enterprises, Inc.

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Figure 1. Maximal oxygen uptake (VO2max; A) and workload (Wmax ; B), before and after 12 weeks of training in nine patients homozygous for the 826C⬎A mutation and in nine healthy subjects matched for age, weight, and height. Black columns represent patients, and white columns represent healthy controls. * p ⬍ 0.0005. † p ⬍ 0.005. Results. Polar pulse watch recordings and patient diaries revealed 100% compliance with the 12-week training program. VO2, workload, heart rate, and plasma lactate levels. Training improved VO2max and maximal workload (p ⬍ 0.0005) in patients with LGMD2I and healthy subjects (figure 1, A and B). The percentage and absolute increases in VO2max and workload did not differ between the two groups. Plasma lactate levels and heart rate at rest and at VO2max did not differ significantly before and after training (table). Creatine kinase levels and questionnaires. Plasma CK levels tended to increase after training in patients (p ⫽ 0.07) and increased in healthy controls (p ⬍ 0.02; table). Self-reported questionnaires showed that a majority of subjects with LGMD2I felt an improvement in physical endurance, leg muscle strength, and walking distance (figure 2). No worsening of their condition or adverse events were reported. Muscle histology. Mean muscle fiber area tended to increase (p ⫽ 0.09 for type II fibers) with training in patients with LGMD2I (table). Fiber type distribution did not change with exercise. Capillary density increased significantly with training in patients (p ⫽ 0.05). As fiber size tended to increase, the number of capillaries per fiber also increased. These changes were not observed in healthy controls, but their absolute capillary density was higher. Training did not change the number of central nucleated, necrotic, or apoptotic fibers; regeneration in new and old fibers; satellite cell activation; or the level of ␣-dystroglycan in the sarcolemma.

Discussion. We found that 12 weeks of lowintensity aerobic training is an effective and safe method to increase fitness in patients with LGMD2I. Training increased the patient’s VO2max and workload capacity in watts by 21% and 27%, corresponding to the normal physiologic response to training in the healthy subjects. These improvements were measured at identical levels of physical exertion during max tests before and after training, as depicted by similar peak plasma lactate and heart rate levels. Increased work capacity was paralleled by selfreported improvements in endurance, leg muscle strength, and walking distance. No muscle damage was inflicted as reflected by no significant increases 60

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Figure 2. Training-induced changes in walking distance, muscle strength, endurance, levels of physical activity, and fatigue in the nine patients with limb-girdle muscular dystrophy type 2I homozygous for the 826C⬎A mutation. The numbers in the black and white bars represent the number of persons reporting improvement (black bars) or no change (white bars) with training. No person reported worsening of any of these items.

in CK levels and number of necrotic, apoptotic, or regenerative fibers during training. This suggests that endurance training may have long-term beneficial effects in this patient group, but studies of long duration are warranted. Previous training studies have included no more than two patients with LGMD with unknown molecular diagnoses, and results were pooled with a heterogeneous group of patients with other neuromuscular conditions.4,7 CK levels and muscle histology responses to training were not assessed, but overall, these studies suggested a beneficial effect of low- to moderate-intensity resistance and aerobic training in slowly progressive myopathies.4,7,8 Capillary density increased by 18% with training in patients. Capillary density before training was 55% lower in patients with LGMD2I vs healthy subjects. This phenomenon is commonly seen in various muscular dystrophies.9 The lower capillary density in patients was associated with an approximately 43% higher fiber type area, vs healthy muscle. The initial low capillary density in patients, caused by the disease process or severe deconditioning, may be the reason why increases in capillary density were only observed in patients. Creatine kinase levels are dependent on muscle mass and physical activity. The small increase in CK levels in healthy subjects is likely a reflection of the increased physical activity, and not training-related muscle damage. A similar mechanism probably operated in the few patients in whom there was a small CK increase with training. There is an increased incidence of cardiomyopathy in persons with LGMD2I, as was also the case in our patients.1 Endurance training is generally advised for patients with cardiomyopathy.10 These recommendations can probably be extended to our patients with LGMD2I and cardiomyopathy, because they improved their oxidative capacity comparable to the other subjects.

Table Pretraining and post-training histologic findings in skeletal muscles of five persons with 826C⬎A/826C⬎A mutations (left) and five healthy subjects (right) Patients with LGMD2I n

Before training

Healthy subjects

After training

n

Before training

After training

Fiber type I, %

5

62 ⫾ 13

62 ⫾ 9

5

55 ⫾ 4

58 ⫾ 9

Fiber type II, %

5

38 ⫾ 13

38 ⫾ 9

5

44 ⫾ 4

42 ⫾ 9

Fiber size type I, ␮m2

5

8,388 ⫾ 788

8,838 ⫾ 843

5

4,647 ⫾ 175

5,278 ⫾ 190

Fiber size type II, mm2

5

7,604 ⫾ 735

8,982 ⫾ 1,204‡

5

4,375 ⫾ 487

4,470 ⫾ 200

Capillaries per mm

2

Central nuclei, %

5

209 ⫾ 19

255 ⫾ 30*

5

427 ⫾ 31

412 ⫾ 18

5

23 ⫾ 7

25 ⫾ 10

5

ND

ND

12 ⫾ 7

Necrotic cells

5

Apoptotic cells

5

nMHC (⫹)/utrophin (⫺)

5

3.4 ⫾ 3

nMHC (⫹)/utrophin (⫹)

5

1.8 ⫾ 0.7

1 ⫾ 0.6

6⫾3

5

ND

ND

0⫾0

5

ND

ND

6.4 ⫾ 4.1

5

ND

ND

0⫾0

5

ND

ND

Creatine kinase

9

661 ⫾ 154

1,068 ⫾ 298†

5

40 ⫾ 4

97 ⫾ 17*

Lactaterest

9

1.2 ⫾ 0.1

1.47 ⫾ 0.3

9

1.1 ⫾ 0.1

1.6 ⫾ 0.5

Lactatemax

9

7.0 ⫾ 0.9

7.1 ⫾ 0.7

9

8.2 ⫾ 0.7

10 ⫾ 1

Heart raterest

9

87 ⫾ 3

81 ⫾ 6

9

76 ⫾ 5

77 ⫾ 5

Heart ratemax

9

168 ⫾ 3

166 ⫾ 7

9

179 ⫾ 3

174 ⫾ 5

Plasma creatine kinase, plasma lactate levels, and heart rate at rest and at maximal exertion were measured before and after the 12week training program. * p⫽ 0.05. † p ⫽ 0.08. ‡ p ⫽ 0.09. LGMD2I ⫽ limb-girdle muscular dystrophy type 2I; ND ⫽ not determined; nMHC (⫹) ⫽ positive staining for neonatal myosin heavy chain; utrophin (⫹)/(⫺) ⫽ positive/negative staining for utrophin.

Acknowledgment The authors thank Danuta Goralska-Olsen and Eva Rahtkens for technical assistance.

References 1. Sveen ML, Schwartz M, Vissing J. High prevalence and phenotypegenotype correlations of limb girdle muscular dystrophy type 2I in Denmark. Ann Neurol 2006;59:808–815. 2. Muntoni F. Journey into muscular dystrophies caused by abnormal glycosylation. Acta Myol 2004;23:79–84. 3. Henry MD, Satz JS, Brakebusch C, et al. Distinct roles for dystroglycan, b1 integrin and perlecan in cell surface laminin organization. J Cell Biol 2001;114:1137–1144. 4. van der Kooi EL, Lindeman E, Riphagen I. Strength training and aerobic exercise training for muscle disease. Cochrane Database Syst Rev 2005;1:CD003907.

5. Clarkson PM, Kearns AK, Rouzier P, Rubin R, Thompson PD. Serum creatine kinase levels and renal function measures in exertional muscle damage. Med Sci Sports Exerc 2006;38:623–627. ˚ stand P-O, Rodahl K. Textbook of work physiology: Physiological 6. A bases of exercise. 3rd ed. New York: McGraw-Hill, 1986:1–756. 7. Ansved T. Muscular dystrophies: influence of physical conditioning on the disease evolution. Curr Opin Clin Nutr Metab Care 2003;6:435–439. 8. Olsen DB, Orngreen MC, Vissing J. Aerobic training improves exercise performance in facioscapulohumeral muscular dystrophy. Neurology 2005;64:1064–1066. 9. Olsen DB, Langkilde AR, Ørngreen MC, Rostrup E, Schwartz M, Vissing J. Muscle structural changes in mitochondrial myopathy relate to genotype. J Neurol 2003;250:1328–1334. 10. Stolen KQ, Kemppainen J, Ukkonen H, et al. Exercise training improves biventricular oxidative metabolism and left ventricular efficiency in patients with dilated cardiomyopathy. J Am Coll Cardiol 2003;41:460–467.

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