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Resistance Training with Vascular Occlusionin Inclusion Body Myositis: A Case Study BRUNO GUALANO1, MANOEL NEVES JR2, FERNANDA RODRIGUES LIMA2, ANA LU GILBERTO LAURENTINO1, CLAUDIA BORGES2, LUCIANA BAPTISTA3, GUILHERME GIANNINI ARTIOLI1,MARCELO SALDANHA AOKI4, ANSELMO MORISCOT4, ANTONIO HERBERT LANCHA JR1, ELOI´SA BONFA 1School of Physical Education and Sport, University of Sa˜o Paulo, Sa˜o Paulo, BRAZIL; 2Division of Rheumatology, Schoolof Medicine, University of Sa˜o Paulo, Sa˜o Paulo, BRAZIL; 3Hospital Nove de Julho, Sa˜o Paulo, BRAZIL; 4Institute of AQ1 Biomedical Sciences, University of Sa˜o Paulo, Sa˜o Paulo, BRAZIL; and 5School of Arts, Sciences, and Humanities, University of Sa˜o Paulo, Sa˜o Paulo, BRAZIL GUALANO, B., M. NEVES JR, F. R. LIMA, A. L. PINTO, G. LAURENTINO, C. BORGES, L. BAPTISTA, G. G. ARTIOLI, M. S.
AOKI, A. MORISCOT, A. H. LANCHA JR, E. BONFA ´ , and C. UGRINOWITSCH. Resistance Training with Vascular Occlusion in Inclusion Body Myositis: A Case Study. Med. Sci. Sports Exerc., Vol. 42, No. 2, pp. 00–00, 2010. Inclusion body myositis (IBM) is a rare idiopathic inflammatory myopathy that produces remarkable muscle weakness. Resistance training with vascular occlusion has been shown to improve muscle strength and cross-sectional area in other muscle wasting conditions. Purpose: We evaluated the efficacy of a moderate-intensity resistance training program combined with vascular occlusion by examining functional capacity, muscle morphology, and changes in the expression of genes related to muscle protein synthesis and proteolysis in a patient with IBM.
Methods: A 65-yr-old man with IBM resistant to all proposed treatments underwent resistance training with vascular occlusion for 12 wk. Leg press one-repetition maximum; thigh cross-sectional area; balance, mobility, and muscle function; quality of life; and blood markers of inflammation and muscle damage were assessed at baseline and after the 12-wk program. The messenger RNA (mRNA) expression levels of mechanogrowth factor, mammalian target of rapamycin, atrogin-1, and muscle RING finger-1 were also quantified.
Results: After the 12-wk training program, the patient’s leg press one-repetition maximum, balance and mobility function, and thigh cross-sectional area increased 15.9%, 60%, and 4.7%, respectively. All Short Form-36 Health Survey Questionnaire subscales demonstrated improvements as well, varying from 18% to 600%. mRNA expression of mechanogrowth factor increased 3.97-fold, whereas that of atrogin-1 decreased 0.62-fold. Muscle RING finger-1 and mammalian target of rapamycin mRNA levels were only slightly altered, 1.18- and 1.28-fold, respectively. Importantly, the exercise did not induce disease flare. Conclusions: We describe a novel, and likely the first, nonpharmacological therapeutic tool that might be able to counteract the muscle atrophy and the declining strength that usually occur in IBM. Key Words: EXERCISE TRAINING, STRENGTH, IDIOPATIC INFLAMMATORY Inclusion body myositis (IBM) is a rare idiopathic in- ease is a remarkable muscle atrophy leading to proximal flammatory myopathy occurring in approximately 14.9 and distal weakness (13). Information available to guide people per million, and it usually affects people at evidence-based IBM treatment is lacking largely because of middle age and beyond (12). The pathogenesis of this spo- the very low prevalence of this disease. Moreover, clinical radic acquired myopathy is still unknown, but some studies practice suggests that, unlike other inflammatory myopa- have revealed histologic evidence of inflammation in the thies, most patients are not responsive to treatment with affected skeletal muscle (12). The major feature of this dis- immunosuppressive or immunomodulatory drugs to coun-teract disease progression (4).
Until a few years ago, physicians have contraindicated Address for correspondence: Bruno Gualano, Ph.D., Mello de Moraes physical exercise to patients with inflammatory myopathies Avenue, 65 – Butanta˜, 5508-030, Sa˜o Paulo, SP, Brazil; E-mail: gualano@ because of the belief that it could increase inflammation
Submitted for publication April 2009.
in the affected muscles. This recommendation has changed after a few recent studies suggesting the safety of physicalexercise for this population (4). Therefore, low-intensity 0195-9131/10/4202-0000/0MEDICINE & SCIENCE IN SPORTS & EXERCISEÒ physical training has been encouraged for patients with Copyright Ó 2010 by the American College of Sports Medicine stable disease to help improve muscle function. However, low-intensity exercise does not seem effective in increasing Copyright @ 2010 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
muscle hypertrophy and strength. Exercise intensities and replaglidine indicated for hypertension, diabetes, and within 70%–85% of one-repetition maximum (1RM) or 6RM–12RM are required to achieve these goals (7). Be- In addition to the pharmacological treatment, the patient cause high-intensity exercises may enhance the inflamma- had been in a physical therapy program for 1 yr including tory response, the ideal type of exercise intervention for moderate-intensity strength exercises (i.e., 3 Â 15RM for IBM patients should increase muscle strength and cross- lower and upper limbs) before the vascular occlusion train- sectional area while minimizing exercise intensity.
ing started. Despite his adherence to the rehabilitation pro- In this regard, Takarada et al. (17) observed that re- gram, he reported a progressive decline on lower extremity stricting muscle blood flow using tourniquet cuffs during strength and an inability to walk without a cane. These ob- moderate-intensity resistance training produces greater ben- servations were further confirmed by his previous physical efits to muscle cross-sectional area than high-intensity train- therapist who reported decrements in thigh circumference ing. These findings have been demonstrated in athletes, the and lower limb strength (assessed by leg press 1 RM) of 7% frail elderly, and in patients undergoing rehabilitation after and 5%, respectively. Moderate-intensity resistance training surgery (18). The clinical application of this intervention with vascular occlusion program was then initiated because may be of particular interest to IBM patients because con- of the patient’s unresponsiveness to conventional training.
ventional resistance training seems ineffective in counter- The exercise program was performed twice a week, and it consisted of 3 Â 15RM (30 s between sets) leg press, knee The current case study describes the efficacy of a 12-wk extension, and squat exercises performed with vascular oc- moderate-intensity resistance training program combined clusion at 50% of total occlusion pressure.
with vascular occlusion in a patient with IBM. The goal was We assessed 1RM leg press strength (3); thigh cross- to determine whether this method of training could improve sectional area (by computed tomography scan); balance, the functional capacity, alter the muscle morphology, and mobility, and muscle function (i.e., timed up-and-go [15] change the expression of genes related to muscle protein and timed-stands test [14]); quality of life (i.e., Short Form- 36 (SF-36) Health Survey Questionnaire and Health As-sessment Questionnaire); and blood markers of inflam-mation (i.e., erythrocytes sedimentation rate (ESR) andC-reactive protein) before the start of the study and after the 12-wk program. Enzymes related to muscle damage (i.e., A 65-yr-old man (weight = 85 kg, height = 180 cm, CK, lactate dehydrogenase (LDH), and aldolase) were ˙ O2peak = 10 mLIkgj1Iminj1 Eassessed by V˙O2max ramp measured on a weekly basis 24 h after the last training ses- test on cycloergometer]) presented 8 yr of symmetric sion. Moreover, muscle samples from before and after the proximal (i.e., quadriceps) and distal (i.e., finger flexor) 12-wk trial were taken from the vastus lateralis of the muscle weakness with insidious onset and slow progres- subject’s right leg using the percutaneous biopsy technique.
sion. Muscle atrophy was noted in the upper and lower Approximately 60 g of sample was obtained, but only ap- limbs, especially in the quadriceps. Recurrent episodes of proximately 20 g corresponded to muscle tissue, which only falls were reported without symptoms of myalgia or mus- allowed for mRNA study. All biopsies were performed after cle tenderness. Muscle enzymes were never elevated, cre- a 10-h overnight fast, and the last meal was a standardized atine kinase (CK) ranged from 167 to 267 UILj1 (reference dinner. It is worth mentioning that the postintervention bi- range = 39–308 UILj1), and aldolase ranged from 4.3 to opsy was executed approximately 24 h after the last train- 6.6 UILj1 (reference range G 7.6 UILj1). Electroneuro- ing session to allow for identifying changes in mRNA myography revealed a myopathic pattern with irritability at expression baseline values (9,19). The mRNA expression rest (fibrillation potentials, complex repetitive discharges, levels of mechanogrowth factor (MGF), mammalian tar- positive sharp waves) and short-duration, low-amplitude, get of rapamycin (mTOR), atrogin-1, and muscle RING and polyphasic potentials on contraction. The diagnosis of finger-1 (MuRF-1) were quantified using real-time poly- IBM was then confirmed by the presence of intracellular merase chain reaction following standard procedures de- lined (rimmed) vacuoles and endomysial inflammatory in- scribed elsewhere (1). After the 12-wk trial, the patient had filtrate with invasion of nonnecrotic fibers in a muscle bi- voluntarily refrained from any physical activity for 10 wk, opsy. Toxic causes of myopathies associated with vacuoles so we assessed the effects of short-term detraining on 1RM were excluded (alcohol, chloroquine, colchicine, glycyrrhi- leg press strength, balance, mobility, and muscle function.
Of note, the patient underwent three familiarization sessions He was treated for 4 yr with prednisone (up to 60 mgIdj1) before the actual baseline physical tests (i.e., 1RM leg press, and methotrexate (up to 20 mgIwkj1) without a significant timed up-and-go, and timed-stands tests), separated by at clinical response. After a minor clinical stabilization, meth- least 96 h. The investigators were blinded to the biochem- otrexate was discontinued, and prednisone was lowered to 2.5 mgIdj1. The patient was also using acetylsalicylic To determine the blood pressure (mm Hg) of vascular acid, enalapril, glimepiride, insulin, metformin, pioglitazone, occlusion, a vascular Doppler (DV-600; Marted, Sa˜o Paulo, Official Journal of the American College of Sports Medicine Copyright @ 2010 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
Brazil) probe was placed over the tibial artery of the ercise program. A significant increase (3.97-fold) in MGF patient’s dominant leg. The subject was kept in a supine mRNA expression was observed, although atrogin-1 position while a customized blood pressure cuff (180 mm  mRNA expression was reduced (0.62-fold). In contrast, 80 mm) was fixed on his right thigh and inflated until it MuRF-1 and mTOR mRNA levels were only slightly al- interrupted the auscultatory pulse of the tibial artery (8).
tered, 1.18- and 1.28-fold, respectively.
The training pressure was established as 50% of the vas-cular occlusion pressure (È65 mm Hg).
Thereafter, after a brief warm-up on a treadmill, the patient performed three exercises per session, including theunilateral leg extension, the leg press, and the half-squat.
This case study suggests that 12 wk of moderate-intensity Two pressure cuffs were positioned near the inguinal fold resistance training combined with vascular occlusion may region on both thighs and inflated to the training pressure.
increase muscle strength, thigh cross-sectional area, bal- The patient performed three sets of 15 repetitions, with 30 s ance, mobility, and quality of life for IBM patients. MGF of rest between sets. The cuff’s pressure was maintained up-regulation and atrogin-1 down-regulation could explain during the whole session, including intervals. Light stretch- the improvements in muscle morphology and function be- ing exercises were performed after the resistance exercises.
cause such a response may ultimately lead to increases in Training intensity was adjusted according to the gradual increase in strength so the patient would be able to perform Some anecdotal effects have been attributed to vascular no more than 15RM. All sessions were monitored by at occlusion training such as thrombosis and damage to blood least two investigators. This trial was approved by the lo- vessels (17), but to the best of our knowledge, there are no cal ethical committee (University of Sa˜o Paulo, School of reports of vascular complications in the literature. In Medicine, General Hospital), and informed written consent addition, Wernbom et al. (18) reviewed 13 studies on occlusion training, with 2–16 wk of follow-up for a total of After the trial, the patient showed improvement in leg 116 subjects trained. Except for acute muscle pain, no press 1RM values (15.9%). In addition, balance and mo- adverse effects were reported. Recently, Nakajima et al. (11) bility function, as assessed by the timed up-and-go test, was published a survey on the safety of this training mode on enhanced (60%), and the thigh cross-sectional area was the basis of reports from 105 fitness and rehabilitation cen- increased (4.7%). These data are presented in Table 1. All ters in Japan. The most common adverse effects reported the SF-36 subscales indicated the patient’s progress. The by the 12,600 participants were subcutaneous hemorrhage specific changes were 150% for physical functioning, (incidence = 13.1%) and temporary numbness (incidence = 7400% for role–physical, 57% for bodily pain, 18% for 1.3%). More serious adverse effects were rare: venous general health, 267% for vitality, 600% for social function- thrombosis (0.055%), deterioration of ischemic heart dis- ing, 200% for role–emotional, and 43% for the mental ease (0.016%), cerebral infarction (0.008%), rhabdomyolysis health scales. However, Health Assessment Questionnaire (0.008%), and pulmonary embolism (0.008%). Supporting scores were not altered. There was no change in the timed- this record of safety, none of these complications was stands test after the training period. In addition, after 10 wk observed in the patient studied herein. Long-term trials with of detraining, there was no difference in the 1RM leg press larger numbers of IBM patients are necessary to validate the (j0.5%) and only a minor impairment in balance and mo- bility function (j20%). The coefficients of variation for IBM is resistant to all proposed treatments, and as a con- thigh cross-sectional area, 1RM leg press, timed-stands test, sequence, the aggravation of the muscle atrophy seems to timed up-and-go test, ESR, C-reactive protein, CK, LDH, progressively decrease the functional capacity (4). In this and aldolase were 2%, 2%, 0%, 0.9%, 1.3%, 2%, 2.2%, context, it has been suggested that physical exercise could result in functional benefits to IBM patients, leading to im- Serum CK, LDH, aldolase, ESR, and C-reactive protein provements in their quality of life (16). However, the out- remained within normal levels (CK = 267 UILj1 and comes of a few previous reports involving exercise training aldolase = 5.1 UILj1). There was no report of excessive have been somewhat disappointing. Spector et al. (16) exhaustion, pain, osteoarticular injury, or muscle soreness.
examined the efficacy of a strength training program in five Arterial blood pressure was also stable throughout the ex- patients with IBM. The program consisted of three sets of10–20 repetitions for lower and upper limb muscles, threetimes a week for 12 wk. An increase in strength was ob-served in five of the eight exercises tested. However, the TABLE 1. Effects of 12-wk resistance training with vascular occlusion on thigh cross- most marked benefits were seen in the least weakened sectional area, 1RM leg press, and timed up-and-go test in a patient with IBM.
muscles. Furthermore, there was no change in muscle size, as estimated by repeated magnetic resonance imaging.
Another important study determined the efficacy of a home-based exercise program in seven patients with IBM Medicine & Science in Sports & Exercise Copyright @ 2010 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
(2). The results indicated no significant alterations in fatigue trophy. Furthermore, the 40% decrease in atrogin-1 gene and isometric peak power. These two studies suggest a expression suggests a decline in muscle proteolysis, a de- limited response to exercise in these patients.
sirable effect in IBM patients because they have marked Alternatively, this lack of relevant benefits may be re- muscle atrophy. Atrogin-1 and MuRF-1 genes encode E3 lated to the low intensity of the resistance training. In fact, ligases, which are involved in protein breakdown mediated loads between 6RM and 12RM (70%–85% of the 1RM) through the ubiquitin–proteasome system. In fact, these seem to be more efficient for muscle hypertrophy (7). In the genes are reliable markers of muscle atrophy through acti- clinical setting, however, it is often difficult and sometimes vation of the ubiquitin–proteasome system (6). It is im- contraindicated to use such high loads (18). Hence, inter- portant to note that the 18% increase in MuRF-1 did not ventions focused on muscle hypertrophy without the use of follow the same pattern as Atrogin-1 because these proteins heavy loads should be of special interest in some chronic are part of the same ubiquitin–proteasome system. Like- diseases where these loads are not recommended. Our wise, expression of mTOR, a protein downstream of MGF, moderate-intensity training program seems to be a valuable was enhanced slightly after the intervention, although a more therapeutic option to improve strength, muscle hypertrophy, dramatic increase was observed for MGF. Further work and most importantly, muscle function. For instance, should investigate the mechanism for these differences.
Mackey et al. (10) reported a 3.7% increase in the cross- Although our case study does not allow comparing sectional area of the quadriceps after 12 wk of high- physiological and functional improvements between resis- intensity resistance training in a healthy elderly group. Our tance training with vascular occlusion and conventional re- patient increased the cross-sectional area of his thigh by sistance training, our findings are very promising. To the 4.7%, which is similar to the response of a healthy elderly best of our knowledge, this is the first report of positive person. Moreover, he was able to walk on the treadmill at changes in quality of life and muscle cross-sectional area in 5 kmIhj1, without a cane, and his falling episodes were an IBM patient after a nonpharmacological treatment. As greatly reduced after this training. Finally, the improve- described previously, other studies that used conventional ments in the SF-36 subscales should also be emphasized training protocols did not report such extensive improve- because IBM patients usually have a poor quality of life ments (16). In addition, the fact that our patient had been (1,14). Overall, such aforementioned benefits are of great previously engaged in a conventional resistance training clinical relevance because there is no established therapy to program (the numbers of sets, repetitions, and lower limb stop disease progression. It could be argued that the ob- exercises were the same as those in the current trial) and served benefits were due to a synergistic effect between our reported decrements in muscle strength supports the role of training program and the increased daily physical activity our intervention. However, caution should be exercised in- levels because the subject was able to walk without a cane terpreting our findings because case studies do not allow by the end of the training program. However, it is important drawing causal conclusion and generalization of the results.
to emphasize that his participation in previous strength In conclusion, our case study describes a novel, and training programs improved neither muscle performance likely the first, nonpharmacological therapeutic tool able to nor spontaneous physical activity levels (i.e., functionality).
counteract the muscle atrophy and decline of strength that Thus, the likelihood that our vascular occlusion training usually occurs in patients with IBM under conventional program produced most of the described improvements is treatment. Interestingly, we show that short-term moderate- very high. It is also interesting to note that even after a intensity resistance training with vascular occlusion using 10-wk detraining period, the patient completely retained the pressure cuffs leads to improvements in muscle function strength benefits and partially retained the mobility and and quality of life, without inducing disease flare. Increased balance benefits of the training program. To the best of our expression of MGF and down-regulation of atrogin-1 may knowledge, this is the first report of an IBM patient main- contribute to the underlying cellular changes that mediate taining the training adaptations after a period of physical muscular improvement. These promising findings deserve additional controlled studies with larger samples.
To shed some light in the molecular mechanisms behind the observed adaptations, we assessed the expression of afew genes related to muscle protein synthesis and degrada-tion. A very encouraging piece of evidence was the marked Bruno Gualano and Manoel Neves Jr contributed equally to this increase in MGF gene expression after training. Although mRNA gene expression is an indirect marker of the muscle Bruno Gualano was supported by the Conselho Nacional de anabolic/catabolic state, previous studies have shown that Desenvolvimento Cientı´fico e Tecnolo´gico. Eloı´sa Bonfa´ wassupported by grant 305468/2006-5 from the Conselho Nacional de mechanical overload does promote large increases in MGF Desenvolvimento Cientı´fico e Tecnolo´gico and Federico Wilhelm gene expression, which has been associated with muscle Agricola Foundation Research grant. Marcelo Saldanha Aoki was hypertrophy (1,5). Therefore, it is reasonable to speculate supported by grant 06/52204-5 from Funda0a˜o de Amparo aPesquisa de Sa˜o Paulo. The authors have no conflicts of interest.
that the fourfold increase in MGF mRNA expression stim- The results of the present study do not constitute endorsement by ulated muscle protein synthesis, leading to muscle hyper- American College of Sports Medicine.
Official Journal of the American College of Sports Medicine Copyright @ 2010 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
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AQ1 0 Please check if the fifth affiliation should be included for no author seems affiliated AQ3 0 As per journal instructions, genes should be italicized whereas proteins are roman.
Those explicitly described in the article were italicized. Please check and makemodifications as necessary.
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British Columbia Reproductive Care Program Newborn Guideline 11 EYE CARE AND PREVENTION OF OPHTHALMIA NEONATORUM INTRODUCTION Ophthalmia neonatorum presents as an inflammation of the conjunctiva in an infant younger than 30 days of age.1 Most ophthalmia infections in the neonatal period are acquired during vaginal delivery and reflect the sexually transmitted diseases

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