OBJECTIVE

Skeletal muscle weakness is a prominent clinical feature in patients with rheumatoid arthritis (RA), but the underlying mechanism(s) is unknown. Here we investigate the mechanisms behind arthritis-induced skeletal muscle weakness with special focus on the role of nitrosative stress on intracellular Ca(2+) handling and specific force production.

METHODS

Nitric oxide synthase (NOS) expression, degree of nitrosative stress and composition of the major intracellular Ca(2+) release channel (ryanodine receptor 1, RyR1) complex were measured in muscle. Changes in cytosolic free Ca(2+) concentration ([Ca(2+)]i) and force production were assessed in single-muscle fibres and isolated myofibrils using atomic force cantilevers.

RESULTS

The total neuronal NOS (nNOS) levels were increased in muscles both from collagen-induced arthritis (CIA) mice and patients with RA. The nNOS associated with RyR1 was increased and accompanied by increased [Ca(2+)]i during contractions of muscles from CIA mice. A marker of peroxynitrite-derived nitrosative stress (3-nitrotyrosine, 3-NT) was increased on the RyR1 complex and on actin of muscles from CIA mice. Despite increased [Ca(2+)]i, individual CIA muscle fibres were weaker than in healthy controls, that is, force per cross-sectional area was decreased. Furthermore, force and kinetics were impaired in CIA myofibrils, hence actin and myosin showed decreased ability to interact, which could be a result of increased 3-NT content on actin.

CONCLUSIONS

Arthritis-induced muscle weakness is linked to nitrosative modifications of the RyR1 protein complex and actin, which are driven by increased nNOS associated with RyR1 and progressively increasing Ca(2+) activation.

OBJECTIVE

Progressive muscle weakness is a common feature in patients with rheumatoid arthritis (RA). However, little is known about whether the intrinsic contractile properties of muscle fibers are affected in RA. This study was undertaken to investigate muscle contractility and the myoplasmic free Ca2+ concentration ([Ca2+](i)) in the soleus, a major postural muscle, in mice with collagen-induced arthritis (CIA).

METHODS

Muscle contractility and [Ca2+](i) were assessed in whole muscle and intact single-fiber preparations, respectively. The underlying mechanisms of contractile dysfunction were assessed by investigating redox modifications using Western blotting and antibodies against nitric oxide synthase (NOS), superoxide dismutase (SOD), 3-nitrotyrosine (3-NT), carbonyl, malondialdehyde (MDA), and S-nitrosocysteine (SNO-Cys).

RESULTS

The tetanic force per cross-sectional area was markedly decreased in the soleus muscle of mice with CIA, and the change was not due to a decrease in the amplitude of [Ca2+](i) transients. The reduction in force production was accompanied by slowing of the twitch contraction and relaxation and a decrease in the maximum shortening velocity. Immunoblot analyses showed a marked increase in neuronal NOS expression but not in inducible or endothelial NOS expression, which, together with the observed decrease in SOD2 expression, favors peroxynitrite formation. These changes were accompanied by increased 3-NT, carbonyl, and MDA adducts content in myofibrillar proteins from the muscles of mice with CIA. Moreover, there was a significant increase in SNO-Cys content in myosin heavy-chain and troponin I myofibrillar proteins from the soleus muscle of mice with CIA.

CONCLUSIONS

These findings show impaired contractile function in the soleus muscle of mice with CIA and suggest that this abnormality is due to peroxynitrite-induced modifications in myofibrillar proteins.

BACKGROUND

This randomized, controlled study on patients with polymyositis or dermatomyositis was based on three hypotheses: patients display impaired endurance due to reduced aerobic capacity and muscle weakness, endurance training improves their exercise performance by increasing the aerobic capacity, and endurance training has general beneficial effects on their health status.

METHODS

In the first part of this study, we compared 23 patients with polymyositis or dermatomyositis with 12 age- and gender-matched healthy controls. A subgroup of patients were randomized to perform a 12-week endurance training program (exercise group, n = 9) or to a non-exercising control group (n = 6). We measured maximal oxygen uptake (VO2 max) and the associated power output during a progressive cycling test. Endurance was assessed as the cycling time to exhaustion at 65% of VO2 max. Lactate levels in the vastus lateralis muscle were measured with microdialysis. Mitochondrial function was assessed by measuring citrate synthase (CS) and β-hydroxyacyl-CoA dehydrogenase (β-HAD) activities in muscle biopsies. Clinical improvement was assessed according to the International Myositis Assessment and Clinical Studies Group (IMACS) improvement criteria. All assessors were blinded to the type of intervention (that is, training or control).

RESULTS

Exercise performance and aerobic capacity were lower in patients than in healthy controls, whereas lactate levels at exhaustion were similar. Patients in the exercise group increased their cycling time, aerobic capacity and CS and β-HAD activities, whereas lactate levels at exhaustion decreased. Six of nine patients in the exercise group met the IMACS improvement criteria. Patients in the control group did not show any consistent changes during the 12-week study.

CONCLUSIONS

Polymyositis and dermatomyositis patients have impaired endurance, which could be improved by 12 weeks of endurance training. The clinical improvement corresponds to increases in aerobic capacity and muscle mitochondrial enzyme activities. The results emphasize the importance of endurance exercise in addition to immunosuppressive treatment of patients with polymyositis or dermatomyositis.

BACKGROUND

ClinicalTrials.gov: NCT01184625.

OBJECTIVE

To evaluate the outcome of resistive home exercise and its possible longterm influence on health, disability, and disease activity in patients with active polymyositis (PM) or dermatomyositis (DM).

METHODS

Nineteen patients with recent-onset PM/DM were included after introduction of high-dose prednisolone. They were assessed by independent assessors as to perceived health, muscle performance, aerobic capacity, and serum creatine phosphokinase (CPK) at baseline and after 24 weeks, including repeated muscle biopsies at 24 weeks (single-blinded randomized controlled study), and in an open-label followup at 52, 78, and 104 weeks. Patients were randomized to 12 weeks, 5 days/week resistive home exercise with telephone support and encouragement for another 12 weeks of twice-a-week home or gym exercise (EG, n = 10) or to 24 weeks, 5 days/week range of motion exercise (CG, n = 9). Patients in the CG group without inflammatory infiltrates in muscle biopsies at 24 weeks were invited to the 12-week resistive home exercises.

RESULTS

At baseline, the EG had poorer perceived health, but otherwise the groups were comparable. At 24 weeks, both groups improved in muscle performance and aerobic capacity (p < 0.001 to < 0.05) with no signs of increased inflammation assessed by CPK levels or muscle biopsies. Both groups improved in muscle performance and aerobic capacity up to 52 weeks (p < 0.05) lasting to 104 weeks in the EG (p < 0.05) and presented minor improvements in perceived health.

CONCLUSIONS

Our study supports the safety of resistive exercise in patients with active PM/DM but did not reveal any between-group differences in exercise effects. An individually adapted physical therapist-supervised home exercise program might be recommended in early active PM/DM, with regular evaluation of muscle performance and health.

OBJECTIVE

To determine the effects of a 12-week endurance exercise program on health, disability, VO2 max, and disease activity in a multicenter randomized controlled trial in patients with established polymyositis (PM) and dermatomyositis (DM), and to evaluate health and disability in a 1-year open extension study.

METHODS

Patients were randomized into a 12-week endurance exercise program group (EG; n = 11) or a control group (CG; n = 10). Assessments of health (Short Form 36 [SF-36]), muscle performance (5 voluntary repetition maximum [5 VRM]), activities of daily living (ADL), patient preference (McMaster Toronto Arthritis Patient Preference Disability Questionnaire), VO2 max, and disease activity (International Myositis Assessment and Clinical Studies criteria of improvement of the 6-item core set) were performed at 0 and 12 weeks. Disability assessments were performed again at 52 weeks in an open extension period. All assessments were performed by blinded observers.

RESULTS

The EG improved compared to the CG in SF-36 physical function and vitality (P = 0.010 and P = 0.046, respectively), ADL score (P = 0.035), 5 VRM (P = 0.026), and VO2 max (P = 0.010). More patients in the EG (7 of 11) were responders with reduced disease activity compared to none in the CG (P = 0.002). Correlations between VO2 max and SF-36 physical function were 0.90 and 0.91 at 0 and 12 weeks, respectively (P < 0.05). The EG improvement in 5 VRM was sustained up to 52 weeks compared to baseline (5.7 kg; P < 0.001), but not in ADL score or SF-36.

CONCLUSIONS

Endurance exercise improves health and may reduce disease activity in patients with established PM/DM. This potentially could be mediated through improved aerobic fitness. The results also indicate sustained muscle strength up to 1 year after a supervised program.

Endurance exercise demonstrates beneficial effects in polymyositis/dermatomyositis (PM/DM); however, the molecular effects of exercise on skeletal muscle are incompletely understood. We undertook this controlled pilot study to investigate the effects of a 12-week endurance exercise training program on the molecular profile of skeletal muscle in patients with established PM/DM compared to a nonexercised control group of patients with established PM/DM.

Fifteen patients (7 in the exercise group and 8 in the control group) with paired baseline and 12-week follow-up muscle biopsy samples were included. Messenger RNA expression profiling, mass spectrometry-based quantitative proteomics, and immunohistochemical analyses were performed on muscle biopsy samples to determine molecular adaptations associated with changes in clinical measurements induced by endurance exercise.

Compared to the control group, the exercise group improved in minutes of cycling time (P < 0.01) and Vo2 max (P < 0.05). The exercise group also had reduced disease activity (P < 0.05) and reduced lactate levels at exhaustion (P < 0.05). Genes related to capillary growth, mitochondrial biogenesis, protein synthesis, cytoskeletal remodeling, and muscle hypertrophy were up-regulated in the exercise group, while genes related to inflammation/immune response and endoplasmic reticulum stress were down-regulated. Mitochondrial pathways including the oxidative phosphorylation metabolic pathway were most affected by the endurance exercise, as demonstrated by proteomics analysis. The exercise group also showed a higher number of capillaries per mm(2) in follow-up biopsy samples (P < 0.05).

Our data indicate that endurance exercise in patients with established PM and DM may activate an aerobic phenotype and promote muscle growth and simultaneously suppress the inflammatory response in these patients' muscles, as supported by a combination of data on gene expression, proteomics, and capillary density in repeated muscle biopsies.

There is growing evidence to support the safety and efficacy of exercise in patients with adult and juvenile idiopathic inflammatory myopathies. Five randomized controlled trials including adult patients with polymyositis and dermatomyositis (DM) and additional open studies have demonstrated reduced impairment and activity limitation as well as improved quality of life. In addition, recent studies have shown reduced disease activity assessed by consensus disease activity measures and reduced expression of genes regulating inflammation and fibrosis. Furthermore, exercise could improve muscle aerobic capacity as shown by increased mitochondrial enzyme activity. These data suggest that intensive aerobic exercise and resistance training could reduce disease activity and inflammation and improve muscle metabolism. Encouraging results have been reported from available open studies including patients with inclusion body myositis (IBM) and juvenile DM, indicating reduced impairment, activity limitation and improved quality of life also in these patients. Larger studies are needed to increase understanding of the effects of exercise in patients with active, recent-onset polymyositis and DM as well as in patients with IBM and juvenile DM.

OBJECTIVE

To investigate the association of low-density (lipid-rich) muscle measured by computed tomography (CT) with skeletal muscle function and health-related quality of life in idiopathic inflammatory myopathies (IIMs).

METHODS

Seventeen patients and 10 healthy controls underwent CT of the midthigh to quantify high- (30-100 HU) and low-density (0-29 HU) skeletal muscle areas. Anthropometric measures, body composition, physical activity level, health-related quality of life, skeletal muscle strength, endurance, and fatigue were assessed. Patients were compared against controls. The relationship of anthropometric, body composition, and disease variables with measures of muscle function were examined using Spearman's test on the patient group. Linear regression was used to assess the age- and disease-adjusted relationship of muscle quality to physical function and muscle strength.

RESULTS

Patients had higher body fat percentage (P = 0.042), trunk fat mass (P = 0.042), android:gynoid fat (P = 0.033), and midthigh low-density muscle/total muscle area (P < 0.001) compared to controls. Midthigh low-density muscle/total muscle area was negatively correlated with self-reported physical function, strength, and endurance (the Short Form 36 [SF-36] health survey physical functioning [P = 0.004], manual muscle testing [P = 0.020], knee maximal voluntary isometric contraction/thigh mineral-free lean mass [P < 0.001], and the endurance step test [P < 0.001]), suggesting that muscle quality impacts function in IIM. Using multiple linear regression adjusted for age, global disease damage, and total fat mass, poor muscle quality as measured by midthigh low-density muscle/total muscle area was negatively associated with SF-36 physical functioning (P = 0.009).

CONCLUSIONS

Midthigh low-density muscle/total muscle area is a good predictor of muscle strength, endurance, and health-related quality of life as it pertains to physical functioning in patients with IIMs.