A Randomized Controlled, Clinical, Histological and mRNA Profiling Pilot Study Of Endurance Exercise In Myositis

Li Alemo Munters^1,2, Ingela M. Loell³, Joan Raouf⁴, Maryam Dastmalchi³, Eva Lindroos⁵, Christina Ottosson⁶, Yi-Wen Chen⁷, Annemarie F van Delden⁸, Mona Esbjörnsson⁹, Marina Korotkova¹⁰, Helene Alexanderson¹¹, Kanneboyina Nagaraju¹² and Ingrid E. Lundberg¹³, ¹Department of Medicine, Rheumatology Unit, , Karolinska University Hospital in Solna, Karolinska Institutet, Stockholm, Sweden, ²Department of Physiotherapy, Rheumatology Unit, Karolinska University Hospital in Solna, Stockholm, Sweden, Stockholm, Sweden, ³Rheumatology Unit, Department of Medicine, Karolinska University Hospital in Solna, Karolinska Institutet, Stockholm, Sweden, ⁴Department of Medicine, Rheumatology Unit, Karolinska University Hospital in Solna, Karolinska Institutet, Stockholm, Sweden, Stockholm, Sweden, ⁵Department of Medicine, Rheumatology Unit, Karolinska University Hospital in Solna, Karolinska Institutet, Stockholm, Sweden., Stockholm, Sweden, ⁶Department of Medicine, Rheumatology Unit, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden., Stockholm, Sweden, ⁷Research Center for Genetic Medicine, Children’s National Medical Center, Washington DC, USA., Washington DC, DC, ⁸Department of Medicine,, Rheumatology Unit, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden., Stockholm, Sweden, ⁹Department of Physiology, Karolinska Institutet, Huddinge, Sweden, ¹⁰Department of Medicine, Rheumatology Unit, Department of Medicine, Karolinska University Hospital in Solna, Karolinska Institutet, Stockholm, Sweden, Stockholm, Sweden, ¹¹Department of Neurobiology, Care Science and Society, Division of Physiotherapy, Division of Physiotherapy, Karolinska Institutet, Huddinge, Stockholm, Sweden, ¹²Research Center for Genetic Medicine, Children’s National Medical Center, Washington DC, DC, ¹³Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden

Meeting: ACR/ARHP Annual Meeting 2013

Keywords: Disability, Disease Activity, exercise and polymyositis/dermatomyositis (PM/DM), Gene Expression

Session Information

Title: Muscle Biology, Myositis and Myopathies I: Insights into Mechanisms of the Idiopathic Inflammatory Myopathies

Session Type: Abstract Submissions (ACR)

Background/Purpose:

This pilot study is a hypothesis-driven exploratory part of a larger randomized controlled trial evaluating effects of a supervised 12-week endurance exercise program (EG) compared to a non-interventional control group (CG) in patients with established polymyositis (PM) and dermatomyositis (DM). The aim was to determine the potential mechanisms underlying the beneficial effects of endurance exercise.

Methods:

A subgroup of 15 patients with paired baseline and 12 week follow-up muscle biopsies (EG n=7 and CG n=8) were included in the analysis. mRNA expression profiling and immunohistochemistry analysis of biopsies from vastus lateralis muscle were used to determine molecular changes associated with the changes in clinical assessments. Clinical assessments consisted of: Maximal oxygen uptake (VO₂ max) and cycling time to exhaustion at 65% of VO₂ max. Lactate levels in the vastus lateralis muscle were measured with microdialysis directly after the cycling. Clinical disease activity was assessed according to the International Myositis Assessment and Clinical Studies Group (IMACS) criteria.

Results:

Patients in the EG clinically improved compared to the CG in cycling time (p<0.01) and VO₂ max (p<0.05), whereas lactate levels at exhaustion were decreased or unchanged. A majority of the patients in the EG were responders with reduced disease activity compared to the CG (p<0.05). These clinical changes were accompanied with down-regulation in genes related to inflammation and ER-stress , such as Eukaryotic translation initiation factor 2C, 4 (-2.6, p<0.01) and Cell adhesion molecule with homology to L1CAM (-1.6, p<0.01); and up-regulation in genes related to capillary growth, cytoskeletal remodeling, muscle hypertrophy, mitochondria biogenesis and protein synthesis, such as Toll-like receptor 7 (1.7 fold, p<0.01), Fms-related tyrosine kinase 3 ligand (4.3 fold, p<0.01), Insulin-like growth factor 1 receptor (1.4, p<0.001), Insulin receptor (1.3, p<0.001). The CG displayed non- synchronized regulation of genes, although up-regulation in genes related to type 1 interferon and apoptosis was determined. No significant changes were displayed in the number of T-cells and macrophages in the EG nor in the CG. The EG but not the CG showed a higher number of capillaries per mm² in the follow up biopsy.

Conclusion:

Our data showed that endurance exercise in patients with PM and DM may induce genes involved in muscle growth and remodeling as previously reported in healthy individuals. In addition, the exercise suppressed inflammation and ER-stress accompanied with reduced clinical disease activity in the patients. The findings suggest that endurance exercise may be beneficial by activating the muscle growth program which overwrites the muscle atrophy process, and suppressing the inflammation responses in parallel in the patients’ muscles.

Disclosure:

L. Alemo Munters,
None;

I. M. Loell,
None;

J. Raouf,
None;

M. Dastmalchi,
None;

E. Lindroos,
None;

C. Ottosson,
None;

Y. W. Chen,
None;

A. F van Delden,
None;

M. Esbjörnsson,
None;

M. Korotkova,
None;

H. Alexanderson,
None;

K. Nagaraju,
None;

I. E. Lundberg,

BMS,

Novartis Pharmaceutical Corporation,

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