A Longitudinal, Integrated, Clinical, Histological and mRNA Profiling Study of Resistance Exercise in Myositis

Gustavo A Nader,Mona Esbjörnsson,Maryam Dastmalchi,Kanneboyina Nagaraju,Ingrid E Lundberg,Eric P Hoffman,Johan Rönnelid,Zuyi Wang,Ramkishore Gernapudi,Helene Alexanderson,Cecilia Grundtman

doi:10.2119/molmed.2010.00016

Abstract

Polymyositis and dermatomyositis are orphan, chronic skeletal muscle disorders characterized by weakness, infiltrations by mononuclear inflammatory cells, and fibrosis. Until recently, patients were advised to refrain from physical activity because of fears of exacerbation of muscle inflammation. However, recent studies have shown that moderate exercise training in combination with immunosuppressive drugs can improve muscle performance. Despite the positive effects of exercise training, the molecular mechanisms underlying the exercise-associated clinical improvements remain poorly understood. The present study was designed to define, at the molecular level, the effects of resistance exercise training on muscle performance and disease progression in myositis patients. We evaluated changes in muscle strength, histology and genome-wide mRNA profiles to determine the beneficial effects of exercise and determine the possible molecular changes associated with improved muscle performance. A total of 8 myositis patients underwent a 7-wk resistance exercise training program that resulted in improved muscle strength and increased maximal oxygen uptake (VO(2max)). Training also resulted in marked reductions in gene expression, reflecting reductions in proinflammatory and profibrotic gene networks, changes that were also accompanied by a reduction in tissue fibrosis. Consistent with the exercise-associated increase in VO(2max), a subset of transcripts was associated with a shift toward oxidative metabolism. The changes in gene expression reported in the present study are in agreement with the performance improvements induced by exercise and suggest that resistance exercise training can induce a reduction in inflammation and fibrosis in skeletal muscle.

Highlights

Polymyositis and dermatomyositis are chronic, autoimmune skeletal muscle disorders characterized by proximal weakness and infiltration of mononuclear inflammatory cells
When these genes were cross-validated against a disease database during the ingenuity pathways analysis, we found that the majority are involved in diseases characterized by inflammation and fibrosis
We demonstrate that 7 weeks of resistance exercise modulated the expression of genes involved in inflammation, fibrosis and metabolism in muscle from polymyositis/dermatomyositis patients

Summary

Introduction

Polymyositis and dermatomyositis are chronic, autoimmune skeletal muscle disorders characterized by proximal weakness and infiltration of mononuclear inflammatory cells. Current pharmacological treatment is based on high doses of glucocorticoids in combination with other immunosuppressive drugs. Most patients respond with improved muscle performance, but many are left with impaired muscle function and reduced health-related quality of life [1]. Several factors could contribute to the sustained muscle impairment despite immunosuppressive treatments. Longitudinal studies of patients with persisting muscle weakness have demonstrated phenotypical changes of muscle tissue, including persisting major histocompatibility complex (MHC) class I expression in muscle fibers and activation markers in endothelial cells of microvessels [2].

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