A longitudinal, integrated, clinical, histological and mRNA profiling study of resistance exercise in myositis

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.

Figure 1

Validation of selected target gene by qRT-PCR. The PCR results suggest a good correlation (R² = 0.62) between the changes in gene expression detected by microarray and qRT-PCR.

Figure 2

(A) Identification of an exercise-induced gene network involved in tissue inflammation using the Ingenuity Pathways Analysis knowledge database. Several genes regulated by TNFα were negatively modulated by resistance exercise, suggesting that they may play a role in the antiinflammatory effects of exercise in myositis patients (see text for further explanations). (B) Model of exercise-induced reduction in inflammation in autoimmune myositis patients. Based on the experimental expression data generated by the microarray analysis, we developed a hypothetical model in which three discrete steps in the regulation of tissue inflammation can be identified, suggesting that exercise could reduce inflammation by downregulating the expression of genes involved in activation and proliferation of T-cells and macrophages, migration and adhesion. (Panel A image: © 2000–2010 Ingenuity Systems, Inc. All rights reserved.)

Figure 3

(A) Identification of an exercise-induced gene network involved in tissue fibrosis using the Ingenuity Pathways Analysis knowledge database. Several genes regulated by TGF-β were negatively modulated, and a negative modulator of TGF-β (LTBP1) was induced by exercise in a manner consistent with the reduction in tissue fibrosis and improved performance in myositis patients (see text for further information). (B) Model of exercise-induced reduction in fibrosis in autoimmune myositis patients. Collagen synthesis is suppressed because of a reduction in growth factor production and an increase in inhibitory molecules such as LTBP1. The reduction in collagen processing likely contributes to the decrease in ECM deposition. This, together with an increase in ECM degradation by collagen-cleaving enzymes and matrix metalloproteases, will result in a reduction in tissue fibrosis. (Panel A image: © 2000–2010 Ingenuity Systems, Inc. All rights reserved.)

Figure 4

Exercise training reduced fibrosis in myositis muscles. Resistance exercise training resulted in a significant reduction in nonmuscle area infiltrates. (A) Gross morphological analysis via Gomori trichrome staining pre-and posttraining (fibrotic areas are indicated by arrows). (B) Quantitative analysis of tissue sections demonstrates a decrease in non-muscle area. (C) Type I collagen protein levels in pre-and posttraining biopsies in individual patients. (D) Type I collagen levels were reduced significantly after resistance training (n = 6; *P = 0.01). AU, arbitrary units. Data are means ± SEM.