Can muscle regeneration fail in chronic inflammation: a weakness in inflammatory myopathies?

Idiopathic inflammatory myopathies (IIMs), collectively termed myositis, include three major subgroups: polymyositis, dermatomyositis and inclusion body myositis. IIMs are characterized clinically by muscle weakness and reduced muscle endurance preferentially affecting the proximal skeletal muscle. In typical cases, inflammatory cell infiltrates and proinflammatory cytokines, alarmins and eicosanoids are present in muscle tissue. Treatment with glucocorticoids and other immunosuppressants results in improved performance, but complete recovery is rarely seen. The mechanisms that cause muscle weakness and reduced muscle endurance are multi-factorial, and different mechanisms predominate in different phases of disease. It is likely that a combination of immune-mediated and nonimmune-mediated mechanisms contributes to clinical muscle symptoms. Immune-mediated mechanisms include immune cell-mediated muscle fibre necrosis as well as direct effects of various cytokines on muscle fibre contractility. Among the nonimmune-mediated mechanisms, an acquired metabolic myopathy and so-called endoplasmic reticulum stress may be important. There is also a possibility of defective repair mechanisms, with an influence of both disease-related factors and glucocorticoid treatment. Several proinflammatory molecules observed in muscle tissue of myositis patients, including interleukin (IL)-1, IL-15, tumour necrosis factor, high-mobility group box-1 and eicosanoids, have a role in muscle fibre regeneration, and blocking these molecule may impair muscle repair and recovery. The delicate balance between immunosuppressive treatment to downregulate proinflammatory molecules and an inhibitory effect on muscle fibre regeneration needs to be further understood. This would also be relevant for other chronic inflammatory diseases.

Higher proportion of fast-twitch (type II) muscle fibres in idiopathic inflammatory myopathies - evident in chronic but not in untreated newly diagnosed patients.

OBJECTIVE: Polymyositis and dermatomyositis are idiopathic, inflammatory myopathies characterized by proximal muscle fatigue. Conventional immunosuppressive treatment gives a variable response. Biopsies from chronic patients display a low proportion type I and a high proportion of type II muscle fibres. This raised a suspicion that the low proportion of type I fibres might play a role in the muscle fatigue. AIM: To investigate whether the muscle fibre attributes evident in chronic myositis are characteristic for the polymyositis and dermatomyosistis diseases themselves. METHODS: Muscle biopsies were obtained from thigh muscle from untreated patients (n = 18), treated responders (n = 14) and non-responders (n = 6) and from healthy controls (n = 11), respectively. For clinical evaluations, creatine kinase, functional index of myositis and cumulative dose of cortisone were established. RESULTS: Chronic patients had a lower proportion of type I fibres and a higher proportion of type II fibres compared to untreated myositis patients and healthy controls. Fibre cross-sectional area (CSA) did not differ between patients and healthy individuals but all women had a 20% smaller type II fibre CSA compared to men. CONCLUSIONS: Untreated polymyositis and dermatomyositis patients and healthy controls have a different fibre type composition than chronic polymyositis and dermatomyositis patients. Fibre CSA did not differ between healthy controls or any of the patient groups. A low proportion of oxidative muscle fibres can therefore be excluded as a contributing factor causing muscle fatigue at disease onset and the gender difference should be taken into consideration when evaluating fibre CSA in myositis.

Effects of immunosuppressive treatment on microsomal prostaglandin E synthase 1 and cyclooxygenases expression in muscle tissue of patients with polymyositis or dermatomyositis.

OBJECTIVES: To investigate the expression of microsomal prostaglandin E (PGE) synthase 1 (mPGES-1) and cyclooxygenase (COX) in muscle biopsies from patients with polymyositis or dermatomyositis before and after conventional immunosuppressive treatment. METHODS: mPGES-1 and COX expression was evaluated by immunohistochemistry in muscle tissue from healthy individuals and from patients with polymyositis or dermatomyositis before and after conventional immunosuppressive treatment. The number of inflammatory cell infiltrates, T lymphocytes and macrophages was estimated before and after treatment. To localise the mPGES-1 expression double immunofluorescence was performed with antibodies against mPGES-1, CD3, CD68, CD163 and a fibroblast marker. A functional index was used to assess muscle function. RESULTS: In patients with myositis, mPGES-1, COX-2 and COX-1 expression was significantly higher compared to healthy individuals and associated with inflammatory cells. Double immunofluorescence demonstrated a predominant expression of mPGES-1 in macrophages. Conventional immunosuppressive treatment resulted in improved but still lower muscle function than normal. A decreased number of CD68-positive macrophages and reduced COX-2 expression in muscle tissue was also seen. By contrast, following the same treatment no significant changes were observed in muscle tissue regarding number of infiltrates, T lymphocytes, CD163-positive macrophages or mPGES-1 protein levels. CONCLUSIONS: Increased expression of mPGES-1, COX-1 and COX-2 at protein level was observed in muscle tissue from patients with myositis compared to healthy individuals. Conventional immunosuppressive treatment led to a significant downregulation of COX-2 in myositis muscle tissue. However, the expression of mPGES-1 and COX-1 remained unchanged indicating a role of these enzymes in the chronicity of these diseases.