The Study Of Clinical And Pathological Mechanism Of Glucocorticoid-induced Muscle Atrophy In PM Patients

BackgroundPolymyositis (PM) is a common idiopathic inflammatory myopathy(IIM) characterized by progressive muscle weakness, increased levels of serum muscle enzymes and abnormal electromyography (EMG) findings. The pathological entity of PM is the T cell, especially those that are CD8 positive. CD8-positive cells surround and invade muscle fibers expressing the major-histocompatibility class-I antigen.Generally, GCs are believed to be the first line of drugs in PM because of their anti-inflammatory and immunosuppressive properties. GC-induced muscle atrophy results from increased protein breakdown and decreased protein synthesis. Increased muscle proteolysis, in particular through the activation of the ubiquitin proteasome and the lysosomal systems, is considered to play a major role in the catabolic action of GC. The stimulation by GC of these two proteolytic systems is mediated through the increased expression of several Atrogenes, such as MAFbx/ Atrogin-1 and MuRF-1. Many studies described cases of patients with chronic obstructive pulmonary disease (COPD) or asthma who developed severe steroid-induced myopathy under prolonged corticosteroid treatment. However, until recently, few clinical studies included glucocorticoid- induced skeletal muscle atrophy in PM patients as endpoint. Therefore, our study aimed to improve the understanding of glucocorticoid-induced skeletal muscle atrophy in polymyositis patients and explore the possible mechanism of glucocorticoid-induced muscle atrophy in polymyositis patients.Part I The clinical and pathological effects of the application of glucocorticoids in polymyositis patientsObjectiveTo investigate the different clinical and histopathological manifestations of PM with glucocorticoid treatment and speculate the possible reason of different effects. The aim of study will be to improve the understanding of glucocorticoid-induced skeletal muscle atrophy in polymyositis patients.MethodsBy restrospectively analyzing the clinical and myopathological datas of 24 cases in polymyositis of glucocorticoid application.We summarized clinical features including Muscle weakness range, muscle pain, Creatine Kinase, EMG, et al. HE, NADH,MGT, ORO and ATPase staining were carried out in all muscle samples. ResultsAll 24 patients exhibited proximal limb muscles. There were 14 cases relieved gradually comparing with early onset of polymyositis by glucocorticoid treatment and CK level and EMG were obviously improved.6 of all 24 patients were corticosteroid resistant.4 of all 24 patients exhibited symptoms worsen. As for muscle pathology,8 cases showed typical pathological finding of mononuclear inflammatory cells that surround, invade and destroy healthy muscle fibers in PM.3 cases exhibited symptoms worsen and only shown selective type Ⅱ fiber atrophy without abnormal pathological findings. specific clinical and myopathological datas of all 3 patients with symptoms worsen were demonstrated in Table 1-2.ConclusionsMost PM patients showed gradual improvement of clinical symptom after GC application. and few muscle histopathology revealed of inflammatory cells infiltration.12.5% PM patients showed symptoms worsen after GC application, but levels of serum CK improved significantly and muscle biopsies revealed atrophy of the type II fiber. It is a clue to think of glucocorticoid-induced skeletal muscle atrophy in PM.Part II The study of clinical and pathological mechanism of glucocorticoid-induced skeletal muscle atrophy in PMObjectiveWe retrospectively analyzed clinical datas and muscle pathology of 12 PM patients with or without GC treatment to help improve early diagnostic accuracy of glucocorticoid- inducesd skeletal muscle atrophy in PM. The other aim of this study is to explore the possible mechanism of glucocorticoid-induced muscle atrophy in PM patients.MethodsIn this single-center retrospective case-control study, clinical datas including muscle weakness, CK and EMG were collected from PM patients. Eligible subjects were distributed into 3 groups:control groups, polymyositis groups, glucocorticoid treatment groups which were primarily proved skeletal muscle atrophy by ATPase staining. Immunohistochemistry and Western-blot were used to detect the expression of glucocorticoid receptor (GR) in muscle biopsies. Western-blot was used to detect the expression of muscle Atrophy F-box (MAFbx) and Muscle Specific Ring Finger Protein 1 (MuRF1).ResultsGC groups showed only affected symmetrical and proximal limb weakness, creatine kinase values and EMG were significantly improved. Exogenous GC had been shown to cause atrophy of type II muscle fibers in PM patients. GR were identified mainly expressing in muscle cell nuclei by immunohistochemistry in all subjects muscle tissues. Western-blot analysis showed marked up-regulation of expression of GR and MuRFl in muscle homogenate from patients with GC groups as compared with that in control groups and PM groups.ConclusionsOur results of specific selective type II fiber atrophy is a sensitive yardstick for pathological diagnosis of steroid-induced myopathy in PM. GR may play an efficient role in glucocorticoid-induced skeletal muscle atrophy in PM patients. MuRFl also plays a specific role in regulating protein expression in atrophic muscle in PM patients.