Inflammatory myopathies with mitochondrial pathology and protein aggregates

doi:10.1016/j.jns.2008.11.010

Journal of the Neurological Sciences

Volume 278, Issues 1–2, 15 March 2009, Pages 25-29

https://doi.org/10.1016/j.jns.2008.11.010 Get rights and content

Abstract

Objectives

To compare the clinical course and muscle biopsy features of polymyositis with mitochondrial pathology (PM-Mito) to inclusion body myositis (IBM) and steroid-responsive inflammatory myopathies (polymyositis).

Methods

We compared clinical, laboratory and myopathologic features in a retrospective study of patients with PM-Mito (23), IBM (26) and polymyositis (12).

Results

Selective weakness in the quadriceps or finger flexors was common in PM-Mito (62%) and IBM (87%). Weakness progressed more slowly in PM-Mito than in IBM. PM-Mito patients with more rapidly progressive weakness had more cytochrome oxidase negative muscle fibers. There was no history of benefit from corticosteroid treatment in any PM-Mito or IBM patients. B-cell foci were absent in IBM and PM-Mito. LC3, an autophagy marker, and αB-crystallin were common in aggregates in PM-Mito and IBM, but not polymyositis. SMI-31 and TDP-43 positive aggregates were common in IBM but not in PM-Mito or polymyositis. β-amyloid showed no differences in aggregates among the three groups.

Conclusions

PM-Mito and IBM may be part of the same disease spectrum. PM-Mito has more slowly progressive weakness than IBM and rarely has TDP-43 or SMI-31 staining aggregates in muscle fibers. The most frequent proteins in aggregates in both PM-Mito and IBM are LC3, an autophagy marker, and αB-crystallin. Alterations in autophagic degradation pathways may be a common pathogenic mechanism in PM-Mito and IBM. In pathologically typical polymyositis, staining for mitochondrial enzyme activity, aggregates and B-cells helps to distinguish PM-Mito from inflammatory myopathy syndromes that are more likely to respond to corticosteroid treatment.

Introduction

Sporadic inclusion body myositis (IBM) is an idiopathic, and untreatable, myopathy syndrome with weakness usually beginning after 50 years of age [1]. IBM manifests clinically with progressive, proximal and distal weakness, most prominently involving knee extensors and ventral muscles of the forearm [2]. The myopathology of IBM includes several features with poorly understood interrelations [3]. T-cell inflammation in muscle, most commonly in the endomysium and focally invading intact muscle fibers, is a constant feature of IBM [4], [5], [6]. Types of muscle fiber pathology that are common in IBM include abnormal upregulation of MHC Class-I antigen and some costimulatory molecules [7], vacuoles or inclusions [2], [8], protein aggregates [9], [10] and multiple mitochondrial DNA deletions in muscle fibers. Mitochondrial pathology is manifest histochemically in scattered muscle fibers as increased succinate dehydrogenase (SDH) staining or reduced cytochrome oxidase (COX) activity [11], [12]. Nuclear pathology has also been described in IBM [13], [14], but is not well characterized molecularly.

In 1997 we reported a series of patients with polymyositis and mitochondrial pathology in muscle (PM-Mito) [15]. Clinical and pathological features in PM-Mito were similar to some of those in IBM, suggesting that they may be variants within one disease spectrum [12]. Clinical similarities included later age of onset, early and selective involvement of the knee extensor muscles, slow progression of weakness over years and no response to corticosteroid treatment. Myopathologic changes in both PM-Mito and IBM were endomysial inflammation with focal invasion of intact muscle fibers and mitochondrial pathology in more than 1% of muscle fibers. No patient with PM-Mito had vacuoles. In this follow-up study we compared clinical and pathologic features of PM-Mito with other inflammatory myopathies, including IBM and corticosteroid-responsive polymyositis.

Section snippets

Methods

This was a retrospective study of consecutive series of patients with pathologically confirmed PM-Mito (23), IBM (26) and corticosteroid-responsive polymyositis (12). All patients included in this study were examined in the Neuromuscular Clinic at the Washington University School of Medicine, St Louis. Follow up examinations were performed at least yearly. The degree and progression of weakness in IBM and PM-Mito patients was evaluated during the clinical examinations by measuring quantitative

Results

Clinical and Laboratory features of PM-Mito and IBM (Table 1): Females comprised 62% (16 of 26) of the PM-Mito group and 45% (13 of 29) of the IBM group. Onset age was typically in the sixth or seventh decade in both IBM and PM-Mito patients. Muscle strength was similar in both groups at the time of presentation to our clinic. Selective weakness in the quadriceps or finger flexors was more common in PM-Mito and IBM compared to steroid-responsive polymyositis (p < 0.001). There was a trend (p =

Discussion

We studied the clinical and pathological features of PM-Mito syndromes as a 10 year follow-up of an earlier series in which we initially described these patients [15]. Our results show that PM-Mito patients have slowly progressive weakness. The PM-Mito patients with the most rapid progression have a higher frequency of cytochrome oxidase negative muscle fibers. Some patients with PM-Mito have muscle discomfort. Laboratory changes in PM-Mito patients include a mildly elevated serum CK in most

Acknowledgements

We thank Rati Choksi and Elizabeth Streif for technical assistance. The study was supported by the Washington University Neuromuscular Research Fund.

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Inflammatory myopathies with mitochondrial pathology and protein aggregates

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgements

Hum Pathol

Neuromuscul Disord

Neuromusc Disord

Eur J Cell Biol

Cell

Update on idiopathic inflammatory myopathies

Autoimmunity

Inclusion body myositis. Observations in 40 patients

Brain

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Neurology

Immune effector mechanisms in inflammatory myopathies

Res Publ Assoc Res Nerv Ment Dis

Monoclonal antibody analysis of mononuclear cells in myopathies III. Immunoelectron microscopy aspects of cell mediated muscle fiber injury

Ann Neurol

Brachio-cervical inflammatory myopathies: clinical, immune, and myopathologic features

Arthritis Rheum

Inclusion body myositis: a distinct variety of idiopathic inflammatory myopathy

Neurology

AlphaB-crystallin immunolocalization yields new insights into inclusion body myositis

Neurology

Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: a study of 56 patients

Ann Neurol

Mitochondrial abnormalities in inclusion-body myositis

Neurology