Polymyositis with cytochrome C oxidase negative fibers—a pathological and clinical challenge

doi:10.1016/j.anndiagpath.2012.10.004

Annals of Diagnostic Pathology

Volume 17, Issue 2, April 2013, Pages 183-186

https://doi.org/10.1016/j.anndiagpath.2012.10.004 Get rights and content

Abstract

Polymyositis (PM) with cytochrome C oxidase negative fibers also referred to as PM with mitochondrial pathology (PM-Mito) is characterized by the symptoms of inclusion body myositis (IBM) and by the myopathological findings of PM except for an increase of muscle fibers with insufficient mitochondrial cytochrome C oxidase activity. Few PM-Mito cases are published; mitochondrial ultrastructure has not been studied in these patients. We report 2 PM-Mito patients with later onset than usually seen in IBM and poor responsiveness to glucocorticoids. Electron microscopy of muscle fibers showed irregular mitochondrial ultrastructure. Sjögren syndrome related antinuclear antibodies (Anti-Ro and Anti-La) were found in one of the two patients but the typical clinical symptoms of Sjögren syndrome such as xerostomia and keratoconjunctivitis were absent in this patient. Taken together, our observations, viewed in conjunction with the current literature, suggest that PM-Mito is an underdiagnosed disease with a multifactorial pathogenesis that should be elucidated in further studies. We want to encourage clinicians and pathologists to consider the possibility of PM-Mito in patients with atypical PM or sIBM.

Introduction

The idiopathic inflammatory myopathies (IIM) are classified into the three disease groups: 1.) polymyositis (PM), 2.) dermatomyositis (DM), and 3.) sporadic inclusion body myositis (sIBM) [1]. Common IIM features are muscle weakness and inflammatory infiltrate of the skeletal muscle. Inflammation in PM and sIBM is characterized by CD8-positive cytotoxic T-cell invasion of muscle fibers that express Major histocompatibility complex (MHC) class-I antigens. In addition to these inflammatory changes, sIBM is characterized by muscle degeneration with amyloid deposits and basophilic vacuolar formation (inclusion bodies). Mitochondrial dysfunction due to mitochondrial DNA deletions is frequent [2]. Immunohistochemical features of the mitochondrial pathology in sIBM include an increase of muscle fibers with insufficient cytochrome C oxidase (COX) activity and ragged red fibers with increased staining for succinate dehydrogenase (SDH). The ultrastructure in sIBM is characterized by paired helical filaments composed of phosphorylated tau protein [1], [2]. Differentiation between sIBM and PM is clinically relevant as sIBM shows poor responsiveness to glucocorticoids as well as later onset and slower progression than PM [3]. There are few reports of patients that present with clinical features of sIBM but histological features of PM except for an excess of COX-negative fibers [4], [5]. In these patients, mitochondrial DNA abnormalities were detected, suggesting a mitochondrial pathomechanism similar to sIBM. There are no investigations of mitochondrial ultra structure in patients with PM-Mito. We studied 2 patients with PM-Mito for clinical, myopathological and ultrastructural features.

Section snippets

Clinical summary

Two patients were studied: patient 1 (68 years, male) had a history of arterial hypertension and grand mal epilepsy, and patient 2 (71 years, female) had a history of glaucoma and paroxysmal sinus tachycardia. No hereditary diseases were known in their families. Both patients presented with progressive skeletal muscle weakness, physical strain induced myalgia, and muscle atrophy. Onset of muscle weakness had been in both proximal thighs in patient 1 (3 years ago) and in all limbs with a focus

Pathological findings

Vastus lateralis samples of both patients were removed by an open biopsy procedure and immediately frozen in isopentane cooled with liquid nitrogen. Frozen sections were stained with hematoxylin and eosin, modified Gomori Trichrome, and Congo Red. Standard techniques of enzyme histochemistry and immunohistochemistry were performed. Both patients met the criteria of polymyositis including inflammatory cell infiltrates and CD8-positive cytotoxic T-cells attacking non-necrotic muscle fibers that

Discussion

A number of studies of COX activity in muscles of patients with inflammatory myopathies have reported varying results: Yamamoto et al. reported no COX-deficient fibers in inflammatory myopathies [6]. In another study, COX-deficiency was limited to analysis of necrotic fibers in the majority of patients with inflammatory myopathies [7]. Chariot et al. observed that the percentage of COX-negative fibers was significantly higher in patients with inflammatory myopathies than in age-matched groups

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The myokine GDF-15 is a potential biomarker for myositis and associates with the protein aggregates of sporadic inclusion body myositis
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An altered mitochondrial phenotype has long been recognized in the subgroup of IBM patients, largely based upon the histological evidence of ragged-red fibres and cytochrome c oxidase deficient muscle fibres in patient biopsies [2]. In addition, hereditary muscular dystrophies may contain mitochondrial abnormalities [3], and prominent mitochondrial damage is observed in individuals with PM poorly responsive to immunosuppressive therapy, a disorder also termed PM with mitochondrial pathology [4]. As growth differentiation factor-15 (GDF-15) is involved in both mitochondrial [5] and inflammatory [6] regulation, we set out to investigate this cytokine in the IIM.
The cytokine growth differentiation factor-15 (GDF-15) has been associated with inflammatory and mitochondrial disease, warranting exploration of its expression in myositis patients.
GDF-15 protein levels are evaluated in 35 idiopathic inflammatory myopathy (IIM) serum samples using enzyme-linked immunosorbent assays, comparing with levels in samples from healthy individuals and from patients with genetically confirmed hereditary muscular dystrophies and mitochondrial disorders. Muscle tissue expression of GDF-15 protein is evaluated using immunofluorescent staining and Western blotting.
GDF-15 protein levels are significantly higher in IIM sera (625 ± 358 pg/ml) than in that of healthy controls (326 ± 204 pg/ml, p = 0.01). Western blotting confirms increased GDF-15 protein levels in IIM muscle. In skeletal muscle tissue of IIM patients, GDF-15 localizes mostly to small regenerating or denervated muscle fibres. In patients diagnosed with sporadic inclusion body myositis, GDF-15 co-localizes with the characteristic protein aggregates within affected muscle fibres.
We describe for the first time that GDF-15 is a myokine upregulated in myositis and present the cytokine as a potential diagnostic serum biomarker.
Human muscle pathology is associated with altered phosphoprotein profile of mitochondrial proteins in the skeletal muscle
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Assessment of muscle pathology in these diseases indicates direct involvement of mitochondrial damage [3]. Mitochondrial abnormalities are evident in Duchenne muscular dystrophy (DMD) [4], collagen VI myopathies, congenital myopathies, calpainopathy, inflammatory myopathies [5,6], facioscapulohumeral dystrophy [7], epidermolysis bullosa simplex with MD, sarcoglycan deficient MDs and others [8,9]. Mitochondrial dysfunction has been noted in the skeletal muscle of the DMD mouse model [10–12].
Analysis of human muscle diseases highlights the role of mitochondrial dysfunction in the skeletal muscle. Our previous work revealed that diverse upstream events correlated with altered mitochondrial proteome in human muscle biopsies. However, several proteins showed relatively unchanged expression suggesting that post-translational modifications, mainly protein phosphorylation could influence their activity and regulate mitochondrial processes. We conducted mitochondrial phosphoprotein profiling, by proteomics approach, of healthy human skeletal muscle (n = 10) and three muscle diseases (n = 10 each): Dysferlinopathy, Polymyositis and Distal Myopathy with Rimmed Vacuoles. Healthy human muscle mitochondrial proteins displayed 253 phosphorylation sites (phosphosites), which contributed to metabolic and redox processes and mitochondrial organization etc. Electron transport chain complexes accounted for 84 phosphosites. Muscle pathologies displayed 33 hyperphosphorylated and 14 hypophorphorylated sites with only 5 common proteins, indicating varied phosphorylation profile across muscle pathologies. Molecular modelling revealed altered local structure in the phosphorylated sites of Voltage-Dependent Anion Channel 1 and complex V subunit ATP5B1. Molecular dynamics simulations in complex I subunits NDUFV1, NDUFS1 and NDUFV2 revealed that phosphorylation induced structural alterations thereby influencing electron transfer and potentially altering enzyme activity. We propose that altered phosphorylation at specific sites could regulate mitochondrial protein function in the skeletal muscle during physiological and pathological processes.
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In recent years, attention has been drawn to the nosological relationship of IBM to the entity of “polymyositis with COX-negative fibers” also referred to as “polymyositis with mt pathology.”74-76 PM-Mito is characterized by clinical features akin to IBM and by histopathologic features consistent with polymyositis, with the exception of an increased number of myofibers with absent or diminished COX histochemical staining.74-76 Although nondescript ultrastructural mt abnormalities have been encountered, to our knowledge, no mt membrane-bound crystalline inclusions have been reported.76
This review deciphers aspects of mitochondrial (mt) dysfunction among nosologically, pathologically, and genetically diverse diseases of the skeletal muscle, lower motor neuron, and peripheral nerve, which fall outside the traditional realm of mt cytopathies. Special emphasis is given to well-characterized mt abnormalities in collagen VI myopathies (Ullrich congenital muscular dystrophy and Bethlem myopathy), megaconial congenital muscular dystrophy, limb-girdle muscular dystrophy type 2 (calpainopathy), centronuclear myopathies, core myopathies, inflammatory myopathies, spinal muscular atrophy, Charcot-Marie-Tooth neuropathy type 2, and drug-induced peripheral neuropathies. Among inflammatory myopathies, mt abnormalities are more prominent in inclusion body myositis and a subset of polymyositis with mt pathology, both of which are refractory to corticosteroid treatment. Awareness is raised about instances of phenotypic mimicry between cases harboring primary mtDNA depletion, in the context of mtDNA depletion syndrome, and established neuromuscular disorders such as spinal muscular atrophy. A substantial body of experimental work, derived from animal models, attests to a major role of mitochondria (mt) in the early process of muscle degeneration. Common mechanisms of mt-related cell injury include dysregulation of the mt permeability transition pore opening and defective autophagy. The therapeutic use of mt permeability transition pore modifiers holds promise in various neuromuscular disorders, including muscular dystrophies.
Quantitative whole-body muscle MRI in idiopathic inflammatory myopathies including polymyositis with mitochondrial pathology: indications for a disease spectrum
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Polymyositis with mitochondrial pathology or atypical form of sporadic inclusion body myositis: case series and review of the literature
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Original ContributionPolymyositis with cytochrome C oxidase negative fibers—a pathological and clinical challenge

Abstract

Introduction

Section snippets

Clinical summary

Pathological findings

Discussion

Update on idiopathic inflammatory myopathies

Autoimmunity

Mitochondrial abnormalities in inclusion-body myositis

Neurology

Correlation of muscle biopsy, clinical course, and outcome in PM and sporadic IBM

Neurology

Polymyositis with cytochrome oxidase negative muscle fibres. Early quadriceps weakness and poor response to immunosuppressive therapy.

Brain

Inflammatory myopathies with mitochondrial pathology and protein aggregates

J Neurol Sci

Focal cytochrome c oxidase deficiency in various neuromuscular diseases

J Neurol Sci

Original Contribution
Polymyositis with cytochrome C oxidase negative fibers—a pathological and clinical challenge