Mitochondrial abnormalities in dermatomyositis: characteristic pattern of neuropathology

Abstract

The objective of the work described in this paper was to evaluate mitochondrial abnormalities in perifascicular atrophic fibers in muscle biopsies from patients with dermatomyositis (DM). We localized cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemically in muscle biopsies of 12 patients with DM, and 12 control patients with neurogenic atrophy. These two histochemical techniques were also combined on single tissue sections in order to accentuate any COX-negative fibers. Eleven out of 12 patients (91.6%) with DM showed histochemical evidence of mitochondrial dysfunction in perifascicular distribution. Similar abnormalities in histochemical staining were not seen in comparably sized myofibers that were atrophic due to denervation. It is concluded that abnormal SDH and COX histochemical activities in atrophic perifascicular fibers are characteristic of dermatomyositis. These abnormal staining characteristics could not be accounted for solely by myofiber atrophy, or by generalized abnormalities in histochemical staining.

Dermatomyositis

“…The endothelial histologic findings of amyopathic and classic DM are equivalent [28], suggesting that the same underlying mechanisms of disease may be active in both. Interestingly, gene expression profiles do not show differential regulation of known intramuscular endothelial cell proteins or growth factors [21,80].…”

“…Endothelial dysfunction in dermatomyositis is also implicated by data showing the presence of both IL-1α and ICAM-1 both in muscle samples with [80] and without [21] inflammatory infiltrates. Although endothelial dysfunction seems to play an important role in the pathogenesis of DM, neither the onset nor the downstream events are well understood.…”

“…Considering muscle anatomy and its vascular supply, vessel damage may induce damage in a watershed distribution, leading to preferential myocyte destruction in the perifascular region and ultimately localized atrophy, although it has been noted that no real evidence exists to support such a claim [7]. However, increased succinate dehydrogenase (SDH) and reduced cytochrome c oxidase (COX) enzyme staining, which indicates mitochondrial dysfunction, was identified in 11/12 patients with DM, suggesting ischemia as the culprit in perifascicular atrophy [80]. Complement activation and subsequent membrane attack complex (MAC) deposition into the larger vessels may cause muscle ischemia and subsequent myocyte damage [1].…”

Pathology of Adult and Paediatric Mitochondrial Myopathies

“…In IBM, the ongoing inflammation and cytokine environment, the associated production of reactive oxygen and nitrogen species and the associated endoplasmic reticulum stress, have a role in the initiation of mitochondrial DNA damage, leading to the accumulation of clonally-expanded mtDNA deletions and respiratory deficiency, a phenomenon that is not compensated by the malfunctioning cell repair mechanisms 137 . Increased numbers of COX-deficient and SDH-positive fibres within atrophic perifascicular zones are a common feature in dermatomyositis 138 . Histochemical and biochemical OXPHOS dysfunction can be induced by the toxic effects of a range of drugs on mitochondrial respiration, including antiretroviral agents and statins 139 , antiepileptics such as valproate, immunosuppressant and cytotoxic chemotherapeutic agents 13,14 .…”

The Cross-Talk Between Mitochondria and the Nucleus in the Response to Oxidative Stress Associated with Mitochondrial Dysfunction in Mitochondrial Encephalomyopathies

“…The histological and histochemical examinations of affected tissues have provided useful clues to determine the mitochondrial defects in the diagnosis of these diseases (Alhatou et al, 2004). There are well-established dye-staining methods for the assay of enzyme activities of cytochrome c oxidase (COX, Complex IV) and succinate dehydrogenase (SDH, Complex II) in affected muscle fibers and brain (DiMauro et al, 2002).…”