Nitric oxide stress in sporadic inclusion body myositis muscle fibres: inhibition of inducible nitric oxide synthase prevents interleukin-1β-induced accumulation of β-amyloid and cell death

Activation of osmolyte pathways in inflammatory myopathy and Duchenne muscular dystrophy points to osmoregulation as a contributing pathogenic mechanism

“…29 As was the case earlier for iNOS, 30 we could, however, not confirm a significant increase of AR protein levels in DM muscle extracts via western blotting, presumably because of its expression being limited to the affected perifascicular areas. 31 The induction of CCL2, specifically in part of the perifascicular atrophic muscle fibers of DM, further corroborates earlier observations. 32 Presumably, CCL2 expression at perifascicular areas guides circulating monocytes to these areas, allowing characteristic local accumulation of responsive macrophages and T cells.…”

Inflammatory Muscle Diseases

“…of inflammatory signaling, such as interferon-γ-receptor signaling. 56 Compelling evidence suggests that aging, abnormal proteostasis (the network controlling proteins), 20 impaired autophagy, cell stress induced by MHC class I or nitric oxide, 21,57 long-standing inflammation, and proinflammatory cytokines such as interferon-γ and interleukin-1β 57,58 may cumulatively trigger or enhance degeneration, leading to further accumulation of stressor molecules and misfolded proteins 59 (Fig. 3).…”

“…Because of T-cell-mediated cytotoxic effects and the enhancement of amyloid-related protein aggregates by proinflammatory cytokines in patients with inclusion-body myositis, 21,57,58 immunosuppressive agents have been tried as treatment for this disease subtype, but all have failed, probably because the disease starts long before patients seek medical advice, when the degenerative cascade is already advanced. 60 Glucocorticoids, methotrexate, cyclosporine, azathioprine, and mycophenolate are ineffective, and although some patients may initially have mild subjective improvements when treated with one of these agents, 60,61 no long-term benefit is achieved.…”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…Pro‐inflammatory stimuli, such as IL‐1 β , TNF‐ α , and IFN γ augment expression of inducible nitric oxide synthase (iNOS), and composite exposure of murine muscle cells with IFN γ and A β peptides provoke robust nitric oxide (NO) production 291, 292, 293. Expression of iNOS in IBM muscle has been reported several years ago294 and more recently confirmed and extended: iNOS expression and concomitant NO production was enhanced in IBM muscle compared to DM and PM muscle 295. More importantly, nitrotyrosine, the product of tyrosine nitration in the presence of metabolically active NO, colocalized with A β in IBM muscle fibers.…”

“…More importantly, nitrotyrosine, the product of tyrosine nitration in the presence of metabolically active NO, colocalized with A β in IBM muscle fibers. In vitro assays revealed that exposure of primary human muscle cells to IL‐1 β together with IFN γ elicits strong NO production, followed by necrotic cell death 295. Conversely, the pharmacological inhibition of iNOS prevented cytokine‐mediated accumulation of A β and necrotic cell death indicative of iNOS being at the interface of proinflammatory stress and degenerative changes in IBM muscle.…”