Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies – potential role of ER stress pathways

Lightfoot, Adam P.; Nagaraju, Kanneboyina; McArdle, Anne; Cooper, Robert G.

doi:10.1097/bor.0000000000000212

Cited by 34 publications

(30 citation statements)

References 58 publications

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“…Without amelioration of such insult(s) to Ca 2+ homeostasis, Ca 2+ dysregulation progresses in the propagation phase. Mitochondria, susceptible to injury in IBM due to conditions of inflammation, mtDNA abnormalities, and impaired proteostasis, are damaged by excessive Ca 2+ influx [7, 31, 32, 48]. This stimulates ROS production, promoting further Ca 2+ efflux from the SR [15] and ER stress signaling [32].…”

Section: Discussionmentioning

confidence: 99%

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Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

Amici

Pinal‐Fernandez

Mázala

et al. 2017

acta neuropathol commun

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Sporadic inclusion body myositis (IBM) is the most common primary myopathy in the elderly, but its pathoetiology is still unclear. Perturbed myocellular calcium (Ca2+) homeostasis can exacerbate many of the factors proposed to mediate muscle degeneration in IBM, such as mitochondrial dysfunction, protein aggregation, and endoplasmic reticulum stress. Ca2+ dysregulation may plausibly be initiated in IBM by immune-mediated membrane damage and/or abnormally accumulating proteins, but no studies to date have investigated Ca2+ regulation in IBM patients. We first investigated protein expression via immunoblot in muscle biopsies from IBM, dermatomyositis, and non-myositis control patients, identifying several differentially expressed Ca2+-regulatory proteins in IBM. Next, we investigated the Ca2+-signaling transcriptome by RNA-seq, finding 54 of 183 (29.5%) genes from an unbiased list differentially expressed in IBM vs. controls. Using an established statistical approach to relate genes with causal transcription networks, Ca2+ abundance was considered a significant upstream regulator of observed whole-transcriptome changes. Post-hoc analyses of Ca2+-regulatory mRNA and protein data indicated a lower protein to transcript ratio in IBM vs. controls, which we hypothesized may relate to increased Ca2+-dependent proteolysis and decreased protein translation. Supporting this hypothesis, we observed robust (4-fold) elevation in the autolytic activation of a Ca2+-activated protease, calpain-1, as well as increased signaling for translational attenuation (eIF2α phosphorylation) downstream of the unfolded protein response. Finally, in IBM samples we observed mRNA and protein under-expression of calpain-3, the skeletal muscle-specific calpain, which broadly supports proper Ca2+ homeostasis. Together, these data provide novel insight into mechanisms by which intracellular Ca2+ regulation is perturbed in IBM and offer evidence of pathological downstream effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0427-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…calpain-1), which cleave Ca 2+ -regulatory proteins like SERCA1 [49, 50]. Ca 2+ and redox imbalances in the ER perturb protein folding, inducing UPR signaling [18, 32]. Together, impairment of mitochondrial buffering, degradation of Ca 2+ -regulatory proteins, and suppression of translation cause progressive increases in cytosolic Ca 2+ .…”

Section: Discussionmentioning

confidence: 99%

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

Amici

Pinal‐Fernandez

Mázala

et al. 2017

acta neuropathol commun

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“…In our article we did not try to imply that the mechanisms of actions of immune cells and ROS generation are mutually exclusive, as clearly inflammatory cell infiltrations are a cause of muscle cell injury and thus weakness. In another recent, and related, review we suggest that inflammatory cell infiltration is in fact a ‘secondary’ feature in IIM 3. We agree that there is likely an interaction between immune cell-mediated and ROS-mediated muscle dysfunction.…”

mentioning

confidence: 51%

Response to: ‘In the idiopathic inflammatory myopathies, reactive oxygen species are at the crossroad between immune and non-immune cell mediated mechanisms’ by Meyeret al

Lightfoot

Cooper

2015

Ann Rheum Dis

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Response to: 'In the idiopathic inflammatory myopathies, reactive oxygen species are at the crossroad between immune and non-immune cell mediated mechanisms' by Meyer et alWe welcome the comments from Meyer et al 1 regarding our recent article which hypothesised a potential role for reactive oxygen species (ROS) as a mediator of muscle weakness induction in the idiopathic inflammatory myopathies (IIM).2 The focus of our article was specifically on the persistence of muscle weakness in the treated paucity or absence of inflammatory cell infiltrates, and the role that ROS may play as a mediator of this residual and non-inflammatory dysfunction.2 In our article we did not try to imply that the mechanisms of actions of immune cells and ROS generation are mutually exclusive, as clearly inflammatory cell infiltrations are a cause of muscle cell injury and thus weakness. In another recent, and related, review we suggest that inflammatory cell infiltration is in fact a 'secondary' feature in IIM. 3 We agree that there is likely an interaction between immune cell-mediated and ROS-mediated muscle dysfunction. The interesting beneficial effects of using ROS-targeted therapies as described by Meyer et al 4 in the context of IIM thus appear timely and indeed fundamentally important. Based on their findings and our own postulates, it is perhaps logical to now consider the role of ROS in immune and non-immune settings in IIM. Moreover, and given the recent advances in ROS-targeted compounds, a new dawn may now be on the horizon regarding novel therapeutics to target weakness in IIM.

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“…These findings clearly suggest that myotoxic factors other than immune cell infiltrates are also pathologically involved. Recent reviews have thus suggested that non-immune cell-mediated mechanisms must also play a significant cytotoxic role, over and above that expected from infiltrating inflammatory cells, [7, 8]. Research in human and murine myositis models suggests that chronic over-activation of the ER stress pathway also contributes to weakness induction, [9].…”

Section: Introductionmentioning

confidence: 99%

17-(Allylamino)-17demethoxygeldanamycin reduces Endoplasmic Reticulum (ER) stress-induced mitochondrial dysfunction in C2C12 myotubes

Lightfoot

Rs²,

et al. 2018

Preprint

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In patients with myositis, persistent skeletal muscle weakness in the absence of significant inflammatory cell infiltrates is a well-recognised, but poorly understood, cause of morbidity. This has led researchers to investigate cellular mechanisms independent of immune cells, which may contribute to this underlying muscle weakness. Chronic ER stress pathway activation is evident in the muscle of myositis patients, and is now a potential mediator of muscle weakness in the absence of inflammation. Abnormal ER stress pathway activation is associated with mitochondrial dysfunction, resulting in bioenergetic deficits and reactive oxygen species (ROS) generation, which in this context may potentially damage muscle proteins and thus impair contractile performance. This study examined whether treatment with the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17AAG) could mitigate these ER stress-induced changes. C2C12 myotubes were treated with the ER stress-inducing compound Tunicamycin, in the presence or absence of 17AAG. Myotubes were examined for changes relating to ER stress pathway activation, mitochondrial function, markers of oxidative damage and in myotubular dimensions. ER stress pathway activation caused mitochondrial dysfunction, as evidenced by reduced oxygen consumption and ATP generation and by increased gene expression levels of the bio-energetic regulator, uncoupling protein 3 (UCP-3), the latter indicative of electron transport chain uncoupling. ER stress pathway activation also caused increased gene expression of superoxide dismutase (SOD) 2 and peroxiredoxin (PRDX) 3, elevated H2O2 levels, and reduced total thiol pool levels and a significant diminution of myotubular dimensions. Exposure to 17AAG ameliorated these ER stress-induced changes. These findings, which suggest that 17AAG can reduce ER stress-induced mitochondrial dysfunction, oxidative damage and myotubular atrophy, have potential implications in the context of human myositis.

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Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies – potential role of ER stress pathways

Abstract: ER stress pathway activation is clearly of etiological relevance in IIM. Research to better understand mechanisms of weakness downstream of ER stress is now required, and which may discover new therapeutic targets for nonimmune cell-mediated weakness.

Cited by 34 publications

References 58 publications

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis

Response to: ‘In the idiopathic inflammatory myopathies, reactive oxygen species are at the crossroad between immune and non-immune cell mediated mechanisms’ by Meyeret al

17-(Allylamino)-17demethoxygeldanamycin reduces Endoplasmic Reticulum (ER) stress-induced mitochondrial dysfunction in C2C12 myotubes

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