Stress and glucocorticoid receptor regulation of mitochondrial gene expression

Lapp, Hannah E.; Bartlett, Andrew A.; Hunter, Richard G.

doi:10.1530/jme-18-0152

Cited by 65 publications

(54 citation statements)

References 65 publications

(75 reference statements)

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“…Moreover, the GC-GRα complex interacts with other transcription factors, such as nuclear factor-κB (NF-κB) or activator protein-1 (AP-1) and alters their transcriptional activities. A recent review reported on the GC regulation of mitochondrial transcription, via activation of mtGRE [ 10 ]. The degree of cytosolic GRα saturation is a direct modulator of the intensity of (therapeutic) GC genomic effects [ 11 ].…”

Section: Pharmacological Principles Of Glucocorticoid Actionsmentioning

confidence: 99%

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS

et al. 2020

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Current literature addressing the pharmacological principles guiding glucocorticoid (GC) administration in ARDS is scant. This paucity of information may have led to the heterogeneity of treatment protocols and misinterpretation of available findings. GCs are agonist compounds that bind to the GC receptor (GR) producing a pharmacological response. Clinical efficacy depends on the magnitude and duration of exposure to GR. We updated the meta-analysis of randomized trials investigating GC treatment in ARDS, focusing on treatment protocols and response. We synthesized the current literature on the role of the GR in GC therapy including genomic and non-genomic effects, and integrated current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. This review addresses the role dosage, timing of initiation, mode of administration, duration, and tapering play in achieving optimal response to GC therapy in ARDS. Based on RCTs’ findings, GC plasma concentration–time profiles, and pharmacodynamic studies, optimal results are most likely achievable with early intervention, an initial bolus dose to achieve close to maximal GRα saturation, followed by a continuous infusion to maintain high levels of response throughout the treatment period. In addition, patients receiving similar GC doses may experience substantial between-patient variability in plasma concentrations affecting clinical response. GC should be dose-adjusted and administered for a duration targeting clinical and laboratory improvement, followed by dose-tapering to achieve gradual recovery of the suppressed hypothalamic–pituitary–adrenal (HPA) axis. These findings have practical clinical relevance. Future RCTs should consider these pharmacological principles in the study design and interpretation of findings. Electronic supplementary material The online version of this article (10.1007/s00134-020-06289-8) contains supplementary material, which is available to authorized users.

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Section: Pharmacological Principles Of Glucocorticoid Actionsmentioning

confidence: 99%

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS

et al. 2020

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“…"Persistent Inflammation, Immunosuppression, and Catabolism Syndrome" (PICS) has been postulated as the underlying pathophysiology of chronic critical illness (CCI) (18,47). About 50% of sepsis patients have a debilitating condition characterized by a self-perpetuating cycle of persistent low-grade systemic inflammation mimicking chronic stress (elevated cortisol) (44,48,49), glucocorticoid resistance, altered hemostasis (50,51), mitochondrial dysfunction (52,53), and accelerated inflamm-aging (9,54), with increased risk for chronic inflammatory systemic diseases (7,55). The evolutionary trade-off between acutely beneficial and chronically harmful homeostatic corrections was the subject of a recent review (7).…”

Section: Innate Immunity and Nuclear Factor-κbmentioning

confidence: 99%

“…After GC binding takes place in the cytoplasm, the activated GC-GRα complex can either (i) bind to several pro-inflammatory transcription factors, or (ii) act as a transcription factor, after translocation into the nucleus and mitochondria (69,82). Glucocorticoids regulation of mitochondrial transcription via activation of mtGRE was the subject of a recent review (53). In pathway (i), the activated GC-GRα complex interacts directly with activated transcription factors NF-κB and AP-1, leading to the transcriptional repression of major downstream proinflammatory factors.…”

Section: Glucocorticoid Receptor-alphamentioning

confidence: 99%

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

Meduri

Chrousos

2020

Front. Endocrinol.

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In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GRα) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GRα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GRα and mitochondria number and function. Present understanding of the activated GC-GRα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GRα interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.

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“…We observed the elevated GR level in the stressed rats only in SOL muscle. A possible mechanism could be linked with the fact that only GR (as opposed to MR) is found in mitochondria, suggesting that GRs drive the direct actions of glucocorticoids on mitochondria [34].…”

Section: Discussionmentioning

confidence: 99%

BST Stimulation Induces Atrophy and Changes in Aerobic Energy Metabolism in Rat Skeletal Muscles—The Biphasic Action of Endogenous Glucocorticoids

Karnia

Myślińska

Dzik

et al. 2020

IJMS

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(1) The primary involvement in stress-induced disturbances in skeletal muscles is assigned to the release of glucocorticoids (GCs). The current study aims to investigate the impact of the biphasic action of the chronic stress response (CSR) induced by the electrical stimulation of the bed nucleus of the stria terminalis (BST) effects on muscle atrophy and aerobic energy metabolism in soleus (SOL) and extensor digitorum longus (EDL) muscles. (2) Male Wistar rats (n = 17) were used. The rats were divided randomly into three groups: the BST two weeks (ST2), four weeks (ST4), and the sham (SHM) electrically stimulated group. The plasma corticosterone (CORT) and irisin concentration were measured. Glucocorticoid and mineralocorticoid receptors (GR and MR), 11β-hydroxysteroid dehydrogenase type 1 and 2 (HSD11B1 and HSD11B2), atrogin-1, and insulin-like growth factor-1 (IGF-1) level were determined in SOL and EDL muscles. Citrate synthase (CS) activity was measured in both muscles. (3) We found elevated plasma concentration of CORT and irisin, raised the level of GR in SOL muscle, and the higher level of MR in both muscles in the ST4 group. The level of HSD11B1 was also higher in the ST4 group compared to the SHM group. Moreover, we observed increased activity of CS in SOL. (4) We suggest that biphasic action of the glucocorticoid induced by the CSR occurs and causes dysregulation of proteins involved in muscle atrophy and aerobic energy metabolism. Our findings potentially contribute to a better understanding of the mechanisms by which GCs and the CSR may regulate muscle atrophy and energy preservation of the red muscle.

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Stress and glucocorticoid receptor regulation of mitochondrial gene expression

Cited by 65 publications

References 65 publications

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS

Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

BST Stimulation Induces Atrophy and Changes in Aerobic Energy Metabolism in Rat Skeletal Muscles—The Biphasic Action of Endogenous Glucocorticoids

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