Adipose tissue protects against sepsis-induced muscle weakness in mice: from lipolysis to ketones

Goossens, Chloë; Weckx, Ruben; Derde, Sarah; Dufour, Thomas; Perre, Sarah Vander; Pauwels, Lies; Thiessen, Steven; Veldhoven, Paul P. Van; Berghe, Greet Van den; Langouche, Lies

doi:10.1186/s13054-019-2506-6

Cited by 62 publications

(86 citation statements)

References 75 publications

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“…Plasma concentrations of 3-HB and insulin were determined on day 2 in PICU or on day 1 for patients with a shorter PICU stay. Boxes show median and IQR, whiskers 10th and 90th percentile the development of muscle weakness [17]. Alternatively, 3HB may act through enhanced autophagy-driven cellular housekeeping [10], a pathway that was previously shown to be activated by late-PN in critically ill adults [13].…”

Section: Discussionmentioning

confidence: 99%

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Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

et al. 2020

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Background: In critically ill children, omitting early use of parenteral nutrition (late-PN versus early-PN) reduced infections, accelerated weaning from mechanical ventilation, and shortened PICU stay. We hypothesized that fasting-induced ketogenesis mediates these benefits. Methods: In a secondary analysis of the PEPaNIC RCT (N = 1440), the impact of late-PN versus early-PN on plasma 3-hydroxybutyrate (3HB), and on blood glucose, plasma insulin, and glucagon as key ketogenesis regulators, was determined for 96 matched patients staying ≥ 5 days in PICU, and the day of maximal 3HB-effect, if any, was identified. Subsequently, in the total study population, plasma 3HB and late-PN-affected ketogenesis regulators were measured on that average day of maximal 3HB effect. Multivariable Cox proportional hazard and logistic regression analyses were performed adjusting for randomization and baseline risk factors. Whether any potential mediator role for 3HB was direct or indirect was assessed by further adjusting for ketogenesis regulators. Results: In the matched cohort (n = 96), late-PN versus early-PN increased plasma 3HB throughout PICU days 1-5 (P < 0.0001), maximally on PICU day 2. Also, blood glucose (P < 0.001) and plasma insulin (P < 0.0001), but not glucagon, were affected. In the total cohort (n = 1142 with available plasma), late-PN increased plasma 3HB on PICU day 2 (day 1 for shorter stayers) from (median [IQR]) 0.04 [0.04-0.04] mmol/L to 0.75 [0.04-2.03] mmol/L (P < 0.0001). The 3HB effect of late-PN statistically explained its impact on weaning from mechanical ventilation (P = 0.0002) and on time to live PICU discharge (P = 0.004). Further adjustment for regulators of ketogenesis did not alter these findings. Conclusion: Withholding early-PN in critically ill children significantly increased plasma 3HB, a direct effect that statistically mediated an important part of its outcome benefit.

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Section: Discussionmentioning

confidence: 99%

“…Ketone bodies or ketogenic diets have shown to increase endurance in healthy athletes [15] and to induce beneficial effects in animal models of brain injury [16]. Moreover, in a mouse model of sepsis, a ketogenic PN formula and supplementation of PN with 3HB have shown to protect against the development of muscle weakness [17].…”

Section: Introductionmentioning

confidence: 99%

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

et al. 2020

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“…Although clinical data are currently still lacking, a series of studies in mice, performed in search of mechanisms underlying protection against ICU-acquired weakness by obesity, revealed that increasing the availability of ketone bodies, either through stimulation of endogenous ketogenesis or through infusion of exogenous ketones, protected against sepsis-induced muscle weakness [103]. This interesting finding still needs to be further explored in patients.…”

Section: Avoiding Early Parenteral Nutritionmentioning

confidence: 99%

ICU-acquired weakness

2020

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Critically ill patients often acquire neuropathy and/or myopathy labeled ICU-acquired weakness. The current insights into incidence, pathophysiology, diagnostic tools, risk factors, short-and long-term consequences and management of ICU-acquired weakness are narratively reviewed. PubMed was searched for combinations of "neuropathy", "myopathy", "neuromyopathy", or "weakness" with "critical illness", "critically ill", "ICU", "PICU", "sepsis" or "burn". ICU-acquired weakness affects limb and respiratory muscles with a widely varying prevalence depending on the study population. Pathophysiology remains incompletely understood but comprises complex structural/functional alterations within myofibers and neurons. Clinical and electrophysiological tools are used for diagnosis, each with advantages and limitations. Risk factors include age, weight, comorbidities, illness severity, organ failure, exposure to drugs negatively affecting myofibers and neurons, immobility and other intensive care-related factors. ICU-acquired weakness increases risk of in-ICU, in-hospital and long-term mortality, duration of mechanical ventilation and of hospitalization and augments healthcare-related costs, increases likelihood of prolonged care in rehabilitation centers and reduces physical function and quality of life in the long term. RCTs have shown preventive impact of avoiding hyperglycemia, of omitting early parenteral nutrition use and of minimizing sedation. Results of studies investigating the impact of early mobilization, neuromuscular electrical stimulation and of pharmacological interventions were inconsistent, with recent systematic reviews/meta-analyses revealing no or only low-quality evidence for benefit. ICU-acquired weakness predisposes to adverse short-and long-term outcomes. Only a few preventive, but no therapeutic, strategies exist. Further mechanistic research is needed to identify new targets for interventions to be tested in adequately powered RCTs.

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“…Skeletal muscle and adipose tissue are two key metabolic tissues that exhibit major functional and histological changes in sepsis survivors. 6 Analogous to cachexia syndrome, muscle and fat wasting post-sepsis can result in many detrimental outcomes that directly impact long-term mortality and quality of life including decreased locomotive capacity, respiratory dysfunction, and altered systemic metabolism. 7,8 Fundamentally, tissue homeostasis involves balancing pro-growth anabolic processes with breakdown-associated catabolism.…”

Section: Introductionmentioning

confidence: 99%

Single‐cell deconstruction of post‐sepsis skeletal muscle and adipose tissue microenvironments

Cho

Schmitt

Dasgupta

et al. 2020

J cachexia sarcopenia muscle

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Background Persistent loss of skeletal muscle mass and function as well as altered fat metabolism are frequently observed in severe sepsis survivors. Studies examining sepsis-associated tissue dysfunction from the perspective of the tissue microenvironment are scarce. In this study, we comprehensively assessed transcriptional changes in muscle and fat at single-cell resolution following experimental sepsis induction. Methods Skeletal muscle and visceral white adipose tissue from control mice or mice 1 day or 1 month following faecal slurry-induced sepsis were used. Single cells were mechanically and enzymatically prepared from whole tissue, and viable cells were further isolated by fluorescence activated cell sorting. Droplet-based single-cell RNA-sequencing (scRNA-seq; 10× Genomics) was used to generate single-cell gene expression profiles of thousands of muscle and fat-resident cells. Bioinformatics analyses were performed to identify and compare individual cell populations in both tissues. Results In skeletal muscle, scRNA-seq analysis classified 1438 single cells into myocytes, endothelial cells, fibroblasts, mesenchymal stem cells, macrophages, neutrophils, T-cells, B-cells, and dendritic cells. In adipose tissue, scRNA-seq analysis classified 2281 single cells into adipose stem cells, preadipocytes, endothelial cells, fibroblasts, macrophages, dendritic cells, Bcells, T-cells, NK cells, and gamma delta T-cells. One day post-sepsis, the proportion of most non-immune cell populations was decreased, while immune cell populations, particularly neutrophils and macrophages, were highly enriched. Proportional changes of endothelial cells, neutrophils, and macrophages were validated using faecal slurry and cecal ligation and puncture models. At 1 month post-sepsis, we observed persistent enrichment/depletion of cell populations and further uncovered a cell-type and tissue-specific ability to return to a baseline transcriptomic state. Differential gene expression analyses revealed key genes and pathways altered in post-sepsis muscle and fat and highlighted the engagement of infection/inflammation and tissue damage signalling. Finally, regulator analysis identified gonadotropin-releasing hormone and Bay 11-7082 as targets/compounds that we show can reduce sepsis-associated loss of lean or fat mass. Conclusions These data demonstrate persistent post-sepsis muscle and adipose tissue disruption at the single-cell level and highlight opportunities to combat long-term post-sepsis tissue wasting using bioinformatics-guided therapeutic interventions.

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Adipose tissue protects against sepsis-induced muscle weakness in mice: from lipolysis to ketones

Cited by 62 publications

References 75 publications

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

Effect of withholding early parenteral nutrition in PICU on ketogenesis as potential mediator of its outcome benefit

ICU-acquired weakness

Single‐cell deconstruction of post‐sepsis skeletal muscle and adipose tissue microenvironments

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