Dataset Information

Efficacy and safety of ketone ester infusion to prevent muscle weakness in a mouse model of sepsis-induced critical illness.

ABSTRACT: In septic mice, 3-hydroxybutyrate-sodium-salt has shown to partially prevent sepsis-induced muscle weakness. Although effective, the excessive sodium load was toxic. We here investigated whether ketone ester 3-hydroxybutyl-3-hydroxybutanoate (3HHB) was a safer alternative. In a mouse model of abdominal sepsis, the effects of increasing bolus doses of 3HHB enantiomers on mortality, morbidity and muscle force were investigated (n = 376). Next, plasma 3HB^- clearance after bolus D-3HHB was investigated (n = 27). Subsequently, in septic mice, the effect on mortality and muscle force of a continuous D,L-3HHB infusion was investigated (n = 72). In septic mice, as compared with placebo, muscle force was increased at 20 mmol/kg/day L-3HHB and at 40 mmol/kg/day D- and D,L-3HHB. However, severity of illness and mortality was increased by doubling the effective bolus doses. Bolus 3HHB caused a higher 3HB^- plasma peak and slower clearance with sepsis. Unlike bolus injections, continuous infusion of D,L-3HHB did not increase severity of illness or mortality, while remaining effective in improving muscle force. Treatment of septic mice with the ketone ester 3HHB partly prevented muscle weakness. Toxicity of 3HHB administered as bolus was completely avoided by continuous infusion of the same dose. Whether continuous infusion of ketone esters represents a promising intervention to also prevent ICU-acquired weakness in human patients should be investigated.

SUBMITTER: Weckx R

PROVIDER: S-EPMC9217969 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Efficacy and safety of ketone ester infusion to prevent muscle weakness in a mouse model of sepsis-induced critical illness.

Weckx Ruben R Goossens Chloë C Derde Sarah S Pauwels Lies L Vander Perre Sarah S Van den Berghe Greet G Langouche Lies L

Scientific reports 20220622 1

In septic mice, 3-hydroxybutyrate-sodium-salt has shown to partially prevent sepsis-induced muscle weakness. Although effective, the excessive sodium load was toxic. We here investigated whether ketone ester 3-hydroxybutyl-3-hydroxybutanoate (3HHB) was a safer alternative. In a mouse model of abdominal sepsis, the effects of increasing bolus doses of 3HHB enantiomers on mortality, morbidity and muscle force were investigated (n = 376). Next, plasma 3HB<sup>-</sup> clearance after bolus D-3HHB wa ...[more]

PMID: 35732826

Similar Datasets

Project description:IntroductionMuscle ultrasound is emerging as a promising tool in the diagnosis of neuromuscular diseases. The current observational study evaluates the usefulness of muscle ultrasound in patients with severe sepsis for assessment of critical illness polyneuropathy and myopathy (CINM) in the intensive care unit.Methods28 patients with either septic shock or severe sepsis underwent clinical neurological examinations, muscle ultrasound, and nerve conduction studies on days 4 and 14 after onset of sepsis. 26 healthy controls of comparable age underwent clinical neurological evaluation and muscle ultrasound only.Results26 of the 28 patients exhibited classic electrophysiological characteristics of CINM, and all showed typical clinical signs. Ultrasonic echogenicity of muscles was graded semiquantitatively and fasciculations were evaluated in muscles of proximal and distal arms and legs. 75% of patients showed a mean echotexture greater than 1.5, which was the maximal value found in the control group. A significant difference in mean muscle echotexture between patients and controls was found at day 4 and day 14 (both p < 0.001). In addition, from day 4 to day 14, the mean grades of muscle echotexture increased in the patient group, although the values did not reach significance levels (p = 0.085). Controls revealed the lowest number of fasciculations. In the patients group, fasciculations were detected in more muscular regions (lower and upper arm and leg) in comparison to controls (p = 0.08 at day 4 and p = 0.002 at day 14).ConclusionsMuscle ultrasound represents an easily applicable, non-invasive diagnostic tool which adds to neurophysiological testing information regarding morphological changes of muscles early in the course of sepsis. Muscle ultrasound could be useful for screening purposes prior to subjecting patients to more invasive techniques such as electromyography and/or muscle biopsy.Trial registrationGerman Clinical Trials Register, DRKS-ID: DRKS00000642.

Project description:BackgroundCritical illness is hallmarked by severe stress and organ damage. Fibroblast growth factor 21 (FGF21) has been shown to rise during critical illness. FGF21 is a pleiotropic hormone that mediates adaptive responses to tissue injury and repair in various chronic pathological conditions. Animal studies have suggested that the critical illness-induced rise in FGF21 may to a certain extent protect against acute lung, liver, kidney and brain injury. However, FGF21 has also been shown to mediate fasting-induced loss of muscle mass and force. Such loss of muscle mass and force is a frequent problem of critically ill patients, associated with adverse outcome. In the present study, we therefore investigated whether the critical illness-induced acute rise in FGF21 is muscle-protective or rather contributes to the pathophysiology of critical illness-induced muscle weakness.MethodsIn a catheterised mouse model of critical illness induced by surgery and sepsis, we first assessed the effects of genetic FGF21 inactivation, and hence the inability to acutely increase FGF21, on survival, body weight, muscle wasting and weakness, and markers of muscle cellular stress and dysfunction in acute (30 h) and prolonged (5 days) critical illness. Secondly, we assessed whether any effects were mirrored by supplementing an FGF21 analogue (LY2405319) in prolonged critical illness.ResultsFGF21 was not required for survival of sepsis. Genetic FGF21 inactivation aggravated the critical illness-induced body weight loss (p = 0.0003), loss of muscle force (p = 0.03) and shift to smaller myofibers. This was accompanied by a more pronounced rise in markers of endoplasmic reticulum stress in muscle, without effects on impairments in mitochondrial respiratory chain enzyme activities or autophagy activation. Supplementing critically ill mice with LY2405319 did not affect survival, muscle force or weight, or markers of muscle cellular stress/dysfunction.ConclusionsEndogenous FGF21 is not required for sepsis survival, but may partially protect muscle force and may reduce cellular stress in muscle. Exogenous FGF21 supplementation failed to improve muscle force or cellular stress, not supporting the clinical applicability of FGF21 supplementation to protect against muscle weakness during critical illness.

Project description:BackgroundSepsis-induced muscle atrophy leads to prolonged physical dysfunction. Although the interaction of muscle atrophy and macrophage has been reported in sepsis, the role of neutrophils in muscle atrophy has not been thoroughly investigated. This study sought to investigate the long-term changes in muscle-localized neutrophils after sepsis induction and their possible role in sepsis.MethodsSepsis was induced in seven-week-old male C57BL/6J mice 8-12 (cecal slurry [CS] model) via intraperitoneal injection of 1 mg/g cecal slurry. The percentage change in body weight and grip strength was evaluated. The tibialis anterior muscles were dissected for microscopic examination of the cross-sectional area of myofibers or Fluorescence-activated cell sorting (FACS) analysis of immune cells. These changes were evaluated in the following conditions: (1) Longitudinal change until day 61, (2) CS concentration-dependent change on day 14 at the low (0.3 mg/g), middle (1.0 mg/g), and high (2.0 mg/g) concentrations, and (3) CS mice on day 14 treated with an anti-Ly6G antibody that depletes neutrophils.ResultsBody weight and grip strength were significantly lower in the CS model until day 61 (body weight: 123.1% ± 1.8% vs. 130.3% ± 2.5%, p = 0.04; grip strength: 104.5% ± 3.8% vs. 119.3% ± 5.3%, p = 0.04). Likewise, cross-sectional muscle area gradually decreased until day 61 from the CS induction (895.6 [606.0-1304.9] μm2 vs. 718.8 [536.2-937.0] μm2, p < 0.01). The number of muscle-localized neutrophils increased from 2.3 ± 0.6 cell/mg on day 0 to 22.2 ± 13.0 cell/mg on day 14, and decreased thereafter. In terms of CS concentration-dependent change, cross-sectional area was smaller (484.4 ± 221.2 vs. 825.8 ± 436.2 μm2 [p < 0.001]) and grip strength was lower (71.4% ± 12.8% vs. 116.3% ± 7.4%, p = 0.01) in the CS High group compared with the control, with increased neutrophils (p = 0.03). Ly6G-depleted mice demonstrated significant increase of muscle cross-sectional area and grip strength compared with control mice (p < 0.01).ConclusionsSepsis causes infiltration of neutrophils in muscles, leading to muscle atrophy and weakness. Depletion of neutrophils in muscle reverses sepsis-induced muscle atrophy and weakness. These results suggest that neutrophils may play a critical role in sepsis-induced muscle atrophy and weakness.

Dataset Information

Efficacy and safety of ketone ester infusion to prevent muscle weakness in a mouse model of sepsis-induced critical illness.

Publications

Efficacy and safety of ketone ester infusion to prevent muscle weakness in a mouse model of sepsis-induced critical illness.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets