A mouse is not a rat is not a man: species-specific metabolic responses to sepsis - a nail in the coffin of murine models for critical care research?

Radermacher, Peter; Haouzi, Philippe

doi:10.1186/2197-425x-1-7

Cited by 33 publications

(26 citation statements)

References 32 publications

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“…An important limitation of our study is the use of a mouse model to study ICU-acquired weakness. Hence, translation to the human patient should be done with caution, given several species-specific differences [68]. Nevertheless, the model of sepsis-induced muscle wasting and weakness resembles human ICU-acquired weakness.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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Background: ICU-acquired weakness is a debilitating consequence of prolonged critical illness that is associated with poor outcome. Recently, premorbid obesity has been shown to protect against such illness-induced muscle wasting and weakness. Here, we hypothesized that this protection was due to increased lipid and ketone availability. Methods: In a centrally catheterized, fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis, we compared markers of lipolysis and fatty acid oxidation in lean and obese septic mice (n = 117). Next, we compared markers of muscle wasting and weakness in septic obese wild-type and adipose tissue-specific ATGL knockout (AAKO) mice (n = 73), in lean septic mice receiving either intravenous infusion of lipids or standard parenteral nutrition (PN) (n = 70), and in lean septic mice receiving standard PN supplemented with either the ketone body 3hydroxybutyrate or isocaloric glucose (n = 49). Results: Obese septic mice had more pronounced lipolysis (p ≤ 0.05), peripheral fatty acid oxidation (p ≤ 0.05), and ketogenesis (p ≤ 0.05) than lean mice. Blocking lipolysis in obese septic mice caused severely reduced muscle mass (32% loss vs. 15% in wild-type, p < 0.001) and specific maximal muscle force (59% loss vs. 0% in wild-type; p < 0.001). In contrast, intravenous infusion of lipids in lean septic mice maintained specific maximal muscle force up to healthy control levels (p = 0.6), whereas this was reduced with 28% in septic mice receiving standard PN (p = 0.006). Muscle mass was evenly reduced with 29% in both lean septic groups (p < 0.001). Lipid administration enhanced fatty acid oxidation (p ≤ 0.05) and ketogenesis (p < 0.001), but caused unfavorable liver steatosis (p = 0.01) and a deranged lipid profile (p ≤ 0.01). Supplementation of standard PN with 3-hydroxybutyrate also attenuated specific maximal muscle force up to healthy control levels (p = 0.1), but loss of muscle mass could not be prevented (25% loss in both septic groups; p < 0.001). Importantly, this intervention improved muscle regeneration markers (p ≤ 0.05) without the unfavorable side effects seen with lipid infusion. Conclusions: Obesity-induced muscle protection during sepsis is partly mediated by elevated mobilization and metabolism of endogenous fatty acids. Furthermore, increased availability of ketone bodies, either through ketogenesis or through parenteral infusion, appears to protect against sepsis-induced muscle weakness also in the lean.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…However, a mouse is not a man. The scale, growth pattern, and cell biology of mouse are highly different from human [ 49 , 50 ]. Besides, as we observed in this study, the distribution of myofiber types in mice is largely different from that in human.…”

Section: Discussionmentioning

confidence: 99%

Ratio of Creatine Kinase to Alanine Aminotransferase as a Biomarker of Acute Liver Injury in Dystrophinopathy

Wang

Chen

et al. 2018

Disease Markers

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Objective To investigate the ratios of creatine kinase (CK) to aminotransferases as biomarkers of acute liver injury in dystrophinopathy. Methods C57 and mdx (dystrophic) mice were treated with a hepatotoxic reagent D-galactosamine (D-GalN). The degrees of liver and muscle injury were assessed using histological examinations. To examine whether serum CK-adjusted aminotransferase levels could indicate liver status in dystrophic mice, the CK/alanine aminotransferase (ALT) and CK/aspartate aminotransferase (AST) ratios were analyzed. Furthermore, we enrolled 658 male patients with dystrophinopathy and 378 male patients without muscle and liver injury as control, whose serum ALT, AST, and CK levels were examined. Results Animal experiments indicated that D-GalN treatment could induce acute liver injury but not muscle injury. Additionally, D-GalN decreased the CK/ALT and CK/AST ratios in both C57 mice and mdx mice (P < 0.001). However, there was an overlap of the CK/AST ratio between dystrophic mice with and without acute liver injury. In patients with dystrophinopathy, CK-adjusted ALT diminished the variability associated with age, genotype, clinical phenotype, and motor function (P > 0.05). Conclusions CK/ALT is a potential biomarker for the differential evaluation of acute liver injury in dystrophic mice, which highlights the value to further evaluate the practice of CK/ALT in dystrophinopathy patients.

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“…While there is dissenting debate that animal-based research has been unable to predict human response to drugs because animals and humans have different evolutionary trajectories, the alternative view is that animal models should be genetically closer to that of humans to be relevant [32]. Observations from small animal models may not be relevant in humans, for instance, current evidence points out that mouse models are remote from human conditions [32,33]. The body size similarities, repeated sampling and the opportunity for continuous invasive monitoring are some of the major benefits of large animal experimental models [34].…”

Section: Perspectivesmentioning

confidence: 88%

The recognition of LpxC inhibitors as potential antibiotics could revolutionise the management of sepsis in veterinary patients if their unknown biological properties are widely evaluated in suitable animal models

Chemonges

2014

International Journal of Veterinary Science and Medicine

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The recognition of LpxC inhibitors as potential antibiotics could revolutionise the management of sepsis in veterinary patients if their unknown biological properties are widely evaluated in suitable animal models Abstract Current studies continue to show that UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetyl glucosamine deacetylase (LpxC) inhibitors such as pyridone methylsulfone hydroxymate 1 and 2a (LpxC-2) downregulate the lethal effects of sepsis initiated by multi-drug resistant Gram-negative bacteria (MDRGNB) by curtailing lipopolysaccharide (LPS) synthesis in murine models. Sepsis initiated by MDRGNB is a leading cause of shock and systemic inflammatory response syndrome (SIRS) in intensive care unit (ICU) patients. To date however, the biological effects of LpxC-2 and related molecules in companion and production animals remain largely unexplored in vivo and are therefore unknown. Such studies would be greatly informative in the expectation of LpxC-2 progressing to human clinical trials. Mechanistic studies to interrogate this novel antibiotic candidate in realistic and clinically applicable large animal models of veterinary importance are sorely lacking. To be relevant, the physiology of the chosen animal models should closely match that of humans such as ovine or porcine, or even better, non-human primate based studies, as they are more genetically similar to humans than murine models. If discovered to have subtle or negligible side effects, LpxC-2 could have a future role in the treatment and management of MDRGNB-induced infections that lead to sepsis in both animals and humans. More research is indicated on LpxC-2 use in many veterinary species, as data remains scarce.

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A mouse is not a rat is not a man: species-specific metabolic responses to sepsis - a nail in the coffin of murine models for critical care research?

Cited by 33 publications

References 32 publications

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

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

Ratio of Creatine Kinase to Alanine Aminotransferase as a Biomarker of Acute Liver Injury in Dystrophinopathy

The recognition of LpxC inhibitors as potential antibiotics could revolutionise the management of sepsis in veterinary patients if their unknown biological properties are widely evaluated in suitable animal models

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