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The physical and biological characterization of a frail mouse model.

ABSTRACT: BACKGROUND:The development of animal models that approximate human frailty is necessary to facilitate etiologic and treatment-focused frailty research. The genetically altered IL-10(tm/tm) mouse does not express the antiinflammatory cytokine interleukin 10 (IL-10) and is, like frail humans, more susceptible to inflammatory pathway activation. We hypothesized that with increasing age, IL-10(tm/tm) mice would develop physical and biological characteristics similar to those of human frailty as compared to C57BL/6J control mice. METHODS:Strength, activity, serum IL-6, and skeletal muscle gene expression were compared between age-matched and gender-matched IL-10(tm/tm) mice on C57BL/6J background and C57BL/6J control mice using a longitudinal design for physical characteristics and cross-sectional design for biological characteristics. RESULTS:Strength levels declined significantly faster in IL-10(tm/tm) compared to control mice with increasing age. Serum IL-6 levels were significantly higher in older compared to younger IL-10(tm/tm) mice and were significantly higher in older IL-10(tm/tm) compared to age- and gender-matched C57BL/6J control mice. One hundred twenty-five genes, many related to mitochondrial biology and apoptosis, were differentially expressed in skeletal muscle between 50-week-old IL-10(tm/tm) and 50-week-old C57BL/6J mice. No expression differences between IL-10(tm/tm) age groups were identified by quantitative polymerase chain reaction. CONCLUSION:These physical and biological findings suggest that the IL-10(tm/tm) mouse develops inflammation and strength decline consistent with human frailty at an earlier age compared to C57BL/6J control type mice. This finding provides rationale for the further development and utilization of the IL-10(tm/tm) mouse to study the biological basis of frailty.

SUBMITTER: Walston J

PROVIDER: S-EPMC5903428 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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The physical and biological characterization of a frail mouse model.

Walston Jeremy J Fedarko Neal N Yang Huanle H Leng Sean S Beamer Brock B Espinoza Sara S Lipton Anne A Zheng Howie H Becker Kevin K

The journals of gerontology. Series A, Biological sciences and medical sciences 20080401 4

<h4>Background</h4>The development of animal models that approximate human frailty is necessary to facilitate etiologic and treatment-focused frailty research. The genetically altered IL-10(tm/tm) mouse does not express the antiinflammatory cytokine interleukin 10 (IL-10) and is, like frail humans, more susceptible to inflammatory pathway activation. We hypothesized that with increasing age, IL-10(tm/tm) mice would develop physical and biological characteristics similar to those of human frailty ...[more]

PMID: 18426963

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Project description:IntroductionPhysical activity (PA) is important for healthy ageing. Better insight into objectively measured PA levels in older adults is needed, since most previous studies employed self-report measures for PA assessment, which are associated with overestimation of PA.AimThis study aimed to provide insight in objectively measured indoor and outdoor PA of older adults, and in PA differences by frailty levels.MethodsData were collected among non-frail (N = 74) and frail (N = 10) subjects, aged 65 to 89 years. PA, measured for seven days with accelerometers and GPS-devices, was categorized into three levels of intensity (sedentary, light, and moderate-to-vigorous PA).ResultsOlder adults spent most time in sedentary and light PA. Subjects spent 84.7%, 15.1% and 0.2% per day in sedentary, light and moderate-to-vigorous PA respectively. On average, older adults spent 9.8 (SD 23.7) minutes per week in moderate-to-vigorous activity, and 747.0 (SD 389.6) minutes per week in light activity. None of the subjects met the WHO recommendations of 150 weekly minutes of moderate-to-vigorous PA. Age-, sex- and health status-adjusted results revealed no differences in PA between non-frail and frail older adults. Subjects spent significantly more sedentary time at home, than not at home. Non-frail subjects spent significantly more time not at home during moderate-to-vigorous activities, than at home.ConclusionsObjective assessment of PA in older adults revealed that most PA was of light intensity, and time spent in moderate-to-vigorous PA was very low. None of the older adults met the World Health Organization recommendations for PA. These levels of MVPA are much lower than generally reported based on self-reported PA. Future studies should employ objective methods, and age specific thresholds for healthy PA levels in older adults are needed. These results emphasize the need for effective strategies for healthy PA levels for the growing proportion of older adults.

Project description:Globally, the proportion of older adults is increasing. Older people face chronic conditions such as sarcopenia and functional decline, which are often associated with disability and frailty. Proteomics assay of potential serum biomarkers of frailty in older adults. Older adults were divided into non-frail and frail groups (n = 6 each; 3 males in each group) in accordance with the Chinese-Canadian Study of Health and Aging Clinical Frailty Scale. Adults were measured for grip power and the 6-min walk test for physical activity, and venous blood was sampled after adults fasted for 8 h. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used for proteomics assay. The groups were compared for levels of biomarkers by t test and Pearson correlation analysis. Non-frail and frail subjects had mean age 77.5±0.4 and 77.7±1.6 years, mean height 160.5±1.3 and 156.6±2.9 cm and mean weight 62.5±1.2 and 62.8±2.9 kg, respectively. Physical activity level was lower for frail than non-frail subjects (grip power: 13.8±0.4 vs 26.1±1.2 kg; 6-min walk test: 215.2±17.2 vs 438.3±17.2 m). Among 226 proteins detected, for 31, serum levels were significantly higher for frail than non-frail subjects; serum levels of Ig kappa chain V-III region WOL, COX7A2, and albumin were lower. The serum levels of ANGT, KG and AT were 2.05-, 1.76- and 2.22-fold lower (all p < 0.05; Figure 1A, 2A and 3A) for non-frail than frail subjects and were highly correlated with grip power (Figure 1B, 2B and 3B). Our study found that ANGT, KG and AT levels are known to increase with aging, so degenerated vascular function might be associated with frailty. In total, 226 proteins were revealed proteomics assay; levels of angiotensinogen (ANGT), kininogen-1 (KG) and antithrombin III (AT) were higher in frail than non-frail subjects (11.26±2.21 vs 5.09±0.74; 18.42±1.36 vs 11.64±1.36; 22.23±1.64 vs 9.52±0.95, respectively, p < 0.05). These 3 factors were highly correlated with grip power (p < 0.05), with higher correlations between grip power and serum levels of ANGT (r = -0.89), KG (r = -0.90), and AT (r = -0.84). In conclusion, this is the first study to demonstrate a serum proteomic profile characteristic of frailty in older adults. Serum ANGT, KG and AT levels could be potential biomarkers for monitoring the development and progression of frailty in older adults.

Project description:Synthetic short interfering RNA (siRNA) oligonucleotides can trigger the RNA interference pathway and lead to selective gene silencing. Despite considerable enthusiasm and investment, formidable challenges remain that may deter translating this breakthrough discovery into clinical applications. In particular, the development of efficient, nontoxic, nonimmunogenic methods for delivering siRNA in vivo has proven to be exceptionally challenging. Thorough analysis of the relationship between the structure and function of siRNA carrier systems, both in isolation and in complex with RNA, will facilitate the design of efficient nonviral siRNA delivery vehicles. In this study, we explore the relationship between the physicochemical characteristics and the biological activity of "lipitoid" compounds as potent siRNA delivery vehicles. Lipitoids are cationic peptidomimetic oligomers incorporating a peptoid and a phospholipid moiety. Lipitoids can associate with siRNA oligonucleotides and self-assemble into spherical lipitoid-based nanoparticles (LNPs), with dimensions that are dependent upon the medium and the stoichiometric ratio between the cationic monomers of the lipitoid and anionic siRNA oligonucleotides. The morphology, gene silencing efficiency, and cytotoxicity of the siRNA-loaded LNPs are similarly sensitive to the stoichiometry of the complexes. The medium in which the LNPs are formed affects the assembled cargo particles' characteristics such as particle size, transfection efficiency, and stability. Formation of the LNPs in the biological, serum-free medium OptiMEM resulted in LNPs an order of magnitude larger than LNPs formed in water, and were twice as efficient in siRNA transfection compared to LNPs formed in water. Inhibitor studies were conducted to elucidate the efficiency of lysosomal escape and the uptake mechanism of the siRNA-loaded LNPs. Our results suggest that these lipitoid-based, siRNA-loaded spherical LNPs are internalized through a lipid raft-dependent and dynamin-mediated pathway, circumventing endosomal and lysosomal encapsulation. The lipitoid-siRNA nanospheres proved to be suitable platforms for investigating the critical parameters determining the efficiency of transfection agents, revealing the necessity for conducting characterization studies in biological media. The investigation of the LNP internalization pathway points to an alternative uptake route that bypasses the lysosome, explaining the surprisingly high efficiency of LNPs and suggesting that the uptake mechanism should be probed rather than assumed for the next generation of rationally designed transfection agents.

Project description:Purpose: Mitochondrial diseases (MD) are among the most prevalent neuromuscular disorders. Unfortunately, no curative treatment is yet available. This study analyzed the effects of exercise training in an animal model of respiratory chain complex I deficiency, the Harlequin (Hq) mouse, which replicates the clinical features of this condition. Methods: Male heterozygous Harlequin (Hq/Y) mice were assigned to an "exercise" (n = 10) or a "sedentary" control group (n = 11), with the former being submitted to an 8 week combined exercise training intervention (aerobic + resistance training performed five times/week). Aerobic fitness, grip strength, and balance were assessed at the beginning and at the end of the intervention period in all the Hq mice. Muscle biochemical analyses (with results expressed as percentage of reference data from age/sex-matched sedentary wild-type mice [n = 12]) were performed at the end of the aforementioned period for the assessment of major molecular signaling pathways involved in muscle anabolism (mTOR activation) and mitochondrial biogenesis (proliferator activated receptor gamma co-activator 1α [PGC-1α] levels), and enzyme activity and levels of respiratory chain complexes, and antioxidant enzyme levels. Results: Exercise training resulted in significant improvements in aerobic fitness (-33 ± 13 m and 83 ± 43 m for the difference post- vs. pre-intervention in total distance covered in the treadmill tests in control and exercise group, respectively, p = 0.014) and muscle strength (2 ± 4 g vs. 17 ± 6 g for the difference post vs. pre-intervention, p = 0.037) compared to the control group. Higher levels of ribosomal protein S6 kinase beta-1 phosphorylated at threonine 389 (156 ± 30% vs. 249 ± 30%, p = 0.028) and PGC-1α (82 ± 7% vs. 126 ± 19% p = 0.032) were observed in the exercise-trained mice compared with the control group. A higher activity of respiratory chain complexes I (75 ± 4% vs. 95 ± 6%, p = 0.019), III (79 ± 5% vs. 97 ± 4%, p = 0.031), and V (77 ± 9% vs. 105 ± 9%, p = 0.024) was also found with exercise training. Exercised mice presented with lower catalase levels (204 ± 22% vs. 141 ± 23%, p = 0.036). Conclusion: In a mouse model of MD, a training intervention combining aerobic and resistance exercise increased aerobic fitness and muscle strength, and mild improvements were found for activated signaling pathways involved in muscle mitochondrial biogenesis and anabolism, OXPHOS complex activity, and redox status in muscle tissue.

Project description:BackgroundListeria monocytogenes is a common cause of bacterial meningitis. We developed an animal model of listerial meningitis.MethodsIn survival studies, C57BL/6 mice received intracisternal injections with different L. monocytogenes sequence type 1 (ST1) colony forming units per milliliter (CFU; n = 48, 105, 106, 107, 108, and 109 CFU/ml). Second, mice were inoculated with 108 CFU/ml ST1 and sacrificed at 6 h and 24 h (n = 12/group). Outcome parameters were clinical score, CFUs, cyto- and chemokine levels, and brain histopathology. Third, 84 mice were inoculated (109 CFU/ml ST1) to determine optimal antibiotic treatment with different doses of amoxicillin and gentamicin. Fourth, mice were inoculated with 109 CFU/ml ST1, treated with amoxicillin, and sacrificed at 16 h and 24 h (n = 12/group) for outcome assessment. Finally, time point experiments were repeated with ST6 (n = 24/group).ResultsMedian survival time for inoculation with 108 and 109 CFU/ml ST1 was 46 h and 40 h; lower doses of bacteria led to minimal clinical signs of disease. Brain levels of IL-6, IL-17A, and IFN-γ were elevated at 24 h, and IL-1β, IL-6, IL-10, IFN-γ, and TNF-α were elevated in blood at 6 h and 24 h. Histopathology showed increased meningeal infiltration, vascular inflammation of meningeal vessels, hemorrhages, and ventriculitis. In the treatment model, brain levels of IL-6 and IL-17A and blood levels of IL-6 and IFN-γ were elevated. Compared to ST6, infection with ST1 led initially to higher levels of IL-1β and TNF-α in blood and more profound neuropathological damage. At 16 h post inoculation, IL-1β, IL-10, and TNF-α in blood and IL-6, IL17A, TNF-α, and IFN-γ levels in brain were higher in ST1 compared to ST6 without differences in CFUs between STs. At 24 h, neuropathology score was higher in ST1 compared to ST6 (p = 0.002) infected mice.ConclusionsWe developed and validated a murine model of listerial meningitis. ST1-infected mice had a more severe inflammatory response and brain damage as compared to ST6-infected mice.

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The physical and biological characterization of a frail mouse model.

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The physical and biological characterization of a frail mouse model.

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