Gait Analyses in Mice: Effects of Age and Glutathione Deficiency

Mock, J. Thomas; Knight, Sherilynn G; Vann, Philip; Wong, Jessica; Davis, Delaney L; Forster, Michael J.; Sumien, Nathalie

doi:10.14336/ad.2017.0925

Cited by 12 publications

(13 citation statements)

References 56 publications

(65 reference statements)

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“…This might be ascribed to the particularly stressful MWM conditions, lowering its inter-individual sensitivity for aged animals [54,55]. Our CatWalk analysis also supports verapamil's rejuvenating effect on senile sensorimotor abnormalities while adding further information to the existing knowledge on age-related gait changes in preclinical rodent models [56].…”

Section: Discussionsupporting

confidence: 66%

TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

Ismael¹,

Nasoohi²,

Yoo³

et al. 2020

Preprint

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Background Immune system hypersensitivity with aging is believed to contribute to mental frailty in elderlies. This is postulated to arise from accumulation of oxidative molecular patterns. Solid evidences delineates thioredoxin interacting protein (TXNIP), an inducible protein involved in oxidative stress, is essential for NOD-like receptor pyrin domain containing-3 (NLRP3)-inflammasome activation which intimately connects “inflammaging” to senile cognitive decline. This study aims to fundamentally explore the plausible involvement of TXNIP/NLRP3 inflammasome pathway in senile dementia and the typical Alzhemier’s disease. Methods In experimental studies cerebral samples from gender-matched mice were compared for TXNIP/NLRP3 inflammasome activation and klotho depletion, through immunoblotting and immunostaining in different life span points. In aged males, genetic or pharmacological ablation of TXNIP were then used to determine effects on cognitive decline and sensorimotor frailty in morris water maze, novel object recognition test and gait control analysis. Immunoblotting/staining experiments were also performed on human postmortem aged hippocampal specimens and 5XFAD transgenic mice, to ultimately address Alzheimer’s disease (AD) as the most age related dementia. Results According to our preclinical studies, cerebral TXNIP was significantly upregulated in aged animals, paralleled by the NLRP3-inflammasome over-activity in both sexes, and closely associated klotho depletion in aged males. TXNIP knock-out reversed age-related NLRP3-hyperactivity and enhanced thioredoxin (TRX) levels in aged brains. Further, pharmacological TXNIP inhibition replicated the TXNIP/NLRP3-inflammasome downregulation in aged animals, with FOXO-1 and mTOR upregulation. These alterations concurred with substantial improvements in both cognitive and sensorimotor abilities. Moreover, our immunostaining shows a significant increase of TXNIP in transgenic 5XFAD mice brain and TXNIP/NLRP3-inflammasome activity in AD human postmortem hippocampal specimens, in proximity of p-tau tangles and β-amyloid plaques. Conclusion Together, these findings substantiate the pivotal role of TXNIP to drive inflammging in parallel with klotho depletion and functional decline. TXNIP co-localization with hallmarks of AD pathology is further supportive of potential mechanistic links between TXNIP and AD. Unraveling new information on upstream pathways, these data support modulating thioredoxin system as a potential approach to decelerate senile frailty.

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Section: Discussionsupporting

confidence: 66%

TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

Ismael¹,

Nasoohi²,

Yoo³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Prior studies focused on male mice ( Bair et al, 2019 ; Tarantini et al, 2019 ) or combined cohorts ( Zhang et al, 2014 ). One study in which male and female mice in different age groups were compared did not reveal sex differences in average speed, cycle duration (sum of swing time and stance time), base or swing speed, but that study did not have a longitudinal design and mice were being followed up to old age only (17 months; Mock et al, 2018 ). Furthermore, the latter study did not control for changes in speed, as discussed above.…”

Section: Discussionmentioning

confidence: 99%

“…To separate changes in walking style from a decline in gait speed alone, measurements of spatial and temporal gait metrics can be helpful ( Wilson et al, 2019 ). While there are many valid methods to capture gait metrics in human or animal models, the challenge lies in the interpretation of changes in gait metrics in the setting of declining speed: key gait metrics that dictate speed, i.e., stride length, stance time and swing time and their derivatives, change as a function of speed and do so independently ( Figure 1 ; Broom et al, 2017 ; Mock et al, 2018 ). This problem is further magnified when datasets are averaged.…”

Section: Introductionmentioning

confidence: 99%

“…This problem is further magnified when datasets are averaged. For example, recent studies in mice reported age-related changes in average cadence ( Bair et al, 2019 ; Tarantini et al, 2019 ) or the inverse, cycle duration ( Mock et al, 2018 ). However, as gait speed declined from running and trotting speeds to trotting or slower speeds and as cadence decreases (or cycle duration increases) as a function of speed, it remains unclear whether these results were due to the decline in speed or represented a change in gait style.…”

Section: Introductionmentioning

confidence: 99%

“…Using this gait signature approach, the primary aim of this study was to determine whether age-related slowing of walking gait is accompanied by fundamental changes in gait style ( Figure 1 ) in the commonly used C57BL/6J strain. We enhanced the translational relevance, by employing an adapted walkway to capture walking gait, rather than faster trotting and bound gaits which are commonly collected using generic rodent runways ( Broom et al, 2017 ; Mock et al, 2018 ). To avoid the potential issue of sub-strains ( Kelmenson, 2016 ), which would interfere with the interpretation of gait signatures ( Broom et al, 2017 ), we followed the same mice up to the age of 28 months, the expected median survivorship of C57BL/6J mice ( Hagan, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Shifts in Gait Signatures Mark the End of Lifespan in Mice, With Sex Differences in Timing

Broom

Stephen

Nayar

et al. 2021

Front. Aging Neurosci.

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Reduced walking speed is a hallmark of functional decline in aging across species. An age-related change in walking style may represent an additional key marker signifying deterioration of the nervous system. Due to the speed dependence of gait metrics combined with slowing of gait during aging, it has been challenging to determine whether changes in gait metrics represent a change in style. In this longitudinal study we employed gait signatures to separate changes in walking style and speed in mice. We compared gait signatures at mature adult age with middle aged, old and geriatric time points and included female and male sub-cohorts to examine sex differences in nature or timing signature shifts. To determine whether gait signature shifts occurred independently from a decline in other mobility domains we measured balance and locomotor activity. We found that walking speed declined early, whereas gait signatures shifted very late during the aging process. Shifts represented longer swing time and stride length than expected for speed, as in slow motion, and were preceded by a decline in other mobility domains. The pattern of shifts was similar between female and male cohorts, but with sex differences in timing. We conclude that changes in walking style, speed and other mobility domains represent separate age-related phenomena. These findings call for careful, sex specific selection of type and timing of outcome measures in mechanistic or interventional studies. The pattern of age-related gait signature shifts is distinct from patterns seen in neurodegenerative conditions and may be a translatable marker for the end of the lifespan.

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Dietary phosphate restriction prevents the appearance of sarcopenia signs in old mice

Alcalde-Estévez

Sosa

Asenjo-Bueno

et al. 2023

J cachexia sarcopenia muscle

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Background Sarcopenia is defined by the progressive and generalized loss of muscle mass and function associated with aging. We have previously proposed that aging-related hyperphosphataemia is linked with the appearance of sarcopenia signs. Because there are not effective treatments to prevent sarcopenia, except for resistance exercise, we propose here to analyse whether the dietary restriction of phosphate could be a useful strategy to improve muscle function and structure in an animal model of aging. Methods Five-month-old (young), 24-month-old (old) and 28-month-old (geriatric) male C57BL6 mice were used. Old and geriatric mice were divided into two groups, one fed with a standard diet (0.6% phosphate) and the other fed with a low-phosphate (low-P) diet (0.2% phosphate) for 3 or 7 months, respectively. A phosphate binder, Velphoro®, was also supplemented in a group of old mice, mixed with a standard milled diet for 3 months. Muscle mass was measured by the weight of gastrocnemius and tibial muscles, and quality by nuclear magnetic resonance imaging (NMRI) and histological staining assays. Muscle strength was measured by grip test and contractile properties of the tibialis muscle by electrical stimulation of the common peroneal nerve. Gait parameters were analysed during the spontaneous locomotion of the mice with footprinting. Orientation and motor coordination were evaluated using a static rod test. Results Old mice fed with low-P diet showed reduced serum phosphate concentration (16.46 ± 0.77 mg/dL young; 21.24 ± 0.95 mg/dL old; 17.46 ± 0.82 mg/dL low-P diet). Old mice fed with low-P diet displayed 44% more mass in gastrocnemius muscles with respect to old mice (P = 0.004). NMRI revealed a significant reduction in T2 relaxation time (P = 0.014) and increased magnetization transfer (P = 0.045) and mean diffusivity (P = 0.045) in low-P diettreated mice compared with their coetaneous. The hypophosphataemic diet increased the fibre size and reduced the fibrotic area by 52% in gastrocnemius muscle with respect to old mice (P = 0.002). Twitch force and tetanic force were significantly increased in old mice fed with the hypophosphataemic diet (P = 0.004 and P = 0.014, respectively). Physical performance was also improved, increasing gait speed by 30% (P = 0.032) and reducing transition time in the static rod by 55% (P = 0.012). Similar results were found when diet was supplemented with Velphoro®. Conclusions The dietary restriction of phosphate in old mice improves muscle quantity and quality, muscle strength and physical performance. Similar results were found using the phosphate binder Velphoro®, supporting the role of phosphate in the impairment of muscle structure and function that occurs during aging.

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Gait Analyses in Mice: Effects of Age and Glutathione Deficiency

Cited by 12 publications

References 56 publications

TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

Shifts in Gait Signatures Mark the End of Lifespan in Mice, With Sex Differences in Timing

Dietary phosphate restriction prevents the appearance of sarcopenia signs in old mice

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