Mouse models of sarcopenia: classification and evaluation

Xie, Wenqing; He, Miao; Dong-sheng, YU; Wu, Yuxiang; Wang, Xiu‐hua; Lv, Shan; Xiao, Wenfeng; Li, Yu‐sheng

doi:10.1002/jcsm.12709

Cited by 133 publications

(87 citation statements)

References 139 publications

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“…For its part, hindlimb clasping showed a higher incidence in the 3xTg-AD group without being associated with the stages of disease progression. This particular sign can indicate the severity of the motor impairment that the mice present [73][74][75].…”

Section: Motor Performance Geotaxis and Hindlimb Claspingmentioning

confidence: 99%

Modeling Functional Limitations, Gait Impairments, and Muscle Pathology in Alzheimer’s Disease: Studies in the 3xTg-AD Mice

Castillo-Mariqueo

Pérez-García

2021

Biomedicines

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Gait impairments in Alzheimer’s disease (AD) result from structural and functional deficiencies that generate limitations in the performance of activities and restrictions in individual’s biopsychosocial participation. In a translational way, we have used the conceptual framework proposed by the International Classification of Disability and Health Functioning (ICF) to classify and describe the functioning and disability on gait and exploratory activity in the 3xTg-AD animal model. We developed a behavioral observation method that allows us to differentiate qualitative parameters of psychomotor performance in animals’ gait, similar to the behavioral patterns observed in humans. The functional psychomotor evaluation allows measuring various dimensions of gait and exploratory activity at different stages of disease progression in dichotomy with aging. We included male 3xTg-AD mice and their non-transgenic counterpart (NTg) of 6, 12, and 16 months of age (n = 45). Here, we present the preliminary results. The 3xTg-AD mice show more significant functional impairment in gait and exploratory activity quantitative variables. The presence of movement limitations and muscle weakness mark the functional decline related to the disease severity stages that intensify with increasing age. Motor performance in 3xTg-AD is accompanied by a series of bizarre behaviors that interfere with the trajectory, which allows us to infer poor neurological control. Additionally, signs of physical frailty accompany the functional deterioration of these animals. The use of the ICF as a conceptual framework allows the functional status to be described, facilitating its interpretation and application in the rehabilitation of people with AD.

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Section: Motor Performance Geotaxis and Hindlimb Claspingmentioning

confidence: 99%

Modeling Functional Limitations, Gait Impairments, and Muscle Pathology in Alzheimer’s Disease: Studies in the 3xTg-AD Mice

Castillo-Mariqueo

Pérez-García

2021

Biomedicines

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“…Mice aged 18-to 24-months are equivalent to 56-to 69-year old humans, and the presence of early signs of sarcopenia in C57BL/6J mice at ~20 months of age has been reported, demonstrated by significantly decreased grip strength, exercise endurance, muscle volume, and muscle mass of these mice compared to 10-week-old C57BL/6J mice (Kim and Hwang 2020). While most studies agree that 24- to 25-month-old mice represent a reliable animal model of sarcopenia, as both muscle mass and strength are affected at this stage and linked with NMJ loss (Barns et al 2014), most studies utilizing the natural aging C57BL/6J mouse model of sarcopenia study mice older than 24 months of age (Xie et al 2021), obscuring the study of molecular mechanisms early in the disease course. As early as 18 months, we detected upregulation of Myog in sciatic nerve which suggests disturbances in presynaptic terminals (NMJs) because expression of this gene increases strongly in denervated muscles.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of aging mouse sciatic nerve reveals early pathways leading to sarcopenia

Comfort

Gade

Strait

et al. 2022

Preprint

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BackgroundSarcopenia, the age-associated decline in skeletal muscle mass and strength, has long been considered a disease of muscle only, but accumulating evidence suggests that sarcopenia could originate from the neural components controlling muscles. To identify early molecular changes in the efferent nerves that may drive sarcopenia initiation, we performed a longitudinal transcriptomic analysis of the sciatic nerve in aging mice.MethodsSciatic nerve and gastrocnemius muscle were obtained from young adult, middleaged, old, and sarcopenic (5,18, 21 and 24 months old, respectively) C57BL/6J female mice (n=6 per age group). Sciatic nerve RNA was extracted and subjected to RNA sequencing (RNA-seq), with real-time quantitative reverse transcription PCR (qRT-PCR) validation of differentially expressed genes (DEGs). Functional enrichment analysis of clusters of genes associated with patterns of gene expression across age groups was performed. Sarcopenia was confirmed with qRT-PCR of previously established markers of sarcopenia onset in gastrocnemius muscle.ResultsWe detected 33 significant DEGs in sciatic nerve of 18-month-old mice compared to 5-month-old mice (absolute value of fold change > 2; false discovery rate [FDR] < 0.05) which we validated with qRT-PCR of the three top up- and down-regulated genes. Up-regulated genes were associated with circadian rhythm and the AMPK signaling pathway, while down-regulated genes were associated with biosynthesis and metabolic pathways and circadian rhythm. Strikingly, we detected a significant increase in Myog expression (log2 fold change = 18.93, FDR q-value = 1.54×10−12) in sciatic nerve of 18-month-old mice, before up-regulation in muscle was observed. We identified seven clusters of genes with similar expression patterns across groups. Functional enrichment analysis of these clusters revealed biological processes that may be implicated in sarcopenia initiation including extracellular matrix organization and circadian regulation of gene expression.ConclusionsGene expression changes in mouse peripheral nerve can be detected prior to overt clinical onset of sarcopenia. These early molecular changes we report shed a new light on biological processes that may be implicated in sarcopenia initiation and pathogenesis. Future studies will validate which of the key changes we reported have disease modifying and/or biomarker potential.

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“…As mentioned above, senescence in MuSCs contributes to sarcopenia. Inhibition of the JAK/STAT3 signaling pathway in MuSCs could be a target for improving the function of aged satellite cells, and ultimately attenuates sarcopenia ( Sousa-Victor et al, 2015 ; Xie et al, 2021 ).…”

Section: Interventions Targeting Cellular Senescence Relevant To Sarcopeniamentioning

confidence: 99%

Cellular Senescence in Sarcopenia: Possible Mechanisms and Therapeutic Potential

Yang

Xie

et al. 2022

Front. Cell Dev. Biol.

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Aging promotes most degenerative pathologies in mammals, which are characterized by progressive decline of function at molecular, cellular, tissue, and organismal levels and account for a host of health care expenditures in both developing and developed nations. Sarcopenia is a prominent age-related disorder in musculoskeletal system. Defined as gradual and generalized chronic skeletal muscle disorder, sarcopenia involves accelerated loss of muscle mass, strength and function, which is associated with increased adverse functional outcomes and evolutionally refers to muscle wasting accompanied by other geriatric syndromes. More efforts have been made to clarify mechanisms underlying sarcopenia and new findings suggest that it may be feasible to delay age-related sarcopenia by modulating fundamental mechanisms such as cellular senescence. Cellular senescence refers to the essentially irreversible growth arrest mainly regulated by p53/p21CIP1 and p16INK4a/pRB pathways as organism ages, possibly detrimentally contributing to sarcopenia via muscle stem cells (MuSCs) dysfunction and the senescence-associated secretory phenotype (SASP) while cellular senescence may have beneficial functions in counteracting cancer progression, tissue regeneration and wound healing. By now diverse studies in mice and humans have established that targeting cellular senescence is a powerful strategy to alleviating sarcopenia. However, the mechanisms through which senescent cells contribute to sarcopenia progression need to be further researched. We review the possible mechanisms involved in muscle stem cells (MuSCs) dysfunction and the SASP resulting from cellular senescence, their associations with sarcopenia, current emerging therapeutic opportunities based on targeting cellular senescence relevant to sarcopenia, and potential paths to developing clinical interventions genetically or pharmacologically.

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Mouse models of sarcopenia: classification and evaluation

Cited by 133 publications

References 139 publications

Modeling Functional Limitations, Gait Impairments, and Muscle Pathology in Alzheimer’s Disease: Studies in the 3xTg-AD Mice

Modeling Functional Limitations, Gait Impairments, and Muscle Pathology in Alzheimer’s Disease: Studies in the 3xTg-AD Mice

Transcriptomic analysis of aging mouse sciatic nerve reveals early pathways leading to sarcopenia

Cellular Senescence in Sarcopenia: Possible Mechanisms and Therapeutic Potential

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