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Effect of genetic background and limb immobilization on tibial metaphysis transcriptomes in 19‑week male mice

ABSTRACT: This study profiles tibial metaphysis RNA expression across eight inbred mouse strains subjected to unilateral hindlimb immobilization. RNA‑seq was performed on metaphyseal tissue from immobilized and contralateral control limbs to identify strain‑specific transcriptional responses to mechanical unloading. Differential expression analysis revealed distinct genetic‑background–dependent signatures associated with bone remodeling, inflammation, and mechanotransduction pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE331381 | GEO | 2026/05/22

REPOSITORIES: GEO

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Project description:Abstract Background: The prevalence of sarcopenia is increasing and effective interventions are required to prevent or reverse age-related muscle loss. However it is often challenging expensive and time-consuming to develop and test the effectiveness of such interventions. Furthermore translational animal models that adequately mimic underlying physiological pathways are scarce. Strong predictors for the incidence of sarcopenia include a sedentary life-style and malnutrition. Therefore our objective was to investigate the translational value of three potential mouse models for sarcopenia namely partial immobilized caloric restricted (CR) and a combination (immobilized & CR) model. Methods: C57BL/6J mice were calorically restricted (-40%) and/or one hindleg was immobilized for two weeks to induce loss of muscle mass and function. Muscle mass function and diameter and distribution of slow (type 1) and fast ( type 2) myofibers were compared to those of young control (4 months) and old reference mice (21 months). Transcriptome analysis of quadriceps muscle was performed to identify underlying pathways and were compared with those being expressed in aged human vastus lateralis muscle-biopsies using a meta-analysis of five different human studies. Results: Caloric restriction induced overall loss of lean body mass (-15% p<0.001) whereas immobilization decreased muscle strength (-28% p<0.001) and muscle mass of hindleg muscles specifically (on average -25% p<0.001). The proportion of slow myofibers increased with aging in mice (+5% p<0.05) and this was not recapitulated by the CR and/or immobilization models. The diameter of fast myofibers decreased with aging (-7% p<0.05) and this was mimicked by all models. Transcriptome analysis revealed that the combination of CR and immobilization recapitulated more pathways characteristic for human muscle-aging (73%) than naturally aged (21 months old) mice (45%). These pathways included critical pathways relevant for protein synthesis/ breakdown (mitochondrial) metabolism neurology and the vascular system. Conclusions: The combination model exhibits loss of both muscle mass (due to CR) and function (due to immobilization) and has a remarkable similarity with pathways underlying human sarcopenia. Our results demonstrate that naturally aging up to 21 months in mice only partially recapitulates the human pathology with fewer overlapping pathways than the combination model. These findings underline that external factors such as sedentary behavior and malnutrition are key elements of a translational mouse model and favor the combination model as a rapid model for testing the treatments against sarcopenia.

Project description:Advancements in animal models and cell culture techniques have been invaluable in the elucidation of molecular events and mechanisms regulating muscle atrophy. However, few studies have examined muscle atrophy in humans using modern experimental techniques. The purpose of this study was to examine and validate changes in global gene transcription during immobilization-induced muscle atrophy in humans. Healthy men and women (N=24) were subjected to two weeks of unilateral limb immobilization, with muscle biopsies obtained before, and after 48 hours (48H) and 14 days (14D) of immobilization. Both muscle cross sectional area (~ 5 %) and strength (10-20 %) were significantly reduced in men and women after 14D of immobilization. Micro-array analysis of total RNA extracted from biopsy samples uncovered 575 and 3,128 probes representing multiple genes, which were significantly altered at 48H and 14D, respectively. As a group, genes involved in mitochondrial bioenergetics and carbohydrate metabolism were predominant features at both 48H and 14D, with genes involved in protein synthesis and degradation significantly down-regulated and up-regulated, respectively, at 14D of muscle atrophy. There was also a significant decrease in the protein content of mitochondrial cytochrome c oxidase, and the enzyme activity of cytochrome c oxidase and citrate synthase after 14D of immobilization. Furthermore, protein ubiquitination and oxidative damage were significantly increased by 48H and 14D of immobilization, respectively. These results suggest that transcriptional and post-transcriptional suppression of mitochondrial processes is sustained throughout 14D of immobilization, while protein ubiquitination plays an early but transient role in the progression of immobilization-induced muscle atrophy in humans. 72 samples taken from quadriceps of healthy ambulatory young men and women. Samples were taken at 3 timepoints throughout a 14 day period, the initial sample was taken at time 0 (PRECAST), then the limb was immobilized via a brace, and the 2nd sample was taken at 48 hours (CAST02D). The third sample was taken following 14 days of immobilization (CAST14D).

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Effect of genetic background and limb immobilization on tibial metaphysis transcriptomes in 19‑week male mice

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