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Caloric Restriction Combined with Immobilization as Translational Model for Sarcopenia Expressing Key-Pathways of
Jelle C B C de Jong1,2, Martien P M Caspers3, Nanda Keijzer1
1Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.
Abstract:
The prevalence of sarcopenia is increasing while it is often challenging, expensive and time-consuming to test the effectiveness of interventions against sarcopenia. Translational mouse models that adequately mimic underlying physiological pathways could accelerate research but are scarce. Here, we investigated the translational value of three potential mouse models for sarcopenia, namely partial immobilized (to mimic sedentary lifestyle), caloric restricted (CR; to mimic malnutrition) and a combination (immobilized & CR) model. 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 parameters 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. 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%). In conclusion, 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. 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.
Insights
Developing effective sarcopenia treatments requires better mouse models. A combined model of caloric restriction and immobilization effectively mimics human sarcopenia pathways, offering a rapid testing platform for interventions.
Area of Science:
- Gerontology
- Muscle Physiology
- Translational Medicine
Background:
- Sarcopenia prevalence is rising, posing challenges for intervention testing.
- Existing translational mouse models for sarcopenia are limited.
- Accelerating sarcopenia research necessitates robust and relevant animal models.
Purpose of the Study:
- To evaluate the translational validity of three mouse models for sarcopenia: partial immobilization, caloric restriction (CR), and a combination (immobilization & CR).
- To compare muscle parameters and transcriptome profiles of these models with young and aged mice, and human sarcopenia data.
- To identify the most effective mouse model for rapid testing of sarcopenia interventions.
Main Methods:
- C57BL/6J mice underwent partial hindleg immobilization and/or 40% caloric restriction for two weeks.
- Muscle mass, strength, and myofiber characteristics were assessed.
- Quadriceps muscle transcriptomes were analyzed and compared to aged human vastus lateralis muscle data via meta-analysis.
Main Results:
- Caloric restriction significantly reduced lean body mass (-15%).
- Immobilization decreased muscle strength (-28%) and hindleg muscle mass (-25%).
- The combination model showed greater overlap (73%) with human muscle-aging pathways compared to aged mice (45%).
Conclusions:
- The combined immobilization and caloric restriction model effectively recapitulates both muscle mass loss and functional decline seen in human sarcopenia.
- This combination model demonstrates significant translational value for studying sarcopenia.
- The findings highlight the importance of sedentary behavior and malnutrition in sarcopenia and support this model for accelerated intervention testing.
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