Department of Geriatric Medicine, All India Institute of Medical Sciences, New Delhi, India.
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Exp Gerontol. 2021 Jul 15;150:111358. doi: 10.1016/j.exger.2021.111358. Epub 2021 Apr 16.
Sarcopenia is the loss of skeletal muscle mass and function. It is a major health issue in old age due to lack of understanding of the origin and molecular mechanism. Altered dietary pattern, sedentary lifestyle and physical inactivity have shown adverse effect of skeletal muscle function. Sedentary behaviour and low protein intake have been well associated with sarcopenia. Here, we aim to develop Sarcopenia mimicking murine model to observe the physiological and biochemical changes with physical activity intervention. We also intended to find the association of muscle stem cells and stress induced protein Sestrins in the developed sarcopenic model.
Male C57BL/6 mice were categorized into 4 groups: young-control (Y-Cntrl), aged-matched control (A-Cntrl), Sarcopenic-model (SAR-model) and Sarcopenic intervention group (SAR-INT) with physical exercises. SAR-model group was kept in a retrofitted confined cage for sedentary lifestyle and was fed with protein-restricted diet. Phenotypic assessment for body mass, grip strength and functional endurance was analysed to confirm the sarcopenic state. Mitochondrial enzymatic assessment, muscle stem cell (MuSCs) proliferation potential and protein quantification of Sestrins expression were performed by enzyme histochemistry, flow cytometry and surface plasmon resonance (SPR), respectively. SAR-model group was given 10 weeks physical activity intervention to assess the physiological and biochemical changes.
Simultaneous implementation of physical inactivity by sedentary confinement and protein restricted diet led the animals to exhibit the features of sarcopenia. SAR-model group showed a decline of 8.6% (p < 0.0001) in the body weight assessment, 32% decline (p < 0.0001) in the grip strength, 28% increase in time elapsed (p < 0.0001) indicating decline in functional performance. Mitochondrial enzymes (ATPase, NADH-TR and SDH/COX) assessment exhibited low expression in SAR-model group. Ki67 positive muscle stem cell declines around 50% in the model group. SPR quantification of Sestrin 2 showed a decline of 14% which significantly improved to 28% upon physical activity intervention (p = 0.0025) in SAR-INT group.
It can be summarized that the mouse model generated in the present study mimics the feature of human Sarcopenia. Physical activity intervention may improve the sarcopenic status via modulation of Sestrin 2 which can serve as potential molecule for therapeutic implication.
肌肉减少症是骨骼肌质量和功能的丧失。由于对其起源和分子机制缺乏了解，它是老年人的一个主要健康问题。饮食模式改变、久坐不动的生活方式和缺乏身体活动对骨骼肌功能有不良影响。久坐不动的行为和低蛋白摄入与肌肉减少症密切相关。在这里，我们旨在开发肌肉减少症模拟鼠模型，以观察生理和生化变化与身体活动干预。我们还旨在发现肌肉干细胞和应激诱导蛋白 Sestrins 在开发的肌肉减少症模型中的关联。
雄性 C57BL/6 小鼠分为 4 组：年轻对照组（Y-Cntrl）、年龄匹配对照组（A-Cntrl）、肌肉减少症模型组（SAR-model）和肌肉减少症干预组（SAR-INT），进行身体锻炼。SAR-model 组被安置在改装的限制笼中进行久坐不动的生活方式，并喂食蛋白质限制饮食。通过身体质量、握力和功能耐力的表型评估来确认肌肉减少症状态。通过酶组织化学、流式细胞术和表面等离子体共振（SPR）分别进行线粒体酶评估、肌肉干细胞（MuSCs）增殖潜力和 Sestrins 表达的蛋白定量。SAR-model 组进行了 10 周的身体活动干预，以评估生理和生化变化。
通过久坐不动的限制和蛋白质限制饮食的同时实施，导致动物表现出肌肉减少症的特征。SAR-model 组的体重评估下降 8.6%（p<0.0001），握力下降 32%（p<0.0001），功能表现下降 28%（p<0.0001）。线粒体酶（ATPase、NADH-TR 和 SDH/COX）评估显示 SAR-model 组表达水平较低。模型组 Ki67 阳性肌肉干细胞下降约 50%。SPR 定量的 Sestrin 2 下降 14%，在 SAR-INT 组进行身体活动干预后显著改善至 28%（p=0.0025）。
可以总结的是，本研究中生成的小鼠模型模拟了人类肌肉减少症的特征。身体活动干预可能通过调节 Sestrin 2 改善肌肉减少症状态，Sestrin 2 可作为治疗的潜在分子。
