Coordinated mechanisms to rescue bioenergetics and sarcopenia in aging

拯救衰老过程中生物能学和肌肉减少症的协调机制

• 批准号: 10672292
• 负责人: Mattia Quattrocelli
• 金额: $ 32.62万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672292
• 关键词: Ablation; Adult; Aging; Alanine; Amino Acids; Anabolism; Animal Model; Bioenergetics; Biogenesis; Carbon; Cell Respiration; Chronic; Citric Acid Cycle; Data; Dose; Energy Metabolism; Genetic; Genetic Diseases; Glucocorticoids; Glucose; Growth; Knock-out; Knockout Mice; Knowledge; Link; Lipids; Mediating; Mitochondria; Modeling; Mus; Muscle; Muscle function; Muscular Dystrophies; Myopathy; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Physiology; Prednisone; Protein Biosynthesis; Pyruvate; Regimen; Rejuvenation; Reporting; Respiration; Role; Steroids; Testing; Thinness; Transgenic Model; age related; aged; aminoacid biosynthesis; density; disability; frailty; lipine; mass spectrometric imaging; mitochondrial dysfunction; muscle aging; muscle form; muscle strength; overexpression; programs; response; risk/benefit ratio; sarcopenia; treatment effect; trend; wasting; young adult

PROJECT SUMMARY A widely conserved hallmark of aging is the decline in muscle mass and strength, promoting frailty, loss of independence and disability. Crucial for this is our gap in knowledge regarding mechanisms linking bioenergetic stimulation to muscle anabolism. Glucocorticoid steroids have pervasive effects on energy metabolism and muscle function. Dosing intermittence appears crucial to the benefits/risks ratio of these drugs in dystrophic animal models and patients, i.e. in genetic myopathies. Here we investigate whether intermittent glucocorticoids increase performance in aged muscle, where weakness and sarcopenia are not dependent on specific genetic insults. Our new results in 24 months-old WT mice show that a chronic regimen of intermittent once-weekly prednisone increased muscle performance in aging mice to levels comparable to young adult mice (4 months- old). Remarkably, treatment rescued both mitochondrial respiration and muscle mass in aging mice to young- like levels. Mechanistically, we found that bioenergetic, functional and anabolic effects of intermittent prednisone were blunted upon inducible ablation of PGC1a in adult muscle. While the role of PGC1a in boosting mitochondrial capacity in aged muscle is more established, its effects on age-related sarcopenia and weakness are still debated with conflicting results from constitutive knockout or overexpression models. Scattered reports have hinted at a role of PGC1a in activating growth pathways, including biosynthesis of amino acids like alanine, but this is still largely unknown in muscle aging. Here we will investigate the mechanisms through which a bioenergetic stimulation like intermittent prednisone rescues both oxidative metabolism and mass gain in muscle aging. In Aim 1, we will determine the extent to which intermittence discriminates deleterious versus beneficial effects of glucocorticoids in aging muscle. We hypothesize that dosing intermittence shifts exogenous glucocorticoid effects from a PGC1a-lowering pro-wasting program to a PGC1a-dependent pro-ergogenic program, i.e. balanced gain of performance and mass. We will test this through inducible muscle-specific PGC1a ablation after natural aging. In Aim 2 we will establish the role of muscle Lipin1 in PGC1a re-activation in muscle aging. We hypothesize that Lipin1 supports mitochondrial function in muscle aging and mediates the PGC1a re- activation in response to intermittent glucocorticoids. To test this, we will use our newly derived mice with muscle- restricted inducible Lipin1 ablation after natural aging. In Aim 3, we will elucidate the extent to which bioenergetics rescue sarcopenia in aging through amino acid biosynthesis. We hypothesize that mitochondrial reactivation fuels amino acid biogenesis, supporting protein synthesis during muscle aging. We will test this by tracing glucose-derived carbons into amino acids in oxidative versus glycolytic myofibers. We will also test the extent to which muscle PGC1a mediates these effects in young versus aging muscle. In summary, here we leverage the unprecedented effects of intermittent glucocorticoids to discern unrecognized mechanisms of aging physiology and rejuvenate muscle bioenergetics and anabolism.

项目概要 衰老的一个广泛存在的标志是肌肉质量和力量下降，导致身体虚弱、丧失活力。 独立性和残疾。对此至关重要的是我们在生物能量联系机制方面的知识差距 刺激肌肉合成代谢。糖皮质激素类固醇对能量代谢和 肌肉功能。给药间歇性对于这些药物在营养不良患者中的获益/风险比至关重要 动物模型和患者，即遗传性肌病。在这里我们研究间歇性糖皮质激素是否 提高老化肌肉的性能，其中无力和肌肉减少症不依赖于特定的遗传 侮辱。我们对 24 个月大的 WT 小鼠的新结果表明，间歇性每周一次的长期治疗方案 泼尼松将衰老小鼠的肌肉性能提高到与年轻成年小鼠相当的水平（4个月- 老的）。值得注意的是，治疗可以挽救衰老小鼠和年轻小鼠的线粒体呼吸和肌肉质量。 就像级别一样。从机制上讲，我们发现间歇性泼尼松的生物能、功能和合成代谢作用 在成人肌肉中诱导消融 PGC1a 后，这些功能被削弱。而 PGC1a 在促进 衰老肌肉中的线粒体能力更加成熟，它对与年龄相关的肌少症和虚弱有影响 仍然存在争议，因为组成型敲除或过度表达模型的结果相互矛盾。零散的报道 暗示 PGC1a 在激活生长途径中的作用，包括丙氨酸等氨基酸的生物合成， 但这在肌肉衰老中仍然很大程度上是未知的。在这里，我们将研究以下机制： 间歇性泼尼松等生物能量刺激可挽救肌肉的氧化代谢和质量增加 老化。在目标 1 中，我们将确定间歇性区分有害与有益的程度 糖皮质激素对衰老肌肉的影响。我们假设给药间歇性改变了外源性 糖皮质激素从降低 PGC1a 的促消瘦计划到依赖 PGC1a 的促增效计划的作用 计划，即性能和质量的平衡增益。我们将通过诱导型肌肉特异性 PGC1a 对此进行测试 自然老化后消融。在目标 2 中，我们将确定肌肉 Lipin1 在肌肉中 PGC1a 重新激活中的作用 老化。我们假设 Lipin1 支持肌肉衰老过程中的线粒体功能并介导 PGC1a 重新启动。 响应间歇性糖皮质激素的激活。为了测试这一点，我们将使用我们新衍生的具有肌肉的小鼠 自然老化后限制诱导性 Lipin1 消融。在目标 3 中，我们将阐明生物能量学的程度 通过氨基酸生物合成拯救衰老过程中的肌肉减少症。我们假设线粒体重新激活 促进氨基酸生物发生，支持肌肉衰老过程中的蛋白质合成。我们将通过跟踪来测试这一点 氧化肌纤维与糖酵解肌纤维中葡萄糖衍生的碳转化为氨基酸。我们还将测试其程度 哪些肌肉 PGC1a 在年轻肌肉和衰老肌肉中介导这些作用。综上所述，我们在这里利用 间歇性糖皮质激素对识别未知的衰老生理机制具有前所未有的作用 并恢复肌肉生物能量和合成代谢的活力。