Coordinated mechanisms to rescue bioenergetics and sarcopenia in aging

项目总结 衰老的一个普遍保守的标志是肌肉质量和力量的下降，促进虚弱，丧失 独立和残疾。关键是我们对连接生物能量的机制的认识上的差距 对肌肉合成代谢有刺激作用。糖皮质激素对能量代谢和 肌肉功能。间歇给药似乎对这些药物在营养不良中的益处/风险比至关重要 动物模型和患者，即遗传性肌病。在这里，我们调查了间歇性糖皮质激素 提高衰老肌肉的表现，其中虚弱和骨骼减少不依赖于特定的基因 侮辱。我们在24月龄WT小鼠身上的新结果表明，一种每周间歇一次的慢性养生法 泼尼松提高了老年小鼠的肌肉性能，达到了与年轻成年小鼠相当的水平(4个月- 旧的)。值得注意的是，治疗将衰老小鼠的线粒体呼吸和肌肉质量都拯救给了年轻小鼠- 就像水平一样。从机制上讲，我们发现间歇性强的松的生物能量、功能和合成代谢作用。 可诱导消融成人肌肉中的PGC1a，使其钝化。而PGC1a在免疫促进中的作用 老年肌肉中的线粒体能力更确定，它对年龄相关的骨骼肌减少和虚弱的影响 对于结构性基因敲除或过度表达模型得出的相互矛盾的结果仍存在争议。零星报告 都暗示了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， 但在肌肉老化方面，这在很大程度上仍然是未知的。在这里，我们将研究一种 生物能量刺激，如间歇性强的松，既拯救了肌肉的氧化新陈代谢，又拯救了肌肉的质量增加 衰老。在目标1中，我们将确定间歇性区分有害和有益的程度 糖皮质激素对衰老肌肉的作用。我们假设给药间歇性转移是外源性的 PGC1a降低促耗竭程序对依赖PGC1a促麦角化程序的糖皮质激素作用 计划，即性能和质量的平衡收益。我们将通过诱导肌肉特异性PGC1a来测试这一点 自然老化后的烧蚀。在目标2中，我们将确定肌肉脂蛋白1在肌肉中PGC1a重新激活中的作用 衰老。我们推测，在肌肉衰老过程中，Lipin1支持线粒体功能，并介导PGC1a重新启动。 对间歇性糖皮质激素反应的激活。为了测试这一点，我们将使用我们新衍生的带有肌肉的小鼠- 自然老化后限制性诱导脂蛋白1消融。在目标3，我们将阐明生物能量学在多大程度上 通过氨基酸生物合成来挽救衰老中的石棺减少症。我们假设线粒体的重新激活 促进氨基酸生物合成，支持肌肉老化过程中的蛋白质合成。我们将通过跟踪测试这一点 葡萄糖衍生的碳在氧化和糖酵解肌纤维中转化为氨基酸。我们还将测试其程度 在年轻肌肉和衰老肌肉中，哪些肌肉的PGC1a介导了这些效应。总而言之，在这里我们利用 间歇性糖皮质激素对识别未知衰老生理机制的前所未有的作用 并使肌肉生物能量和合成代谢恢复活力。

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.