Coordinated mechanisms to rescue bioenergetics and sarcopenia in aging

项目摘要 一个广泛保存的衰老标志是肌肉质量和力量的下降，促进脆弱，失去肌肉， 独立和残疾。关键是我们对生物能与生物能之间的联系机制的认识存在差距。 刺激肌肉痉挛。糖皮质激素类固醇对能量代谢具有广泛的影响， 肌肉功能剂量依赖性似乎对这些药物治疗营养不良的获益/风险比至关重要。 动物模型和患者，即在遗传性肌病中。在这里，我们调查是否间歇性糖皮质激素 增加老年肌肉表现，其中虚弱和肌肉减少症不依赖于特定的遗传 侮辱。我们在24个月大的WT小鼠中的新结果表明，每周一次的间歇性慢性方案 泼尼松使衰老小鼠的肌肉性能增加到与年轻成年小鼠（4个月- 旧）。值得注意的是，治疗拯救了衰老小鼠的线粒体呼吸和肌肉质量， 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 在成年肌肉中PGC 1a的诱导消融后变钝。虽然PGC 1a在促进 老年肌肉中的线粒体能力更加确定，其对年龄相关的肌肉减少症和虚弱的影响 仍然存在争议，与组成型敲除或过表达模型的结果相矛盾。零星报道 暗示PGC 1a在激活生长途径中的作用，包括氨基酸如丙氨酸的生物合成， 但这在肌肉老化中仍然是未知的。在这里，我们将调查的机制，通过它 生物能量刺激，如间歇性强的松，可挽救肌肉中的氧化代谢和质量增加 衰老在目标1中，我们将确定顺应性在多大程度上区分有害和有益 糖皮质激素在衰老肌肉中的作用。我们假设，剂量耐受性转移外源性 糖皮质激素的作用从PGC 1a降低促消耗程序到PGC 1a依赖性促运动 程序，即性能和质量的平衡增益。我们将通过诱导型肌肉特异性PGC 1a来测试这一点。 自然老化后的消融。在目的2中，我们将确定肌肉Lipin 1在肌肉中PGC 1a再激活中的作用 衰老我们假设Lipin 1支持肌肉衰老中线粒体的功能，并介导PGC 1a的重新表达。 对间歇性糖皮质激素的反应。为了验证这一点，我们将使用我们新衍生的小鼠与肌肉- 自然老化后的限制性诱导Lipin 1消融。在目标3中，我们将阐明生物能量学在多大程度上 通过氨基酸的生物合成来拯救衰老中的肌肉减少症。我们假设线粒体的重新激活 为氨基酸生物合成提供燃料，支持肌肉老化期间的蛋白质合成。我们将通过追踪 葡萄糖衍生的碳转化为氧化与糖酵解肌纤维中的氨基酸。我们还将测试 哪种肌肉PGC 1a在年轻肌肉与衰老肌肉中介导这些作用。总之，在这里，我们利用 间歇性糖皮质激素对识别未被认识的衰老生理机制的前所未有的作用 恢复肌肉的生物能量和活力。

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.