PDF(Pubmed)
Abstract：
Sarcopenia burdens the older population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are lacking. The glucocorticoid prednisone remodels muscle metabolism on the basis of frequency of intake, but its mechanisms in sarcopenia are unknown. We found that once-weekly intermittent prednisone administration rescued muscle quality in aged 24-month-old mice to a level comparable to that seen in young 4-month-old mice. We discovered an age- and sex-independent glucocorticoid receptor transactivation program in muscle encompassing peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1α) and its cofactor Lipin1. Treatment coordinately improved mitochondrial abundance through isoform 1 and muscle mass through isoform 4 of the myocyte-specific PGC1α, which was required for the treatment-driven increase in carbon shuttling from glucose oxidation to amino acid biogenesis. We also probed myocyte-specific Lipin1 as a nonredundant factor coaxing PGC1α upregulation to the stimulation of both oxidative and anabolic effects. Our study unveils an aging-resistant druggable program in myocytes for the coordinated rescue of energy and mass in sarcopenia.
摘要：
肌肉减少症通过肌肉能量和质量的损失给老年人带来负担，然而，在功能上挽救这两个参数的治疗方法都缺失。糖皮质激素泼尼松根据摄入频率重塑肌肉代谢，但其在少肌症中的作用机制尚不清楚。我们发现，每周一次的间歇性泼尼松可以将24个月大的老年小鼠的肌肉质量恢复到与4个月大的年轻小鼠相当的水平。我们在包含PGC1α及其辅因子Lipin1的肌肉中发现了一种与年龄和性别无关的糖皮质激素受体反式激活程序。治疗通过肌细胞特异性PGC1α的同工型1和通过同工型4协调改善线粒体丰度，这是处理驱动的从葡萄糖到氨基酸生物合成的碳穿梭增加所必需的。我们还探讨了肌细胞特异性Lipin1作为非冗余因子诱使PGC1α上调以刺激氧化和合成代谢作用。我们的研究揭示了一种在肌细胞中抗衰老的药物程序，以协调地挽救肌肉减少症的能量和质量。
