Glucocorticoid intermittence coordinates rescue of energy and mass in aging-related sarcopenia through the myocyte-autonomous PGC1alpha-Lipin1 transactivation.
Glucocorticoid intermittence coordinates rescue of energy and mass in aging-related sarcopenia through the myocyte-autonomous PGC1alpha-Lipin1 transactivation.
复制标题
糖皮质激素间歇性通过肌细胞自主 PGC1α-Lipin1 反式激活来协调与衰老相关的肌肉减少症的能量和质量的挽救。
DOI：
10.1101/2023.10.16.562573
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Quattrocelli,Mattia
中科院分区：
文献类型：
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作者：
Prabakaran,AshokDaniel;McFarland,Kevin;Miz,Karen;Durumutla,HimaBindu;Piczer,Kevin;ElAbdellaouiSoussi,Fadoua;Latimer,Hannah;Werbrich,Cole;Blair,NScott;Millay,DouglasP;Prideaux,Brendan;Finck,BrianN;Quattrocelli,Mattia
肌肉减少症通过肌肉能量和质量的损失给老年人群带来负担，但功能性挽救这两个参数的治疗方法缺失。糖皮质激素泼尼松根据摄入频率重塑肌肉代谢，但其在肌肉减少症中的机制尚不清楚。我们发现，每周一次的间歇性强的松可以将24个月大的老年小鼠的肌肉质量挽救到与4个月大的年轻小鼠相当的水平。我们发现了一个年龄和性别无关的糖皮质激素受体的反式激活程序在肌肉中包括PGC1 α和它的辅因子Lipin1。治疗通过肌细胞特异性PGC1 α的亚型1协调改善线粒体丰度，通过亚型4协调改善肌肉质量，这是治疗驱动的从葡萄糖氧化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作为诱导PGC1 α上调的非冗余因子，以刺激氧化和合成代谢能力。我们的研究揭示了一种抗衰老的药物程序，在肌细胞中协调拯救肌肉减少症的能量和质量。
Sarcopenia burdens the elderly population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are missing. The glucocorticoid prednisone remodels muscle metabolism based on frequency of intake, but its mechanisms in sarcopenia are unknown. We found that once-weekly intermittent prednisone rescued muscle quality in aged 24-month-old mice to levels comparable to young 4-month-old mice. We discovered an age- and sex-independent glucocorticoid receptor transactivation program in muscle encompassing PGC1alpha and its co-factor Lipin1. Treatment coordinately improved mitochondrial abundance through isoform 1 and muscle mass through isoform 4 of the myocyte-specific PGC1alpha, which was required for the treatment-driven increase in carbon shuttling from glucose oxidation to amino acid biogenesis. We also probed the myocyte-specific Lipin1 as non-redundant factor coaxing PGC1alpha upregulation to the stimulation of both oxidative and anabolic capacities. Our study unveils an aging-resistant druggable program in myocytes to coordinately rescue energy and mass in sarcopenia.