A membrane glucocorticoid receptor mediates the rapid/non-genomic actions of glucocorticoids in mammalian skeletal muscle fibres.
A membrane glucocorticoid receptor mediates the rapid/non-genomic actions of glucocorticoids in mammalian skeletal muscle fibres.
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膜糖皮质激素受体介导糖皮质激素在哺乳动物骨骼肌纤维中的快速/非基因组作用。
DOI：
10.1113/jphysiol.2013.256586
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Pérez MH
中科院分区：
文献类型：
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作者：
Pérez MH
糖皮质激素是一种应激激素，用于治疗包括哮喘在内的多种慢性炎症性疾病。它们通过调节参与炎症反应的基因的活性来发挥其大部分生理/药理作用。然而，它们也具有快速/非基因组效应，其功能知之甚少。在这项研究中，我们使用了两种广泛使用的糖皮质激素，丙酸倍氯米松和醋酸泼尼松龙，以研究这些激素是否在哺乳动物骨骼肌中具有快速/非基因组效应。这两种糖皮质激素都增加了慢缩肌纤维/细胞的最大力，但对快缩肌纤维的最大力没有显著影响。力的增加在10分钟内发生，并被糖皮质激素受体的抑制剂和结合受体的蛋白质（抗体）阻断。·这些研究结果表明，这些激素/药物在哺乳动物骨骼肌中具有快速/非基因组效应;这些效应是由膜糖皮质激素受体介导的，并且在生理学上是有益的，特别是在慢肌中。它们也是目前临床使用的一些最有效的抗炎和免疫抑制药物。它们通过经典/基因组途径发挥其大部分生理和药理作用。然而，它们也具有快速/非基因组作用，其生理和药理学功能仍然知之甚少。因此，本研究的主要目的是研究两种广泛使用的糖皮质激素，二丙酸倍氯米松（BDP）和醋酸泼尼松龙（PDNA）对分离的完整小鼠骨骼肌纤维束力产生的快速/非基因组效应。结果表明，两种GC对最大等长力（Po）的影响取决于纤维类型。因此，它们增加了慢缩纤维束的Poc，而没有显著影响快缩纤维束的Poc。inPo的增加在10 min内发生，并且对转录抑制剂放线菌素D不敏感。此外，它在250 nm处最大，并被糖皮质激素受体（GCR）抑制剂RU 486和单克隆抗GCR阻断，表明它是由膜（m）GCR介导的。两种肌纤维类型表达的胞质GCR。然而，mGCR仅存在于慢缩纤维中。该受体在氧化纤维中比在糖酵解纤维中更丰富，并且主要局限于与层粘连蛋白共定位的纤维外周。从这些发现中，我们得出结论，GC的快速/非基因组作用是由mGCR介导的，并且它们在生理学/治疗上是有益的，特别是在慢收缩肌纤维中。
Key points•Glucocorticoids are stress hormones used in the treatment of many chronic inflammatory diseases including asthma. They exert most of their physiological/pharmacological actions by regulating the activity of genes involved in the inflammatory response. However, they also have rapid/non‐genomic effects whose functions are poorly understood.•In this study we used two widely prescribed glucocorticoids, beclomethasone dipropionate and prednisolone acetate, to investigate whether these hormones have rapid/non‐genomic effects in mammalian skeletal muscles.•Both glucocorticoids increased maximum force in slow‐twitch muscle fibres/cells without significantly affecting that of fast‐twitch muscle fibres.•The increase in force occurred within 10 min and was blocked by an inhibitor of the glucocorticoid receptor and a protein (antibody) that binds the receptor.•These findings suggest that these hormones/drugs have rapid/non‐genomic effects in mammalian skeletal muscles; these effects are mediated by a membrane glucocorticoid receptor and are physiologically/pharmacologically beneficial, especially in slow muscles.AbstractGlucocorticoids (GCs) are steroid hormones released from the adrenal gland in response to stress. They are also some of the most potent anti‐inflammatory and immunosuppressive drugs currently in clinical use. They exert most of their physiological and pharmacological actions through the classical/genomic pathway. However, they also have rapid/non‐genomic actions whose physiological and pharmacological functions are still poorly understood. Therefore, the primary aim of this study was to investigate the rapid/non‐genomic effects of two widely prescribed glucocorticoids, beclomethasone dipropionate (BDP) and prednisolone acetate (PDNA), on force production in isolated, intact, mouse skeletal muscle fibre bundles. The results show that the effects of both GCs on maximum isometric force (Po) were fibre‐type dependent. Thus, they increasedPoin the slow‐twitch fibre bundles without significantly affecting that of the fast‐twitch fibre bundles. The increase inPooccurred within 10 min and was insensitive to the transcriptional inhibitor actinomycin D. Also, it was maximal at ∼250 nmand was blocked by the glucocorticoid receptor (GCR) inhibitor RU486 and a monoclonal anti‐GCR, suggesting that it was mediated by a membrane (m) GCR. Both muscle fibre types expressed a cytosolic GCR. However, a mGCR was present only in the slow‐twitch fibres. The receptor was more abundant in oxidative than in glycolytic fibres and was confined mainly to the periphery of the fibres where it co‐localised with laminin. From these findings we conclude that the rapid/non‐genomic actions of GCs are mediated by a mGCR and that they are physiologically/therapeutically beneficial, especially in slow‐twitch muscle fibres.