Glucocorticoids counteract hypertrophic effects of myostatin inhibition in dystrophic muscle
Glucocorticoids counteract hypertrophic effects of myostatin inhibition in dystrophic muscle
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DOI：
10.1172/jci.insight.133276
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发表时间：
2020-01-16
期刊：
影响因子：
8
通讯作者：
Sweeney, H. Lee
中科院分区：
文献类型：
--
作者：
Hammers, David W.;Hart, Cora C.;Sweeney, H. Lee
杜氏肌营养不良症（DMD）是一种破坏性的遗传性肌肉疾病，导致进行性肌肉变性和萎缩。糖皮质激素，特别是泼尼松/泼尼松龙和地夫可特，是DM患者常用的药物。新兴的DWD疗法包括靶向肌肉消耗因子肌生长抑制素（MSTK）的疗法。本研究的目的是研究长期糖皮质激素治疗如何影响DMD D2.mdx小鼠模型中MclO抑制的疗效。我们报告，慢性治疗的营养不良小鼠与泼尼松龙（Pred）导致显着的肌肉萎缩，需要激活的泛素-蛋白酶体降解途径和抑制肌肉蛋白质的合成。将Pred与Mcl 3抑制结合，使用修饰的Mcl 3前肽（dnMcl 3），完全消除了Mcl 3抑制的肌肉肥大作用，而与Mcl 3表达或SMAD 3激活无关。转录组学分析确定，Pred与dnMlR治疗的组合影响与炎症、代谢和纤维化相关的基因表达谱。此外，我们证明Pred诱导的肌肉萎缩不能通过MRF消融来预防。因此，糖皮质激素会干扰与靶向MMD相关的潜在肌肉质量益处，在DMD治疗药物的临床试验设计期间，应考虑糖皮质激素使用的后果。这些结果对过去和未来DMD中的MdR抑制试验具有重要意义。
Duchenne muscular dystrophy (DMD) is a devastating genetic muscle disease resulting in progressive muscle degeneration and wasting. Glucocorticoids, specifically prednisone/prednisolone and deflazacort, are commonly used by DM patients. Emerging DWD therapeutics include those targeting the muscle-wasting factor, myostatin (Mstn). The aim of this study was to investigate how chronic glucocorticoid treatment impacts the efficacy of Mstn inhibition in the D2.mdx mouse model of DMD. We report that chronic treatment of dystrophic mice with prednisolone (Pred) causes significant muscle wasting, entailing both activation of the ubiquitin-proteasome degradation pathway and inhibition of muscle protein synthesis. Combining Pred with Mstn inhibition, using a modified Mstn propeptide (dnMstn), completely abrogates the muscle hypertrophic effects of Mstn inhibition independently of Mstn expression or SMAD3 activation. Transcriptomic analysis identified that combining Pred with dnMstn treatment affects gene expression profiles associated with inflammation, metabolism, and fibrosis. Additionally, we demonstrate that Pred-induced muscle atrophy is not prevented by Mstn ablation. Therefore, glucocorticoids interfere with potential muscle mass benefits associated with targeting Mstn, and the ramifications of glucocorticoid use should be a consideration during clinical trial design for DMD therapeutics. These results have significant implications for past and future Mstn inhibition trials in DMD.