Department of Pharmacology and Therapeutics and.
Myology Institute, University of Florida College of Medicine, Gainesville, Florida, USA.
JCI Insight. 2020 Jan 16;5(1):133276. doi: 10.1172/jci.insight.133276.
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 DMD patients. Emerging DMD 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.
杜氏肌营养不良症（DMD）是一种破坏性的遗传性肌肉疾病，导致进行性肌肉退化和消瘦。糖皮质激素，特别是泼尼松/泼尼松龙和地夫可特，常用于 DMD 患者。新兴的 DMD 治疗方法包括针对肌肉消耗因子肌生成抑制素（Mstn）的治疗方法。本研究旨在探讨慢性糖皮质激素治疗如何影响 Mstn 抑制在 DMD 的 D2.mdx 小鼠模型中的疗效。我们报告称，用泼尼松（Pred）慢性治疗营养不良小鼠会导致显著的肌肉消耗，既激活了泛素-蛋白酶体降解途径，又抑制了肌肉蛋白合成。用改良的 Mstn 前肽（dnMstn）将 Pred 与 Mstn 抑制联合使用，完全消除了 Mstn 抑制的肌肉肥大作用，而与 Mstn 表达或 SMAD3 激活无关。转录组分析确定，Pred 与 dnMstn 联合治疗会影响与炎症、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 Mstn 缺失来预防。因此，糖皮质激素会干扰针对 Mstn 治疗可能带来的肌肉质量益处，在为 DMD 治疗方法设计临床试验时应考虑糖皮质激素的使用。这些结果对过去和未来的 DMD 中 Mstn 抑制试验具有重要意义。
