Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury.
Mineralocorticoid Receptor Signaling in the Inflammatory Skeletal Muscle Microenvironments of Muscular Dystrophy and Acute Injury.
复制标题
DOI：
10.3389/fphar.2022.942660
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
Rafael-Fortney, Jill A.
中科院分区：
文献类型：
--
作者：
Howard, Zachary M.;Gomatam, Chetan K.;Piepho, Arden B.;Rafael-Fortney, Jill A.
关键词：
杜氏肌营养不良症 (DMD) 是一种由于功能性肌营养不良蛋白缺失而导致的横纹肌退行性疾病。肌营养不良蛋白的缺失导致肌膜易受损伤，导致肌肉变性以及持续的炎症和纤维化，从而进一步加剧病理学。长期糖皮质激素受体 (GR) 激动剂治疗是目前 DMD 的治疗标准，可适度改善预后，但具有严重的副作用。盐皮质激素受体 (MR) 是一种存在于许多细胞类型中的配体激活转录因子，已被认为是 DMD 的治疗靶点。 MR拮抗剂（MRA）比GR激动剂副作用更少，临床上用于治疗心力衰竭。 MRA 对 DMD 心肌病的疗效最近已得到证实，并且在临床前研究中，MRA 还可以缓解营养不良性骨骼肌病理。 MRA 可改善肌肉力量和膜稳定性，并减少营养不良肌肉的变性、炎症和纤维化。肌纤维特异性 MR 敲除导致了大部分改善，支持 MR 依赖性作用机制，但 MRA 还以不依赖 MR 的方式稳定肌纤维膜。营养不良和急性损伤的正常肌肉中的免疫细胞 MR 信号传导有助于伤口愈合，而骨髓特异性 MR 敲除是有害的。需要更多的研究来充分阐明横纹肌微环境中的 MR 信号。直接比较糖皮质激素和 MRA 对骨骼肌和心脏的基因组和非基因组影响将有助于这些药物的最佳时间使用，因为它们竞争结合保守受体。尽管出现了基因药物，但为了实现最佳的患者治疗效果，针对炎症和纤维化的治疗仍然是必要的。
Duchenne muscular dystrophy (DMD) is a striated muscle degenerative disease due to loss of functional dystrophin protein. Loss of dystrophin results in susceptibility of muscle membranes to damage, leading to muscle degeneration and continuous inflammation and fibrosis that further exacerbate pathology. Long-term glucocorticoid receptor (GR) agonist treatment, the current standard-of-care for DMD, modestly improves prognosis but has serious side effects. The mineralocorticoid receptor (MR), a ligand-activated transcription factor present in many cell types, has been implicated as a therapeutic target for DMD. MR antagonists (MRAs) have fewer side effects than GR agonists and are used clinically for heart failure. MRA efficacy has recently been demonstrated for DMD cardiomyopathy and in preclinical studies, MRAs also alleviate dystrophic skeletal muscle pathology. MRAs lead to improvements in muscle force and membrane stability and reductions in degeneration, inflammation, and fibrosis in dystrophic muscles. Myofiber-specific MR knockout leads to most of these improvements, supporting an MR-dependent mechanism of action, but MRAs additionally stabilize myofiber membranes in an MR-independent manner. Immune cell MR signaling in dystrophic and acutely injured normal muscle contributes to wound healing, and myeloid-specific MR knockout is detrimental. More research is needed to fully elucidate MR signaling in striated muscle microenvironments. Direct comparisons of genomic and non-genomic effects of glucocorticoids and MRAs on skeletal muscles and heart will contribute to optimal temporal use of these drugs, since they compete for binding conserved receptors. Despite the advent of genetic medicines, therapies targeting inflammation and fibrosis will be necessary to achieve optimal patient outcomes.
登录
查看更多内容
影响因子：
20.1
作者：
Ferrario CM;Schiffrin EL
通讯作者：
Schiffrin EL
影响因子：
3.5
作者：
Chadwick, Jessica A.;Swager, Sarah A.;Rafael-Fortney, Jill A.
通讯作者：
Rafael-Fortney, Jill A.
影响因子：
20.1
作者：
Good, Miranda E.;Chiu, Yu-Hsin;Ravichandran, Kodi S.
通讯作者：
Ravichandran, Kodi S.
影响因子：
4.8
作者：
Gomez-Sanchez, EP;Ahmad, N;Gomez-Sanchez, CE
通讯作者：
Gomez-Sanchez, CE
影响因子：
8.3
作者：
Frieler RA;Meng H;Duan SZ;Berger S;Schütz G;He Y;Xi G;Wang MM;Mortensen RM
通讯作者：
Mortensen RM