Herbelet Sandrine, Merckx Caroline, De Paepe Boel
Department of Neurology, Ghent University and Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium.
Neuromuscular Reference Center, Ghent University Hospital, C. Heymanslaan 10, 9000 Ghent, Belgium.
Biomedicines. 2021 Mar 30;9(4):350. doi: 10.3390/biomedicines9040350.
In Duchenne muscular dystrophy (DMD), the absence of dystrophin from the dystrophin-associated protein complex (DAPC) causes muscle membrane instability, which leads to myofiber necrosis, hampered regeneration, and chronic inflammation. The resulting disabled DAPC-associated cellular pathways have been described both at the molecular and the therapeutical level, with the Toll-like receptor nuclear factor kappa-light-chain-enhancer of activated B cells pathway (NF-ƘB), Janus kinase/signal transducer and activator of transcription proteins, and the transforming growth factor-β pathways receiving the most attention. In this review, we specifically focus on the protein kinase A/ mitogen-activated protein kinase/nuclear factor of activated T-cells 5/organic osmolytes (PKA-p38MAPK-NFAT5-organic osmolytes) pathway. This pathway plays an important role in osmotic homeostasis essential to normal cell physiology via its regulation of the influx/efflux of organic osmolytes. Besides, NFAT5 plays an essential role in cell survival under hyperosmolar conditions, in skeletal muscle regeneration, and in tissue inflammation, closely interacting with the master regulator of inflammation NF-ƘB. We describe the involvement of the PKA-p38MAPK-NFAT5-organic osmolytes pathway in DMD pathophysiology and provide a clear overview of which therapeutic molecules could be of potential benefit to DMD patients. We conclude that modulation of the PKA-p38MAPK-NFAT5-organic osmolytes pathway could be developed as supportive treatment for DMD in conjunction with genetic therapy.
在杜兴氏肌营养不良症（DMD）中，肌营养不良蛋白相关蛋白复合物（DAPC）中缺乏肌营养不良蛋白会导致肌膜不稳定，进而导致肌纤维坏死、再生受阻和慢性炎症。在分子和治疗层面都描述了由此导致的与DAPC相关的细胞通路功能障碍，其中Toll样受体核因子κB轻链增强子（NF-κB）通路、Janus激酶/信号转导和转录激活蛋白通路以及转化生长因子-β通路受到了最多关注。在本综述中，我们特别关注蛋白激酶A/丝裂原活化蛋白激酶/活化T细胞核因子5/有机渗透物（PKA-p38MAPK-NFAT5-有机渗透物）通路。该通路通过调节有机渗透物的流入/流出，在对正常细胞生理至关重要的渗透稳态中发挥重要作用。此外，NFAT5在高渗条件下的细胞存活、骨骼肌再生和组织炎症中起着至关重要的作用，与炎症的主要调节因子NF-κB密切相互作用。我们描述了PKA-p38MAPK-NFAT5-有机渗透物通路在DMD病理生理学中的作用，并清晰概述了哪些治疗分子可能对DMD患者具有潜在益处。我们得出结论，PKA-p38MAPK-NFAT5-有机渗透物通路的调节可作为与基因治疗相结合的DMD支持性治疗方法来开发。
