Organic Osmolytes and Duchenne Muscular Dystrophy: From Homeostasis, Inflammation and Skeletal Muscle Regeneration to Therapeutic Target

In this study, we pay particular attention to the PKA-p38MAPK-NFAT5-organic osmolytes pathway, which involves protein kinase A, mitogen-activated protein kinase, nuclear factor of activated T cells 5, and organic osmolytes. Through its control of the inflow and outflow of organic osmolytes, this route contributes significantly to the osmotic balance necessary for optimal cell function. Duchenne muscular dystrophy (DMD) is not only one of the most severe forms of inherited muscular dystrophies but also the most common hereditary neuromuscular disease. 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-KB), Janus kinase/signal transducer and activator of transcription proteins, and the transforming growth factor-
pathways receiving the most attention. 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-KB. 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.