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Targeting muscle pathology using multifunctional small molecules

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked hereditary disorder that affects 1 in every 3500 males. Of the broad spectrum of muscular dystrophies, DMD has the highest incidence rate, and is characterized by a recessive, nonsense mutation in the gene coding for dystrophin. Loss of dystrophin leads to compromised connectivity between the sarcolemma and the surrounding extracellular matrix (ECM), causing a cascade of pathologies such as chronic muscle damage, inflammation, and fibrosis. To date, no cures for DMD have been found, although multiple routes of research to ameliorate the disease are being pursued. Cell- and gene therapy-based approaches appear promising but ultimately suffer from difficult delivery methods and potential detrimental side effects. DMD pathology is characterized by inflammation and fibrosis. Therefore, an approach that targets these pathologies could be a promising alternative strategy to treat DMD and improve prognosis. In this study, we propose such an alternative approach to treat DMD pathology. Our approach involves a multifunctional small molecule - a short chain fatty acid hexosamine (SCFAH) - to ameliorate inflammation and fibrosis associated with DMD pathology. We show that the SCFAH suppresses both the nuclear factor kappa-B (NF-[kappa]B) and transforming growth factor-beta (TGF-[beta]) pathways, thereby reducing inflammation and fibrosis in muscles of mdx mice, a mouse model for DMD. This effect was found to be apparent in biochemical, histological, and protein analyses. Our results show the potential of a single molecule to target multiple pathologies of DMD and establish a foundation for a promising alternative conventional treatment strategy

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