Tetrahydrobiopterin shifts the balance from oxidative stress to NO signalling in Duchenne muscular dystrophy

In this issue, Lindsay et al, 2021 investigated if patients with Duchenne muscular dystrophy (DMD) had reduced levels of the antioxidant and arginine-NO coupling cofactor Tetrahydrobiopterin (BH4) determined supplementation BH4 DMD disease progression in mdx mouse model DMD.1 is a fatal X-linked genetic that affects approximately 1 5,000 newborn boys for which there no cure limited treatments. have complete loss functional dystrophin protein show progressive muscle weakness leading to ambulation their teens, death second or third decade life from cardiopulmonary dysfunction.2 Mutations gene cause partial Becker (BMD) results later onset effective treatments.2 Dystrophin 427 kDa forms scaffold Dystrophin-Associated Protein Complex (DAPC), transmembrane linkage system binds laminin extracellular matrix cell cytoskeleton.3 Loss associated complex sarcolemma instability altered nitric oxide (NO) signalling unopposed ?-adrenergic vasoconstriction, along angiogenesis, inadequate blood supply muscle.4 The structural instability, cellular signaling, inflammation, vascular function, oxidative stress contribute function DMD. critical multiple biochemical pathways including conversion arginine produce NO regulates angiogenesis (Figure 1). addition, has important roles reducing tissues reduces free radicals through oxidization BH2 then biopterin nNOS tissue homeostasis, vascularization?, inflammatory responses.5 Several studies indicate contributes preventing can reduce DMD.6, 7 To test hypothesis muscle, authors collected urine showed were lower compared those unaffected. went on low BMD indicating normal are biosynthesis. These also revealed like was decrease resulted decreased Sepiaterin reductase, enzyme synthesizes BH4, confirming dystrophin's role regulating biosynthesis.1 Transgenic mice expressed micro-dystrophin construct includes spectrin-liked repeats 16 17 rod domain, localization restored biosynthesis muscle. comparison, not transgenic overexpressed utrophin constructs do properly localize nNOS. Together these confirmed serves couple muscle.1 Finally, adminstration improved vivo strength resistance fatigue Improved increased capillary density restore dystrophin-deficient current study shows balancing re-coupling as synthesis BMD.1 questions arise study. Are benefits observed long-term administration models DMD? same seen BMD? Will treatment improve respiratory cardiac outcomes Could combination currently approved treatments corticosteroids exon skipping further Answers could translate new paradigm either by itself other therapies BMD. declared conflict interest.