Attempting to Compensate for Reduced Neuronal Nitric Oxide Synthase Protein with Nitrate Supplementation Cannot Overcome Metabolic Dysfunction but Rather Has Detrimental Effects in Dystrophin-Deficient mdx Muscle

摘要: Duchenne muscular dystrophy arises from the loss of dystrophin and is characterized by calcium dysregulation, atrophy, metabolic dysfunction. The secondary reduction neuronal nitric oxide synthase (nNOS) sarcolemma reduces NO production bioavailability. As modulates glucose uptake, metabolism, mitochondrial bioenergetics, we investigated whether an 8-week nitrate supplementation regimen could overcome dysfunction in mdx mouse. Dystrophin-positive control (C57BL/10) dystrophin-deficient mice were supplemented with sodium (85 mg/l) drinking water. Following period, extensor digitorum longus soleus excised radioactive uptake was measured at rest (basal) during contraction. Gastrocnemius respiration using Oroboros Oxygraph. Tibialis anterior analyzed immunohistochemically for presence dystrophin, nNOS, nitrotyrosine, IgG CD45+ cells, histologically to assess areas damage regeneration. Glucose basal contracting states normal unsupplemented muscles but reduced following only. utilization substrates also impaired gastrocnemius phosphorylating maximal uncoupled respiration, not improve muscle. Although hydrogen peroxide emission, it induced uncoupling red gastrocnemius, increased muscle fiber peroxynitrite (nitrotyrosine), promoted skeletal damage. Our novel data suggest that despite lower nNOS protein expression likely muscle, enhancing these has detrimental effects on This may have important relevance those DMD.