Duchenne Muscular Dystrophy (DMD) is a severe, progressive muscular disease that affects both muscle and bone. To date, effective therapies for DMD are limited. Studies have shown that reduced nitric oxide (NO) bioavailability resulted from secondary loss of neuronal nitric oxide synthase (nNOS) in the absence of dystrophin is a key contributor to disease progression. Restoring NO homeostasis via dietary nitrite and nitrate representing a novel therapeutic approach due to its ability to be converted to NO in low oxygen and ischemic states that can bypass nNOS. The purpose of this study is to test the efficacy of inorganic nitrite and explore its mechanism of action on both skeletal muscle and bone. Our preliminary data, based on a severe dystrophic mouse model (dKO-dystrophin/utrophin double knock out), demonstrated disrupted NO homeostasis in dystrophic muscle and more excitingly, oral administration of nitrite significantly improved the life span and a series of pathological changes in dystrophic mice, both in skeletal muscle and bone tissues. The mechanisms underlying these improvements deserve further investigation to provide important preclinical and mechanistic information for identifying novel therapeutic targets. We hypothesize that inorganic nitrite administration improves both muscle and bone pathologies in DMD by enhancing NO signaling pathways in dystrophic muscle and by modulating the expression and secretion of bone- regulating myokines. We will test this hypothesis in three specific aims.
Aim 1 : To test the hypothesis that inorganic nitrite restores nitrate/nitrite pool in dystrophic mice and improves muscle/bone pathologies and preserves muscle function.
Aim 2 : To test the hypothesis that nitrite affects skeletal muscle via myoglobin-mediated NO-cGMP signaling pathway.
Aim 3 : To test the hypothesis that in addition to increased mechanical loading, nitrite affects bone homeostasis via modulating the expression and secretion of bone-regulating myokines from dystrophic muscle. We anticipate that these findings will provide a novel, safe and low-cost therapeutic approach benefiting both muscle and bone for the currently untreatable DMD. Completion of these aims will advance our knowledge of novel mechanisms for the pathogenesis of bone abnormalities in DMD through bone-regulating myokines as well; which may uncover new potential therapeutic targets. Importantly, our findings may have profound translational implications not only to DMD but also to other neuromuscular diseases that lack normal NO signaling pathway function.
The purpose of this project is to evaluate the efficacy and study the mechanisms of its actions of oral nitrite administration as a novel therapeutic approach to replenish NO in dystrophic muscle by targeting nitrate-nitrite-NO pathway, which is significantly disturbed in DMD. The unique beneficial effects of nitrite to both dystrophic skeletal muscle and bone tissues represent a novel intervention targeting musculoskeletal comorbidities in DMD. If succeed, this innovative strategy could represent a safe and cost-effective therapeutic pharmacological approach benefiting both muscle and bone for the currently untreatable DMD; and provide new mechanistic understanding of DMD muscle and bone pathogenesis in DMD.