Therapeutic strategies to address neuronal nitric oxide synthase deficiency and the loss of nitric oxide bioavailability in Duchenne Muscular Dystrophy

Abstract

Duchenne Muscular Dystrophy is a rare and fatal neuromuscular disease in which the absence of dystrophin from the muscle membrane induces a secondary loss of neuronal nitric oxide synthase and the muscles capacity for endogenous nitric oxide synthesis. Since nitric oxide is a potent regulator of skeletal muscle metabolism, mass, function and regeneration, the loss of nitric oxide bioavailability is likely a key contributor to the chronic pathological wasting evident in Duchenne Muscular Dystrophy. As such, various therapeutic interventions to re-establish either the neuronal nitric oxide synthase protein deficit or the consequential loss of nitric oxide synthesis and bioavailability have been investigated in both animal models of Duchenne Muscular Dystrophy and in human clinical trials. Notably, the efficacy of these interventions are varied and not always translatable from animal model to human patients, highlighting a complex interplay of factors which determine the downstream modulatory effects of nitric oxide. We review these studies herein.

The Role of Macrophage Migration Inhibitory Factor in Alzheimer′s Disease: Conventionally Pathogenetic or Unconventionally Protective?

“…It is also worth noting that the biological function of MIF can be inhibited by nitrosylation [72], and hence nitric oxide (NO) donors may indirectly promote MIF inhibition. Along these lines, we propose that together with NO-NSAID, that have been proven effective in both preclinical and clinical settings [73,74], and also other NO-donors such as the recently characterized lopinavir-NO and ritonavir-NO [75][76][77][78], deserve consideration as drugs to be used in the treatment of AD patients. These drugs NO donors could combine beneficial anti-inflammatory properties along with beneficial effects of NO on vascular conditions associated with AD.…”

Metabolic Alterations in Cardiomyocytes of Patients with Duchenne and Becker Muscular Dystrophies

“…The use of transgenic NOS1 over-expression in mdx mice prevents the development of many signs of cardiomyopathy [49]. Therapeutic strategies have been developed to address neuronal nitric oxide synthase deficiency and the loss of nitric oxide availability in DMD [27] (Table 1).…”

Skeletal Muscle Metabolism in Duchenne and Becker Muscular Dystrophy—Implications for Therapies

“…Usually, nNOS is held at the sarcolemma by its inclusion in the dystrophin glycoprotein complex, but it is absent from the sarcolemma in DMD and mdx [ 67 ]. These nNOS changes are pathogenic, although the data is unclear if it is the absence of nNOS at the sarcolemma or its relocalization to the cytoplasm that is pathogenic (reviewed in [ 68 ]). For example, nNOS is required for vessel dilation during exercise, which is absent in mdx mice [ 69 ] and DMD patients [ 70 , 71 ].…”

“…These mice did not have a decreased pathology with respect to the mdx mice, indicating that additional NO within the cytoplasm is not pathogenic [ 72 ]. Multiple mdx nNOS overexpressing strategies have demonstrated a reduced mdx pathology, including reduced fibrosis, inflammation, and immune cell infiltration, as well as increased nitric oxide and force (reviewed in [ 68 ]). nNOS is included in this review because it is a metabolic molecule, which is increased with exercise, increased through activated AMP-activated protein kinase (pAMPK) signaling, and when in-excess causes dysfunction of the mitochondria, specifically within the electron transport chain [ 73 ].…”