| Title |
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
|
|---|---|
| Published in |
Neurotherapeutics, December 2016
|
| DOI | 10.1007/s13311-016-0494-7 |
| Pubmed ID | |
| Authors |
Cara A. Timpani, Adam J. Trewin, Vanesa Stojanovska, Ainsley Robinson, Craig A. Goodman, Kulmira Nurgali, Andrew C. Betik, Nigel Stepto, Alan Hayes, Glenn K. McConell, Emma Rybalka |
| Abstract |
Duchenne muscular dystrophy arises from the loss of dystrophin and is characterized by calcium dysregulation, muscular atrophy, and metabolic dysfunction. The secondary reduction of neuronal nitric oxide synthase (nNOS) from the sarcolemma reduces NO production and bioavailability. As NO modulates glucose uptake, metabolism, and mitochondrial bioenergetics, we investigated whether an 8-week nitrate supplementation regimen could overcome metabolic dysfunction in the mdx mouse. Dystrophin-positive control (C57BL/10) and dystrophin-deficient mdx mice were supplemented with sodium nitrate (85 mg/l) in drinking water. Following the supplementation period, extensor digitorum longus and soleus were excised and radioactive glucose uptake was measured at rest (basal) and during contraction. Gastrocnemius was excised and mitochondrial respiration was measured using the Oroboros Oxygraph. Tibialis anterior was analyzed immunohistochemically for the presence of dystrophin, nNOS, nitrotyrosine, IgG and CD45+ cells, and histologically to assess areas of damage and regeneration. Glucose uptake in the basal and contracting states was normal in unsupplemented mdx muscles but was reduced following nitrate supplementation in mdx muscles only. The mitochondrial utilization of substrates was also impaired in mdx gastrocnemius during phosphorylating and maximal uncoupled respiration, and nitrate could not improve respiration in mdx muscle. Although nitrate supplementation reduced mitochondrial hydrogen peroxide emission, it induced mitochondrial uncoupling in red gastrocnemius, increased muscle fiber peroxynitrite (nitrotyrosine), and promoted skeletal muscle damage. Our novel data suggest that despite lower nNOS protein expression and likely lower NO production in mdx muscle, enhancing NO production with nitrate supplementation in these mice has detrimental effects on skeletal muscle. This may have important relevance for those with DMD. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Australia | 1 | 50% |
| Unknown | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Scientists | 1 | 50% |
| Members of the public | 1 | 50% |
Mendeley readers
The data shown below were compiled from readership statistics for 59 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 2% |
| Unknown | 58 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 12 | 20% |
| Student > Ph. D. Student | 10 | 17% |
| Student > Master | 7 | 12% |
| Researcher | 4 | 7% |
| Student > Doctoral Student | 3 | 5% |
| Other | 9 | 15% |
| Unknown | 14 | 24% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 11 | 19% |
| Biochemistry, Genetics and Molecular Biology | 10 | 17% |
| Sports and Recreations | 6 | 10% |
| Nursing and Health Professions | 5 | 8% |
| Agricultural and Biological Sciences | 5 | 8% |
| Other | 5 | 8% |
| Unknown | 17 | 29% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 08 December 2016.
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#19,944,994
of 25,374,647 outputs
Outputs from Neurotherapeutics
#1,128
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#298,265
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Outputs of similar age from Neurotherapeutics
#18
of 21 outputs
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