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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

Timpani, Cara A., Trewin, Adam J., Stojanovska, Adam J., Robinson, Ainsley, Goodman, Craig A., Nurgali, Kulmira, Betik, Andrew C., Stepto, Nigel, Hayes, Alan, McConell, Glenn K. and Rybalka, Emma 2017, 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, Neurotherapeutics, vol. 14, no. 2, pp. 429-446, doi: 10.1007/s13311-016-0494-7.

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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
Author(s) Timpani, Cara A.
Trewin, Adam J.
Stojanovska, Adam J.
Robinson, Ainsley
Goodman, Craig A.
Nurgali, Kulmira
Betik, Andrew C.
Stepto, Nigel
Hayes, Alan
McConell, Glenn K.
Rybalka, Emma
Journal name Neurotherapeutics
Volume number 14
Issue number 2
Start page 429
End page 446
Total pages 18
Publisher Springer
Place of publication Berlin, Germany
Publication date 2017-04
ISSN 1878-7479
Keyword(s) Duchenne muscular dystrophy
Glucose uptake
Metabolism
Mitochondria
Nitrate supplementation
Animals
Dystrophin
Electron Transport
Glucose
Male
Mice, Inbred C57BL
Mice, Inbred mdx
Muscle, Skeletal
Muscular Dystrophy, Duchenne
Nitrates
Nitric Oxide Synthase Type I
Reactive Oxygen Species
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Pharmacology & Pharmacy
Neurosciences & Neurology
DUCHENNE MUSCULAR-DYSTROPHY
SKELETAL-MUSCLE
DIETARY NITRATE
MITOCHONDRIAL BIOGENESIS
GLUCOSE-UPTAKE
L-ARGININE
RADICAL PRODUCTION
SATELLITE CELLS
MOUSE MUSCLE
STEM-CELL
Summary 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.
Language eng
DOI 10.1007/s13311-016-0494-7
Field of Research 110699 Human Movement and Sports Science not elsewhere classified
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2016, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30109977

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.