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Tetrahydrobiopterin synthesis and metabolism is impaired in dystrophin-deficient mdx mice and humans
- Source :
- Acta physiologica (Oxford, England)REFERENCES. 231(4)
- Publication Year :
- 2021
-
Abstract
- Aim Loss of dystrophin causes oxidative stress and affects nitric oxide synthase-mediated vascular function in striated muscle. Because tetrahydrobiopterin is an antioxidant and co-factor for nitric oxide synthase, we tested the hypothesis that tetrahydrobiopterin would be low in mdx mice and humans deficient for dystrophin. Methods Tetrahydrobiopterin and its metabolites were measured at rest and in response to exercise in Duchenne and Becker muscular dystrophy patients, age-matched male controls as well as wild-type, mdx and mdx mice transgenically overexpressing skeletal muscle-specific dystrophins. Mdx mice were also supplemented with tetrahydrobiopterin and pathophysiology was assessed. Results Duchenne muscular dystrophy patients had lower urinary dihydrobiopterin + tetrahydrobiopterin/specific gravity1.020 compared to unaffected age-matched males and Becker muscular dystrophy patients. Mdx mice had low urinary and skeletal muscle dihydrobiopterin + tetrahydrobiopterin compared to wild-type mice. Overexpression of dystrophins that localize neuronal nitric oxide synthase restored dihydrobiopterin + tetrahydrobiopterin in mdx mice to wild-type levels while utrophin overexpression did not. Mdx mice and Duchenne muscular dystrophy patients did not increase tetrahydrobiopterin during exercise and in mdx mice tetrahydrobiopterin deficiency was likely because of lower levels of sepiapterin reductase in skeletal muscle. Tetrahydrobiopterin supplementation improved skeletal muscle strength, resistance to fatiguing and injurious contractions in vivo, increased utrophin and capillary density of skeletal muscle and lowered cardiac muscle fibrosis and left ventricular wall thickness in mdx mice. Conclusion These data demonstrate that impaired tetrahydrobiopterin synthesis is associated with dystrophin loss and treatment with tetrahydrobiopterin improves striated muscle histopathology and skeletal muscle function in mdx mice.
- Subjects :
- musculoskeletal diseases
0301 basic medicine
Male
congenital, hereditary, and neonatal diseases and abnormalities
medicine.medical_specialty
Utrophin
Physiology
Duchenne muscular dystrophy
030204 cardiovascular system & hematology
Dystrophin
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Dihydrobiopterin
Internal medicine
medicine
Animals
Humans
Muscular dystrophy
Muscle, Skeletal
Tetrahydrobiopterin deficiency
biology
business.industry
Skeletal muscle
Tetrahydrobiopterin
musculoskeletal system
medicine.disease
Biopterin
Muscular Dystrophy, Duchenne
030104 developmental biology
Endocrinology
medicine.anatomical_structure
chemistry
cardiovascular system
biology.protein
Mice, Inbred mdx
business
circulatory and respiratory physiology
medicine.drug
Subjects
Details
- ISSN :
- 17481716
- Volume :
- 231
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Acta physiologica (Oxford, England)REFERENCES
- Accession number :
- edsair.doi.dedup.....d7bd6951e7dcb353ecbea1f38e94c922