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Because tetrahydrobiopterin is an antioxidant and co\u2010factor for nitric oxide synthase, we tested the hypothesis that tetrahydrobiopterin would be low in <jats:italic>mdx<\/jats:italic> mice and humans deficient for dystrophin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Tetrahydrobiopterin and its metabolites were measured at rest and in response to exercise in Duchenne and Becker muscular dystrophy patients, age\u2010matched male controls as well as wild\u2010type, <jats:italic>mdx<\/jats:italic> and <jats:italic>mdx<\/jats:italic> mice transgenically overexpressing skeletal muscle\u2010specific dystrophins. <jats:italic>Mdx<\/jats:italic> mice were also supplemented with tetrahydrobiopterin and pathophysiology was assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Duchenne muscular dystrophy patients had lower urinary dihydrobiopterin\u00a0+\u00a0tetrahydrobiopterin\/specific gravity<jats:sub>1.020<\/jats:sub> compared to unaffected age\u2010matched males and Becker muscular dystrophy patients. <jats:italic>Mdx<\/jats:italic> mice had low urinary and skeletal muscle dihydrobiopterin\u00a0+\u00a0tetrahydrobiopterin compared to wild\u2010type mice. Overexpression of dystrophins that localize neuronal nitric oxide synthase restored dihydrobiopterin\u00a0+\u00a0tetrahydrobiopterin in <jats:italic>mdx<\/jats:italic> mice to wild\u2010type levels while utrophin overexpression did not. <jats:italic>Mdx<\/jats:italic> mice and Duchenne muscular dystrophy patients did not increase tetrahydrobiopterin during exercise and in <jats:italic>mdx<\/jats:italic> 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 <jats:italic>mdx<\/jats:italic> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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 <jats:italic>mdx<\/jats:italic> mice.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13627","type":"journal-article","created":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T08:12:46Z","timestamp":1613203966000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Tetrahydrobiopterin synthesis and metabolism is impaired in dystrophin\u2010deficient <i>mdx<\/i> mice and humans"],"prefix":"10.1111","volume":"231","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5195-1901","authenticated-orcid":false,"given":"Angus","family":"Lindsay","sequence":"first","affiliation":[{"name":"Division of Rehabilitation Science and Division of Physical Therapy Department of Rehabilitation Medicine University of Minnesota Minneapolis MN USA"},{"name":"Department of Biochemistry, Molecular Biology and Biophysics University of Minnesota Minneapolis MN USA"},{"name":"Institute for Physical Activity and Nutrition School of Exercise and Nutrition Sciences Deakin University Geelong Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bailey","family":"Kemp","sequence":"additional","affiliation":[{"name":"Lillehei Heart Institute Cancer and Cardiovascular Research Center University of Minnesota Minneapolis MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexie 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