Division of Rehabilitation Science and Division of Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota, Minneapolis, MN, USA.
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Acta Physiol (Oxf). 2021 Apr;231(4):e13627. doi: 10.1111/apha.13627. Epub 2021 Mar 8.
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.
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.
Duchenne muscular dystrophy patients had lower urinary dihydrobiopterin + tetrahydrobiopterin/specific gravity 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.
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.
肌营养不良蛋白缺失会导致氧化应激，并影响横纹肌中一氧化氮合酶介导的血管功能。由于四氢生物蝶呤是一种抗氧化剂和一氧化氮合酶的辅助因子，我们检验了这样一个假设，即在缺乏 dystrophin 的 mdx 小鼠和人类中，四氢生物蝶呤的含量会降低。
在休息和运动时，我们测量了杜氏肌营养不良症和贝克肌营养不良症患者、年龄匹配的男性对照组以及过表达骨骼肌特异性肌营养不良蛋白的野生型、mdx 和 mdx 小鼠中的四氢生物蝶呤及其代谢物。我们还向 mdx 小鼠补充了四氢生物蝶呤，并评估了其病理生理学情况。
与未受影响的年龄匹配男性和贝克肌营养不良症患者相比，杜氏肌营养不良症患者的尿二氢生物蝶呤+四氢生物蝶呤/比重较低。mdx 小鼠的尿和骨骼肌中二氢生物蝶呤+四氢生物蝶呤均低于野生型小鼠。将定位于神经元型一氧化氮合酶的肌营养不良蛋白过表达后，mdx 小鼠中二氢生物蝶呤+四氢生物蝶呤恢复至野生型水平，而肌联蛋白过表达则没有。mdx 小鼠和杜氏肌营养不良症患者在运动过程中并未增加四氢生物蝶呤，并且 mdx 小鼠中四氢生物蝶呤缺乏可能是由于骨骼肌中色氨酸羟化酶还原酶水平较低所致。四氢生物蝶呤补充改善了 mdx 小鼠的骨骼肌力量、抗疲劳和损伤性收缩能力，增加了骨骼肌中的肌联蛋白和毛细血管密度，并降低了 mdx 小鼠的心肌纤维化和左心室壁厚度。
这些数据表明，四氢生物蝶呤合成受损与肌营养不良蛋白缺失有关，用四氢生物蝶呤治疗可改善 mdx 小鼠的横纹肌组织病理学和骨骼肌功能。
