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Table 1 Summary of methods utilised to increase NO production and the effects observed in dystrophic skeletal and cardiac muscle from DMD animal models and patients

From: Therapeutic strategies to address neuronal nitric oxide synthase deficiency and the loss of nitric oxide bioavailability in Duchenne Muscular Dystrophy

Method/Mechanism Dosage Range Model Effects Other Reference
nNOS restoration
Breeding with transgenic nNOS overexpressors
Transfection with nNOS
N/A mdx mouse
Dystrophin/utrophin knockout mouse
mdx mouse
Skeletal muscle: reduces inflammation, macrophage and neutrophil infiltration, damage
Cardiac muscle: reduces fibrosis, macrophage infiltration, improves impulse conduction
Skeletal muscle: increases DPC expression, NO production, reduces damage and fatigue, prevents force production loss
  [39,40,41,42,43,44,45, 47,48,49]
˪-arginine supplementation 200–1000 mg/kg/day DMD patients
mdx mouse
Skeletal muscle: increases DPC expression, reduces damage, fibrotic and fatty tissue infiltration, inflammatory cell infiltration, oxidative stress, improves grip strength, contractile function and reduces fatigability Administered in combination with metformin and prednisone [18, 29,30,31,32,33,34,35,36]
PDE inhibition
Sildenafil
Tadalafil
0.7–80 mg/kg/day
30–300 mg/kg/day
DMD patients
mdx mouse
DMD patients
mdx mouse
Skeletal muscle: reduces collagen and inflammatory cell infiltration, improves sarcolemmal integrity
Cardiac muscle: reduces membrane permeability, induces cardiac remodelling, improves heart function
Skeletal muscle: improves functional ischemia, reduces contraction-induced damage, fibrotic infiltration, histological variability, improves exercise performance, increases expression of ETC. genes
  [52, 55, 57,58,59,60,61]
NO donation 21–80 mg/kg/day mdx mouse Skeletal muscle: increases vascularisation, blood flow, exercise performance and strength, decreases free Ca2+ concentration, damage, inflammation, fibrotic and collagenous infiltration
Cardiac muscle: decreases damage, inflammation, fibrotic and collagenous infiltration, improves cardiac function and architecture
Administered in combination with NSAIDs [62,63,64,65,66,67,68,69]
Expansion of nitrate-nitrite-NO pool 85 mg/L mdx mouse Skeletal muscle: does not improve mitochondrial deficits, increases damage and peroxynitrite production Only one study to date [107]