Introduction: In mouse models of Duchenne or Becker muscular dystrophy (BMD) lacking sarcolemmal neuronal nitric oxide synthase (nNOS), exercise paradoxically induces spasm of skeletal muscle microvessels, which can cause ischemic injury and fatigue. In the mice, vasospasm and its injurious consequences can be eliminated by treatment with small molecules that restore NO-cGMP signaling.
Hypothesis: To translate the mouse work to the clinical setting by determining if a) exercise also engenders spasm of human skeletal muscle microvessels in patients with BMD; and b) the putative vasospasm, if present, can be rescued by treatment with an oral NO donor.
Methods: Using contrast enhanced ultrasound, perfusion images of the flexor digitorum profundus were made after rhythmic handgrip up to 75% maximal voluntary contraction (MVC) in a) 5 unmedicated BMD patients (mean age 30 ± 3.5Y) lacking sarcolemmal nNOS on muscle biopsy, and b) 10 healthy age-matched male controls. Experiments have been repeated after BMD patients (n=4 to date) received oral sodium nitrate (140ml), an inorganic NO donor. Muscle blood flow (MBF) was calculated as microvascular flow rate x capillary blood volume.
Results: The major new findings are two-fold: First, in BMD, MBF fails to increase further and even decreased paradoxically when handgrip intensity was increased to 75% MVC, indicating vasospasm. It increases progressively in healthy controls. The mechanism of the abnormal MBF response in BMD was caused by both failure of microvascular flow rate to increase in feed arteries plus a frank reduction in capillary blood volume, indicating adverse constriction of precapillary sphincters. Second, the abnormal vascular phenotype can be rescued by an oral NO donor. In each of the BMD patients restudied to date (n=4), acute sodium nitrate treatment augmented the fold-increase in MBF induced by handgrip at 75% MVC from 16.5 ±2.9 to 24.7 ±4.8.
Conclusions: These imaging data provide the first translational evidence in human patients with BMD that loss of sarcolemmal nNOS engenders exercise-induced spasm of intramuscular microvessels and further implicate the NO-cGMP pathway as a novel drug target for BMD. Additional studies are underway.