Abstract 18211: Exercise-Induced Vasospasm in Skeletal Muscle of Patients With Becker Muscular Dystrophy Lacking Sarcolemmal nNOS
Introduction: Neuronal nitric oxide synthase (nNOS) is the main source of nitric oxide (NO) in skeletal muscle. In mouse models of Duchenne or Becker muscular dystrophy (BMD), absence of sarcolemma localized nNOS engenders exercise-induced spasm of skeletal muscle microvessels, causing injury and fatigue. To test for exercise-induced vasospasm in human dystrophic muscle, we performed parametric analysis of skeletal muscle perfusion with contrast enhanced ultrasound to measure: capillary blood volume (A), highly regulated by NO; microvascular flux rate (β), regulated by classical resistance arteriolar tone; and muscle blood flow (Aхβ).
Methods: Perfusion images of the flexor digitorum profundus were made after rhythmic handgrip (90s) at 25%, 50%, and 75% maximal voluntary contraction (MVC) in 5 unmedicated BMD patients (mean age 30 ± 3.5Y) and 10 healthy age-matched male controls (Ctrls). All patients had mutated dystrophin that cannot bind nNOS and muscle biopsy showing no antibody staining for sarcolemmal nNOS.
Results: In Ctrls, flow (Aβ) increased more (p<0.01) at each level of graded exercise: by 4.7±1.3, 9.5±2.5, and 17.6±3.7 fold over resting values at 25, 50, and 75% MVC, respectively. In patients, flow also increased progressively with handgrip at 25 and 50% MVC (by 5.5±1.4 and 12.8±3.4 fold) but failed to increase further at 75% and the value (12.2 ±3 fold) was even lower than that at 50% MVC (p<0.05), indicating partial vasospasm. Moreover, β failed to increase at 75 vs 50% MVC (3.7±1.3 vs 3.5±1.3 fold, p=ns), possibly due to defective NO modulation of adrenergic constriction, while A fell well below the 50% MVC level (1.1 vs 1.4 fold increase, P<0.01), suggesting adverse constriction of precapillary sphincters. The impaired hyperemic responses in patients are not simply due to less force output (MVC: 28±5 vs 39±8 kg, BMD vs Ctrls), because group differences in microcirculatory responses at 75% MVC persist when absolute force is matched in the 3 strongest patients vs 3 weakest Ctrls.
Conclusions: These imaging data provide the first translational evidence in human patients with BMD that loss of sarcolemmal nNOS engenders spasm of intramuscular microvessels at high-intensity exercise and further implicates the NO pathway as a novel drug target for BMD.
Author Disclosures: M. Hakimi: None. B. Hsu: None. O. Mason: None. R. Rosenberry: None. F. Rader: None. R. Baresi: None. J.R. Lindner: Research Grant; Significant; Investigator-initiated grant from GE Healthcare. R.G. Victor: Research Grant; Modest; Coalition Duchenne. Consultant/Advisory Board; Modest; Eli Lilly, Capricor.
- © 2016 by American Heart Association, Inc.