Enhanced dimethylarginine degradation improves coronary flow reserve and exercise tolerance in Duchenne muscular dystrophy carrier mice

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by null mutations in dystrophin and characterized by muscle degeneration. Cardiomyopathy is common and often prevalent at similar frequency in female DMD carriers irrespective of whether they manifest skeletal muscle disease. Impaired muscle nitric oxide (NO) production in DMD disrupts muscle blood flow regulation and exaggerates post-exercise fatigue. We show that circulating levels of endogenous methylated arginines including asymmetric dimethylarginine (ADMA), which act as NO synthase inhibitors, are elevated by acute necrotic muscle damage and in chronically-necrotic dystrophin-deficient mice. We therefore hypothesized that excessive ADMA impairs muscle NO production and diminishes exercise tolerance in DMD. We used transgenic expression of dimethylarginine dimethylaminohydrolase 1 (DDAH), which degrades methylated arginines, to investigate their contribution to exercise-induced fatigue in DMD. Although infusion of exogenous ADMA was sufficient to impair exercise performance in wild-type mice, transgenic DDAH expression did not rescue exercise-induced fatigue in dystrophin-deficient male mdx mice. Surprisingly, DDAH transgene expression did attenuate exercise-induced fatigue in dystrophin-heterozygous female mdx carrier mice. Improved exercise tolerance was associated with reduced heart weight and improved cardiac β-adrenergic responsiveness in DDAH-transgenic mdx carriers. We conclude that DDAH overexpression increases exercise tolerance in female DMD carriers, possibly by limiting cardiac pathology and preserving the heart's responses to changes in physiological demand. Methylated arginine metabolism may be a new target to improve exercise tolerance and cardiac function in DMD carriers, or act as an adjuvant to promote NO signaling alongside therapies that partially restore dystrophin expression in DMD patients.

DDAH1 Promotes Lung Endothelial Barrier Repair by Decreasing Leukocyte Transendothelial Migration and Oxidative Stress in Explosion-Induced Lung Injury

“…Recent studies suggested that activating the eNOS-VEGF signaling pathway could promote angiogenesis via enhancing the viability, migration, and tube formation of endothelial cells [ 51 ]. Garbincius et al found that DDAH1 overexpression could increase exercise tolerance via promoting NO signaling and partially restoring dystrophin expression in patients with Duchenne muscular dystrophy [ 52 ]. Additionally, a deficiency in the eNOS signaling pathway could exacerbate peritoneal fibrosis in mice by increasing the expression of vimentin.…”

A scalable, clinically severe pig model for Duchenne muscular dystrophy

“…We also showed that myocardial glucose utilization, as detected by PET/CT, is a promising parameter for identifying DMD +/− carriers with cardiac abnormalities at an earlier age (3 months), which may be useful for longitudinal studies of disease progression in carriers or the translational validation of new therapeutic concepts. An example is targeted degradation of the nitric oxide synthase inhibitor asymmetric dimethylarginine, which was recently shown to improve cardiac function and exercise tolerance in mdx carrier mice ( Garbincius et al, 2020 ).…”

A scalable, clinically severe pig model for Duchenne muscular dystrophy

“…We also showed that myocardial glucose utilization as detected by PET/CT is a promising parameter for identifying DMD +/carriers with cardiac abnormalities at an earlier age (3 months), which may be useful for longitudinal studies of disease progression in carriers or the translational validation of new therapeutic concepts. An example is targeted degradation of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), which was recently shown to improve cardiac function and exercise tolerance in mdx carrier mice (37).…”