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Modulation of Methylated Arginine Metabolism to Target Exercise‐Induced Fatigue in Duchenne Muscular Dystrophy
Author(s) -
Garbincius Joanne F.,
Merz Lauren E.,
Cuttitta Ashley J.,
Bayne Kaitlynn V.,
Schrade Sara,
Armstead Emily A.,
Whitesall Steven E.,
D'Alecy Louis G.,
Michele Daniel E.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1291.5
Subject(s) - medicine , endocrinology , duchenne muscular dystrophy , asymmetric dimethylarginine , dystrophin , nitric oxide synthase , muscular dystrophy , nitric oxide , chemistry , arginine , biochemistry , amino acid
Duchenne muscular dystrophy (DMD) is an X‐linked disease caused by mutations in dystrophin and characterized by muscle degeneration, cardiomyopathy, and impaired muscle nitric oxide (NO) production that leads to misregulated muscle blood flow and excessive post‐exercise fatigue. Data from our laboratory show that serum levels of the NO synthase inhibitor asymmetric dimethylarginine (ADMA) are elevated in dystrophin‐deficient mdx mice and after acute muscle injury, and that infusion of ADMA is sufficient to impair exercise performance in wild‐type mice. Therefore, we hypothesized that excessive circulating ADMA impairs NO production and exaggerates exercise‐induced fatigue in DMD. To determine the impact of ADMA on fatigue resistance in this disease, female mdx mice were crossed to wild‐type males expressing a transgene encoding human dimethylarginine dimethylaminohydrolase 1 (DDAH), an enzyme that degrades ADMA. Voluntary ambulatory activity of transgenic (TG) and non‐transgenic (NTG) offspring was measured in open field assays prior to and following acute bouts of treadmill running to assess exercise‐induced fatigue. DDAH expression lowered serum ADMA concentration in TG offspring, but failed to attenuate the post‐exercise decrease in voluntary activity in mdx males. However, transgene expression resulted in a significant, 20% attenuation of the decrease in voluntary activity following exercise in female mdx carriers. The heart weight/tibia length ratio was significantly reduced in TG versus NTG carriers, although examination of the gastrocnemius and soleus muscles revealed no difference between genotypes in histological markers of dystrophy or ischemic muscle injury, suggesting that improved fatigue resistance was due to cardiac‐specific effects of DDAH expression. We conclude that ADMA contributes to excessive exercise‐induced fatigue in dystrophin heterozygous females, possibly by promoting pathological cardiac remodeling and impairing heart performance. These findings emphasize the importance of NO signaling to cardiac function in dystrophinopathies and reveal a new therapeutic target to mitigate the risk of cardiomyopathy in DMD carriers. Support or Funding Information Supported by the Muscular Dystrophy Association, the University of Michigan CVRE Training Program, and NIH T32 GM‐08322.