Sarcolemmal damage in dystrophin deficiency is modulated by synergistic interactions between mechanical and oxidative/nitrosative stresses.
Dystrophin deficiency is the cause of Duchenne muscular dystrophy, but the precise physiological basis for muscle necrosis remains unclear. To determine whether dystrophin-deficient muscles are abnormally susceptible to oxidative and nitric oxide (NO)-driven tissue stress, a hindlimb ischemia/reperfusion (I/R) model was used. Dystrophic mdx mice exhibited abnormally high levels of lipid peroxidation and protein nitration, which were preceded by exaggerated NO production during ischemia. Visualization of NO with the fluorescent probe 4,5-diaminofluorescein diacetate suggested that excess NO production during ischemia occurred within a subset of mdx fibers. In mdx muscles only, prior exposure to I/R dramatically increased the level of sarcolemmal damage resulting from stretch-mediated mechanical stress, indicating greatly exacerbated hyperfragility of the dystrophic fiber membrane. Treatment with NO synthase inhibitors (l-N(G)-nitroarginine methyl ester hydrochloride or 7-nitroindazol) effectively blocked the synergistic interaction between I/R and mechanical stress-mediated sarcolemmal damage under these conditions. Taken together, our findings provide direct ex-perimental evidence that several prevailing hy-potheses regarding the cause of muscle fiber damage in dystrophin-deficient muscle can be integrated into a common pathophysiological framework involving interactions between oxidative stress, ab-normal NO regulation, and hyperfragility of the sarcolemma.
Dudley
Roy W R
RW
Royal Victoria Hospital, Room L411, 687 Pine Ave. West, Montreal, Quebec H3A 1A1, Canada.
Danialou
Gawiyou
G
Govindaraju
Karuthapillai
K
Lands
Larry
L
Eidelman
David E
DE
Petrof
Basil J
BJ
D000818:Animals; D016189:Dystrophin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D006614:Hindlimb; D007191:Indazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000098:blood supply / Q000503:physiopathology* / Q000648:ultrastructure; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D012508:Sarcolemma / Q000187:drug effects / Q000502:physiology*; D013314:Stress, Mechanical
D016189:Dystrophin; D007191:Indazoles; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester