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Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy
Yi Lai, … , Ronald L. Terjung, Dongsheng Duan
Yi Lai, … , Ronald L. Terjung, Dongsheng Duan
Published February 23, 2009
Citation Information: J Clin Invest. 2009;119(3):624-635. https://doi.org/10.1172/JCI36612.
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Research Article

Dystrophins carrying spectrin-like repeats 16 and 17 anchor nNOS to the sarcolemma and enhance exercise performance in a mouse model of muscular dystrophy

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Abstract

Sarcolemma-associated neuronal NOS (nNOS) plays a critical role in normal muscle physiology. In Duchenne muscular dystrophy (DMD), the loss of sarcolemmal nNOS leads to functional ischemia and muscle damage; however, the mechanism of nNOS subcellular localization remains incompletely understood. According to the prevailing model, nNOS is recruited to the sarcolemma by syntrophin, and in DMD this localization is altered. Intriguingly, the presence of syntrophin on the membrane does not always restore sarcolemmal nNOS. Thus, we wished to determine whether dystrophin functions in subcellular localization of nNOS and which regions may be necessary. Using in vivo transfection of dystrophin deletion constructs, we show that sarcolemmal targeting of nNOS was dependent on the spectrin-like repeats 16 and 17 (R16/17) within the rod domain. Treatment of mdx mice (a DMD model) with R16/17-containing synthetic dystrophin genes effectively ameliorated histological muscle pathology and improved muscle strength as well as exercise performance. Furthermore, sarcolemma-targeted nNOS attenuated α-adrenergic vasoconstriction in contracting muscle and improved muscle perfusion during exercise as measured by Doppler and microsphere circulation. In summary, we have identified the dystrophin spectrin-like repeats 16 and 17 as a novel scaffold for nNOS sarcolemmal targeting. These data suggest that muscular dystrophy gene therapies based on R16/17-containing dystrophins may yield better clinical outcomes than the current therapies.

Authors

Yi Lai, Gail D. Thomas, Yongping Yue, Hsiao T. Yang, Dejia Li, Chun Long, Luke Judge, Brian Bostick, Jeffrey S. Chamberlain, Ronald L. Terjung, Dongsheng Duan

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Figure 8

Schematic outline of sarcolemmal nNOS recruitment by an R16/17-containing microdystrophin gene.

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Schematic outline of sarcolemmal nNOS recruitment by an R16/17-containin...
(A) The N-terminal domain (N) of the DR2–15/DR18–23/DC microgene interacts with γ-actin. The cysteine-rich domain (CR) of this microgene interacts with the dystroglycan complex (DG). Syntrophin (Syn) is brought to the sarcolemma by dystrobrevin (Dbr), which binds to the sarcoglycan complex (SG). nNOS recruitment requires 2 independent interactions, one between the nNOS PDZ β-finger and the syntrophin PDZ domain and the other between the nNOS PDZ groove and R16/17. Numbers denote spectrin-like repeats; H1 and H4, hinge 1 and hinge 4. (B) The hypothetical nNOS-R16/17 interaction model. The C-terminal helix of R16 joins the N-terminal helix of R17 to form a long helix. The R16/17 dimer then binds to the groove in the nNOS PDZ domain. Yellow, R16; blue, R17; dotted, flanking repeats.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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