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Background  Loss of sarcolemmal nNOSμ is a common manifestation in a wide variety of muscle diseases and contributes to the dysregulation of multiple muscle activities. Given the critical role sarcolemmal nNOSμ plays in muscle, restoration of sarcolemmal nNOSμ should be considered as an important therapeutic goal.    Methods  nNOSμ is anchored to the sarcolemma by dystrophin spectrin-like repeats 16 and 17 (R16/17) and the syntrophin PDZ domain (Syn PDZ). To develop a strategy that can independently restore sarcolemmal nNOSμ, we engineered an R16/17-Syn PDZ fusion construct and tested whether this construct alone is sufficient to anchor nNOSμ to the sarcolemma in three different mouse models of Duchenne muscular dystrophy (DMD).    Results  Membrane-associated nNOSμ is completely lost in DMD. Adeno-associated virus (AAV)-mediated delivery of the R16/17-Syn PDZ fusion construct successfully restored sarcolemmal nNOSμ in all three models. Further, nNOS restoration was independent of the dystrophin-associated protein complex.    Conclusions  Our results suggest that the R16/17-Syn PDZ fusion construct is sufficient to restore sarcolemmal nNOSμ in the dystrophin-null muscle.    Electronic supplementary material  The online version of this article (10.1186/s13395-018-0182-x) contains supplementary material, which is available to authorized users.

Dystrophin R16/17-syntrophin PDZ fusion protein restores sarcolemmal nNOSμ