Abstract
BackgroundLoss 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.MethodsnNOSμ 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).ResultsMembrane-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.ConclusionsOur results suggest that the R16/17-Syn PDZ fusion construct is sufficient to restore sarcolemmal nNOSμ in the dystrophin-null muscle.
Highlights
Loss of sarcolemmal nNOSμ is a common manifestation in a wide variety of muscle diseases and contributes to the dysregulation of multiple muscle activities
The membrane-bound repeats 16 and 17 (R16/17)-Syn PDZ construct did not restore other dystrophin-associated protein complex (DAPC) components (Fig. 3), nor was the muscle disease attenuated, the fusion construct successfully restored sarcolemmal nNOSμ. These results suggest that R16/17 and the syntrophin PDZ domain are the only components required for the sarcolemmal localization of nNOSμ
In this study, we found that the fusion protein containing dystrophin R16/17 and syntrophin PDZ domain restored sarcolemmal nNOSμ in dystrophin-null mice
Summary
Loss of sarcolemmal nNOSμ is a common manifestation in a wide variety of muscle diseases and contributes to the dysregulation of multiple muscle activities. NNOSμ is the primary nNOS isoform in muscle and it is localized at the sarcolemma. Sarcolemmal nNOSμ plays an important role in regulating multifaceted activities of muscle, including blood perfusion [3, 4], glucose metabolism [5,6,7,8], oxidative stress [9, 10], muscle contractility [11, 12], muscle satellite cell activation and muscle repair [13,14,15,16,17,18], mitochondria biogenesis [19,20,21,22], muscle mass [23,24,25,26], and muscle fatigue [26,27,28,29]. Activation of nNOSμ is dependent on dimerization of nNOSμ proteins. The interactions of two oxygenase domains mediate nNOSμ dimer formation (2018) 8:36 syntrophins, dystrobrevin, and nNOSμ) into the dystrophin-associated protein complex (DAPC) at the sarcolemma [44, 45]
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