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Gene transfer of arginine kinase to skeletal muscle using adeno-associated virus

Gene Therapy volume 21, pages 387–392 (2014)Cite this article

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Abstract

In this study, we tested the feasibility of non-invasively measuring phosphoarginine (PArg) after gene delivery of arginine kinase (AK) using an adeno-associated virus (AAV) to murine hindlimbs. This was achieved by evaluating the time course, regional distribution and metabolic flux of PArg using 31phosphorus magnetic resonance spectroscopy (31P-MRS). AK gene was injected into the gastrocnemius of the left hindlimb of C57Bl10 mice (age 5 weeks, male) using self-complementary AAV, type 2/8 with desmin promoter. Non-localized 31P-MRS data were acquired over 9 months after injection using 11.1-T and 17.6-T Bruker Avance spectrometers. In addition, 31P two-dimensional chemical shift imaging and saturation transfer experiments were performed to examine the spatial distribution and metabolic flux of PArg, respectively. PArg was evident in each injected mouse hindlimb after gene delivery, increased until 28 weeks, and remained elevated for at least 9 months (P<0.05). Furthermore, PArg was primarily localized to the injected posterior hindimb region and the metabolite was in exchange with ATP. Overall, the results show the viability of AAV gene transfer of AK gene to skeletal muscle, and provide support of PArg as a reporter that can be used to non-invasively monitor the transduction of genes for therapeutic interventions.

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Acknowledgements

This study was supported by National Institutes of Health (P01 HL59412 to GAW), Muscular Dystrophy Association Development Grant (175552 to SCF) and the National High Magnetic Field Laboratory. We thank Huadong Zeng, PhD, of the Advanced Magnetic Resonance Imaging and Spectroscopy (AMRIS) facility in the McKnight Brain Institute of the University of Florida.

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Authors and Affiliations

  1. Department of Physical Therapy, University of Florida, Gainesville, FL, USA

    S C Forbes, F Ye & K Vandenborne

  2. Department of Physiology, University of Pennsylvania, Philadelphia, PA, USA

    L T Bish & H L Sweeney

  3. Department of Anatomy and Cell Biology, University of Pennsylvania, Philadelphia, PA, USA

    J Spinazzola & E R Barton

  4. Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA

    C Baligand & G A Walter

  5. Advanced Magnetic Resonance Imaging and Spectroscopy Facility, University of Florida, Gainesville, FL, USA

    D Plant

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  1. S C Forbes
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Correspondence to S C Forbes or G A Walter.

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Forbes, S., Bish, L., Ye, F. et al. Gene transfer of arginine kinase to skeletal muscle using adeno-associated virus. Gene Ther 21, 387–392 (2014). https://doi.org/10.1038/gt.2014.9

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