Truncated dystrophin ameliorates the dystrophic phenotype of mdx mice by reducing sarcolipin-mediated SERCA inhibition
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira (Japan)
- Third Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto (Japan)
- Department of Cell Physiology, The Jikei University School of Medicine, Minato (Japan)
- Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva, Geneva (Switzerland)
Duchenne muscular dystrophy (DMD) and the less severe Becker muscular dystrophy (BMD) are due to mutations in the DMD gene. Previous reports show that in-frame deletion of exons 45–55 produces an internally shorted, but functional, dystrophin protein resulting in a very mild BMD phenotype. In order to elucidate the molecular mechanism leading to this phenotype, we generated exon 45–55 deleted dystrophin transgenic/mdx (Tg/mdx) mice. Muscular function of Tg/mdx mice was restored close to that of wild type (WT) mice but the localization of the neuronal type of nitric oxide synthase was changed from the sarcolemma to the cytosol. This led to hyper-nitrosylation of the ryanodine receptor 1 causing increased Ca{sup 2+} release from the sarcoplasmic reticulum. On the other hand, Ca{sup 2+} reuptake by the sarcoplasmic/endoplasmic reticulum Ca{sup 2+}-ATPase (SERCA) was restored to the level of WT mice, suggesting that the Ca{sup 2+} dysregulation had been compensated by SERCA activation. In line with this, expression of sarcolipin (SLN), a SERCA-inhibitory peptide, was upregulated in mdx mice, but strongly reduced in Tg/mdx mice. Furthermore, knockdown of SLN ameliorated the cytosolic Ca{sup 2+} homeostasis and the dystrophic phenotype in mdx mice. These findings suggest that SLN may be a novel target for DMD therapy.
- OSTI ID:
- 23107844
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 505, Issue 1; Other Information: Copyright (c) 2018 The Authors. Published by Elsevier Inc.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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