Premium
Nitric oxide generated by muscle corrects defects in hippocampal neurogenesis and neural differentiation caused by muscular dystrophy
Author(s) -
Deng Bo,
Glanzman David,
Tidball James G.
Publication year - 2009
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2008.166256
Subject(s) - neurogenesis , dystrophin , duchenne muscular dystrophy , muscular dystrophy , biology , dentate gyrus , neun , microbiology and biotechnology , endocrinology , hippocampal formation , medicine , neuroscience , immunology , genetics , immunohistochemistry
Duchenne muscular dystrophy (DMD) results from null mutation of dystrophin, a membrane‐associated structural protein that is expressed in skeletal muscle. Dystrophin deficiency causes muscle membrane lesions, muscle degeneration and eventually death in afflicted individuals. However, dystrophin deficiency also causes cognitive defects that are difficult to relate to the loss of dystrophin. We assayed neurogenesis in the dentate gyrus (DG) in the mdx mouse model of DMD, using bromodeoxyuridine incorporation as a marker of proliferation and NeuN expression as a marker of differentiation. Our findings show that dystrophin mutation disrupts adult neurogenesis by promoting cell proliferation in the DG and suppressing neuronal differentiation. Because loss of dystrophin from muscle results in the secondary loss of neuronal nitric oxide synthase (nNOS), and NO is able to modulate neurogenesis, we assayed whether the genetic restoration of nNOS to mdx muscles corrected defects in adult, hippocampal neurogenesis. Assays of NO in the sera of active mice showed significant reductions in NO caused by the dystrophin mutation. However, over‐expression of nNOS in the muscles of mdx mice increased serum NO and normalized cell proliferation and neuronal differentiation in the DG. These findings indicate that muscle‐derived NO regulates adult neurogenesis in the brain and loss of muscle nNOS may underlie defects in the central nervous system in DMD.