Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1812, Issue 4, Pages 439-446Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2011.01.002
Keywords
alpha 7 Integrin; Muscular dystrophy; Integrin linked kinase (ILK); AKT; Cell signaling; Apoptosis
Funding
- NIH [RO1-AG014632, R01AR053697]
- Muscular Dystrophy Association
- Ellison Medical Foundation
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Transgenic expression of the alpha 7 integrin can ameliorate muscle pathology in a mouse model of Duchenne muscular dystrophy (mdx/utr(-/-)) and thus can compensate for the loss of dystrophin in diseased mice. In spite of the beneficial effects of the alpha 7 integrin in protecting mice from dystrophy, identification of molecular signaling events responsible for these changes remains to be established. The purpose of this study was to determine a role for signaling in the amelioration of muscular dystrophy by alpha 7 integrin. Activation of PI3K, ILK, AKT, mTOR, p7056K, BAD. ERK, and p38 was measured in the muscle from wild type (WT), mdx/utr(-/-) and alpha 7BX2-mdx/utr(-/-) mice using in vitro activity assays or phosphospecific antibodies and western blotting. Significant increases in PI3K activity (47%), ILK activity (2.0-fold), mTOR (Ser2448) (57%), p7056K (Thr389) (11.7-fold), and ERK (Thr202/Cyr204) (66%) were demonstrated in dystrophic mdx/utr(-/-) muscle compared to WT. A significant decrease in p38 phosphorylation (2.9-fold) was also observed. Although most of these signaling events were similar in dystrophic mdx/utr(-/-) mice overexpressing the alpha 7 integrin, the AKT (Ser473): Ala ratio (2-fold vs. WT) and p7056K phosphorylation (18-fold vs. WT) were higher in alpha 7BX2-mdx/utr(-/-) compared to mdx/utr(-/-) mice. In addition, increased phosphorylation of BAD Serine 112 may contribute to the significant reduction in TUNEL(+) cells observed in alpha 7BX2-mdx/utr(-/-) mice. We conclude that the alpha 7 beta 1 integrin confers a protective effect in dystrophic muscle through the activation of the ILK, AKT, p7056K and BAD signaling to promote muscle cell survival. (C) 2011 Elsevier B.V. All rights reserved.
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