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Published online March 10, 2008
doi:10.1083/jcb.200707175
The Journal of Cell Biology, Vol. 180, No. 5, 1037-1049
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Wang et al.
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Article

 Integrin-linked kinase stabilizes myotendinous junctions and protects muscle from stress-induced damage

Hao-Ven Wang1, Ling-Wei Chang1,2, Klara Brixius3, Sara A. Wickström1, Eloi Montanez1, Ingo Thievessen1, Martin Schwander4, Ulrich Müller4, Wilhelm Bloch3, Ulrike Mayer5, and Reinhard Fässler1

1 Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany
2 Department of Obstetrics and Gynecology, National Cheng Kung University Medical College and Hospital, 70428 Tainan, Taiwan
3 Department of Molecular and Cellular Sport Medicine, 50933 Cologne, Germany
4 Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
5 Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, England, UK

Correspondence to Reinhard Fässler: Faessler{at}biochem.mpg.de

Skeletal muscle expresses high levels of integrin-linked kinase (ILK), predominantly at myotendinous junctions (MTJs) and costameres. ILK binds the cytoplasmic domain of β1 integrin and mediates phosphorylation of protein kinase B (PKB)/Akt, which in turn plays a central role during skeletal muscle regeneration. We show that mice with a skeletal muscle–restricted deletion of ILK develop a mild progressive muscular dystrophy mainly restricted to the MTJs with detachment of basement membranes and accumulation of extracellular matrix. Endurance exercise training enhances the defects at MTJs, leads to disturbed subsarcolemmal myofiber architecture, and abrogates phosphorylation of Ser473 as well as phosphorylation of Thr308 of PKB/Akt. The reduction in PKB/Akt activation is accompanied by an impaired insulin-like growth factor 1 receptor (IGF-1R) activation. Coimmunoprecipitation experiments reveal that the β1 integrin subunit is associated with the IGF-1R in muscle cells. Our data identify the β1 integrin–ILK complex as an important component of IGF-1R/insulin receptor substrate signaling to PKB/Akt during mechanical stress in skeletal muscle.

Abbreviations used in this paper: BM, basement membrane; ddH2O, double-distilled H2O; DGC, dystrophin–glycoprotein complex; DM, differentiation medium; E, embryonic day; EGF, epithelial growth factor; GC, gastrocnemius; GM, growth medium; HSA, human skeletal {alpha}-actin; IGF, insulin-like growth factor; IGF-1R, IGF receptor 1; ILK, integrin-linked kinase; MTJ, myotendinous junction.


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