DMD TREATMENT: ANIMAL MODELS: P.202Low Kindlin-2 levels in patients and mouse model of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) occurs due to mutations in dystrophin, a part of the dystrophin-glycoprotein complex (DGC). This complex links the extracellular matrix (ECM) and the myofiber cytoskeleton, protecting the skeletal muscle against contraction-induced damage. Similar to the DGC, the integrin complex functions as a structural link between the ECM and the cytoskeleton, playing an important role in muscle fiber stability. In this complex, Integrin linked kinase (ILK) is responsible for signaling between the ECM and the muscle fiber. Kindlin-2 (also known as Mig-2/FERMT2) is physically attached to both integrin-and ILK proteins, thus it may serve as an anchor between the ECM and the inside of the cell in this integrin-kindlin-2-ILK complex. Gene expression profiling study at our laboratory has demonstrated that integrin complex molecules and ILK pathway are significantly increased in dystrophin deficient skeletal muscle from mdx mice, the DMD mouse model, and in children with DMD. Upregulation of these molecules occurs probably due to compensatory mechanisms for dystrophin deficiency. On the other hand, in our RNA-Seq and western-blot results, kindlin-2 is downregulated in the mdx mice and also in DMD boys' muscles, probably secondary to the dystrophic process in an unknown mechanism. Kindlin-2 is important for cell membrane integrity, via its interaction with the integrin complex as an alternative to the disrupted DGC, and for myogenesis, thus kindlin-2 may promote survival and regeneration in dystrophin deficient muscle. Further evaluation of kindlin-2 role in muscular dystrophy and as potential for therapeutic intervention is recommended.