Effects of CaMKII activity on cardiac and skeletal muscle pathology in a mouse model of Duchenne muscular dystrophy (1102.3)

Abstract

Patients with Duchenne Muscular Dystrophy (DMD) lack functional dystrophin, an essential member of the dystrophin‐glycoprotein complex. Without dystrophin, the actin cytoskeleton is not anchored to the extracellular matrix, which leads to membrane damage. Patients with DMD have dystrophic and weakened skeletal muscle and often develop dilated cardiomyopathy. The aim of this project is to study the effects of Ca2+ and Calmodulin‐dependent protein kinase II (CaMKII) activity on the development of the dystrophic phenotype. CaMKII is an intracellular signaling protein involved in many pathways, including excitation‐contraction coupling and Ca2+ homeostasis. Hyperactivity of CaMKII is linked with cardiac hypertrophy, arrhythmias, and heart failure. We hypothesized that increased CaMKII activity would cause an increase in skeletal muscle and cardiac pathology in mdx mice, which lack dystrophin and serve as a model of DMD. A mouse model of inhibited CaMKII activity expresses a transgenic peptide inhibitor of CaMKII. A mouse model of CaMKII hyperactivity lacks the CaMKII regulatory protein, Methionine Sulfoxide Reductase A. We crossed the mouse models of inhibited and hyperactive CaMKII activity onto a dystrophic mdx background. Several pathological parameters were used to quantitatively measure disease progression in the different models.Grant Funding Source: Supported by a Wellstone Muscular Dystrophy Cooperative Research Center grant (KPC), HHMI, APS (NMJ)