Abstract

Abstract
The role of the calcineurin/NFAT signaling pathway and its regulation in muscle diseases
Manal Al Zein, PhD
Concordia University, 2013

Elevations in intracellular calcium activate the phosphatase Calcineurin (Cn) and its downstream target the Nuclear Factor of Activated T cells (NFAT), leading to the expression of genes involved in skeletal muscle growth and cardiac remodeling. In this thesis, we set out to investigate the role of the Cn/NFAT signaling pathway in the progression of two muscle diseases: Duchenne Muscular Dystrophy (DMD), which is characterized by the loss of the functional protein dystrophin, and cardiac hypertrophy. First, to understand the roles of Cn and Cn regulators in DMD, we used mdx mice crossed with mice expressing transgenes that manipulate the Cn/NFAT pathway. For instance, the expression of the transgene Parvalbumin (PV) in mdx mice leads to attenuation of Cn activity and reduction in the expression of utrophin, a protein that compensates for the loss of dystrophin. Our results show that strategies promoting Ca2+/Cn signaling are considered an effective countermeasure in the treatment of DMD and that Cn regulators might have a critical role in the progression of the disease. Secondly, the role of the NFATc2 transcription factor in Cn-dependent cardiac hypertrophy is emphasized using adult NFATc2 knockout mice in the presence and absence of biochemical stress. Here we show a cardio-protective role for NFATc2 in normotensive hearts, but not in hearts exposed to stress. Together, the results of this thesis provide a better understanding of the role of the Cn/NFAT pathway in the regulation of various muscle diseases.