Cellular and molecular aspects of muscular plasticity

Abstract

Muscles are tension generators that play a key role in 1) skeleton position; 2) moving blood along the circulatory system allowing tissue perfusion; 3) venous return; 4) peripheral vascular resistance control; 5) visceral movements and 6) ocular movements. Muscle tissues are highly plastic and respond quickly to injury and hormonal stimuli. Conditions in which muscle tissues are debilitated highlight well their role in homeostatic control. For example, 1) a major cause of death in developed and developing countries is heart failure, which is commonly linked to vascular diseases, specially associated with endothelial tissue; 2) loss of skeletal muscle mass (eventually leading to cachexia) in severe cardiac failure is retated to poor prognostic; 3) loss of skeletal muscle mass over aging is an important element of the senile syndrome, where decreased immune response is a major concern. The development of new strategies aiming a better outcome of muscle function necessarily depends upon a deeper knowledge of cellular and molecular biology of tissue responses. Therefore, the aim of this study is to gain further insight on cellular and molecular mechanisms underlying muscle plasticity. In subproject 1 the effect of certain mechanical stimuli will be stressed, to further investigate the role of Akt/mTOR on skeletal muscle mass control. In subproject 2, we will address the effects of increased skeletal muscle mass upon energy balance control. This will be achieved by using muscular IGF-1 transgenic mice. In subprojects 3 and 4 we will evaluate cellular and molecular effects of hormones extremely important to the homeostasis of muscle tissues: thyroid hormone (T3) and angiotensin II. In subproject 5 a molecular approach of skeletal muscle proteolysis triggered by T3 will be performed. In subprojects 6 and 7, the activity of Akt/mTOR and calcineurin will be investigated in skeletal muscle of mice undergoing cardiac failure. Finally, in subproject 8, we will determine the effects of GC-24 (a thyroid hormone receptor β selective agonist) upon the global gene expression pattern in all three muscle tissues. (AU)