The role of Calcium/calmodulin-dependent kinase and Calcineurin pathways in activity-dependent gene regulation in skeletal muscle

5 1. INTRODUCTION 1.1 Skeletal muscle fiber properties In vertebrates three different muscular tissues can be distinguished: smooth, cardiac and skeletal. Smooth muscle surrounds internal organs and major blood vessels, is innervated by the autonomous nervous system and it is made of mono-nucleated cells (called myocytes). The cells of cardiac muscle are mono-nucleated, and together with skeletal muscles form the complex of striated muscles. The functional units of skeletal muscles are the muscle fibers, long cylindrical multinucleated, with about 100 nuclei cells, 10-50 µm of diameter, 1-10 mm of length in rat muscles. The great majority of the cytoplasm of these cells is occupied by fascicles of longitudinal filaments called myofibrils, subdivided in light and dark bands, called I band and A band respectively. The basic structural and functional unit of skeletal muscle is called sarcomer: this repeated element has a length of 2 µm. Adjacent sarcomeric units are perfectly aligned, giving rise to the characteristic striated morphology that can be seen with the microscope. Each sarcomer contains two kinds of filaments: thin filaments, made of actin (that constitutes the light I band), thick filaments, made of myosin (dark A band). Contraction speed is related to the ATPase activity of myosin, and to the enzymes of the sarcoplasmic reticulum (SR) that sequester calcium (Ca 2+ ). Myosins are composed of three couple of subunits: two heavy chains (MyHC), two light chains (MLC) and two essential or alkaline chains. The two C-terminal domains of the MyHC subunits are coiled to form an α-helix tails, responsible for the association of many other MyHC dimers in a single filament. ATPasic activity and actin binding site are localized within the globular region of the protein (head). 1.1.1 Myofiber diversity Muscle fibers vary considerably with respect to their morphological, biochemical and physiological properties, enabling different muscles to fulfill a variety of functions, from maintaining the body posture to performing a wide range of movements and motions. Mammalian skeletal muscles are composed of two major fiber-types (I and II), basically distinguished on the basis of the myosin heavy chain isoform (MyHC) that they express, and differ in terms of size, metabolism, and contractile properties. MyHCs