GENE INACTIVATION OF MELUSIN, A NEW MUSCLE SPECIFIC PROTEIN OF THE INTEGRIN TRANSDUCTION PATHWAY IN HEART AND SKELETAL MUSCLE. POSSIBLE IMPLICATION IN HEART AND MUSCLE PATHOLOGIES

The connection of actin to the plasma membrane in muscle cells is required to transmit the mechanical tension during muscle contraction. Such connection is stabilized by membrane receptors of the integrin families and their importance is demonstrated by the presence of severe muscle pathologies when integrin genes are mutated in man or in different animal systems. In previous work founded by Telethon we have identified an integrin isoform (b1D) selectively expressed in cardiac and skeletal muscles. This protein is characterized by a unique sequence in the region of the protein interacting with actin. Functional analysis indicated that b1D integrin isoform provides a strong actin-membrane interaction across the plasma membrane necessary to support the mechanical tension during muscle contraction. More recently we discovered a new muscle specific protein, melusin, capable to interact with the region of b1D involved in anchoring actin filaments to the membrane, which is a likely candidate as mediator of specific b1 function in muscle. To test the functional importance of melusin we have generated a mouse in which melusin gene has been inactivated. These mice are apparently normal, but develop severe skeletal and cardiac defects when subjected to intense muscular exercise or treated to induce high blood pressure. With this project we will utilize the mutated mouse strain as model system to investigate the molecular mechanisms of melusin function in muscle and to define a possible role of melusin in human cardiac and skeletal muscle pathologies.