Integrins in the Development and Pathology of Skeletal Muscle

Skeletal muscle is composed of many multinucleated myofibres each of which is surrounded by a connective tissue matrix that is essential for the function and the structural integrity of muscle. Apposed to each myofibre is a basement membrane, composed of a mixture of extracellular matrix (ECM) proteins, including collagen, fibronectin, glycoproteins (laminins, perlecan and nidogen) and proteoglycans. The proteins bind to multiple receptors expressed on the surface of muscle fibres: this is most notable at the level of the Z discs where an assembly of cytoskeletal proteins including dystrophin and integrins maintain continuity between the contractile apparatus, cytoskeleton and the ECM. This association of proteins is commonly referred to as the costamere, which is derived from the Latin word costa, meaning rib, because they encircle the whole muscle fibre and are arranged at regular intervals, thus conferring the appearance of a rib-like structure (Ervasti, 2003). Costameres are the means by which mechanical stress generated by contraction is diffused laterally across the myofibre. An additional structure where stress is transmitted to the ECM is the myotendinous junction (MTJ), where a connection to the tendon is made at the termini of muscle fibres (Tidball, 1991). This tight association between the muscle fibre and its surrounding matrix not only confers tensile strength to the entire muscle but also plays an important role in development, regeneration and synaptogenesis (Sanes, 2003). Indeed genetic defects in proteins that localise to the costameres and MTJs are a common cause of muscle disease, underscoring their importance in maintaining normal muscle function (Campbell and Stull, 2003).