Melusin is a protein selectively expressed in skeletal muscle and heart, and binding to the beta1 integrin cytoplasmic domain (Brancaccio et al., 1999) (Fig. 1). Primary amino acidic sequence of melusin (Fig. 2) revealed the presence of two cysteine/histidine rich domains capable of binding Zn2+ known as CHORD domains at the N-terminal portion of the protein (red globules). The C terminal half of the protein is characterized by a CS domain (blue element) found in proteins, such as alpha-crystallin and cochaperones p23 and Sgt1, and containing the integrin binding site. Further downstream, a stretch of 44 residues rich in glutammic and aspartic acids and binding Ca2+ with low affinity is present at the extreme C-terminal end (green element) (Brancaccio et al., 2003a). Melusin function has been investigated by inactivating the corresponding gene in mice by homologous recombination. The melusin null mice are viable and fertile and do not show appreciable muscle or heart defects during their natural life, showing that melusin is not required for development and differentiation of striated muscle tissue (Brancaccio et al., 2003b). However, when heart is exposed to conditions of chronic pressure overload, such as after surgical transverse aortic banding, melusin null mice develop an impaired left ventricular hypertrophy that in four weeks evolves in left ventricle dilation and contractile dysfunction (Fig. 3 lower panels). Control mice subjected to the same treatment develop concentric compensatory hypertrophy, which is maintained for the whole period of four weeks (Fig. 3 upper panels). The impaired hypertrophy developed by melusin null mice is limited to the mechanical stimulus of aortic constriction, since normal hypertrophy is developed in response to neurohumoral factors, such as angiotensin II and phenylephrine, administered at doses which do not increase blood pressure, and thus do not alter the hemodynamic load (Brancaccio et al., 2003b). These data strongly indicate that melusin is involved in transducing the mechanical stimulus in agreement with its ability to bind to integrins.
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The functional properties of melusin have been further investigated by generating transgenic mice that overexpress melusin in the heart (De Acetis et al., 2005). These mice showed a mild cardiac hypertrophy in basal conditions with no obvious structural and functional alterations. After prolonged pressure overload (12 weeks), melusin over-expressing hearts retain concentric cardiac remodeling and full contractile function, while wild type showed pronounced left ventricle chamber dilation with an impaired contractility (Fig. 4). In addition, after 12 weeks of pressure overload heart of melusin over-expressing mice showed very low level of cardiomyocyte apoptosis and stromal tissue deposition, as well as increased capillary density compared to wild type (De Acetis et al., 2005).

Analysis of the signaling pathways activated in cardiomyocytes shortly after aortic constriction (5-10 min) demonstrates that phosphorylation of AKT and GSK3β is markedly impaired in heart of melusin-null mice. On the other hand melusin over-expressing heart shows increased basal phosphorylation of GSK3β and ERK1/2. Moreover, AKT, GSK3β and ERK1/2 are hyper-phosphorylated upon pressure overload in melusin over-expressing, compared to wild type mice. Melusin, thus, senses high threshold levels of mechanical stress and activates AKT/GSK3β dependent signaling pathways controlling cardiomyocyte hypertrophy (Brancaccio et al., 2003b; De Acetis et al., 2005).

Melusin is thus an important molecule with the unique property of triggering cardiac compensatory hypertrophy and preventing cardiac dilation and failure (Fig. 5).