We have previously shown that genetic ablation of melusin, a muscle specific beta 1 integrin interacting protein, accelerates left ventricle (LV) dilation and heart failure in response to pressure overload. Here we show that melusin expression was increased during compensated cardiac hypertrophy in mice subjected to 1 week pressure overload, but returned to basal levels in LV that have undergone dilation after 12 weeks of pressure overload. To better understand the role of melusin in cardiac remodeling, we overexpressed melusin in heart of transgenic mice. Echocardiography analysis indicated that melusin over-expression induced a mild cardiac hypertrophy in basal conditions (30% increase in interventricular septum thickness) with no obvious structural and functional alterations. After prolonged pressure overload (12 weeks), melusin overexpressing hearts underwent further hypertrophy retaining concentric LV remodeling and full contractile function, whereas wild-type LV showed pronounced chamber dilation with an impaired contractility. Analysis of signaling pathways indicated that melusin overexpression induced increased basal phosphorylation of GSK3beta and ERK1/2. Moreover, AKT, GSK3beta and ERK1/2 were hyper-phosphorylated on pressure overload in melusin overexpressing compared with wild-type mice. In addition, after 12 weeks of pressure overload LV of melusin overexpressing mice showed a very low level of cardiomyocyte apoptosis and stromal tissue deposition, as well as increased capillary density compared with wild-type. These results demonstrate that melusin overexpression allows prolonged concentric compensatory hypertrophy and protects against the transition toward cardiac dilation and failure in response to long-standing pressure overload.