Alterations at the intercalated disk associated with the absence of muscleLIM protein

In this study, we investigated cardiomyocyte cytoarchitecture in a mouse mo del for dilated cardiomyopathy (DCM), the muscle LIM protein (MLP) knockout mouse and substantiated several observations in a second DCM model, the tr opomodulin-over-expressing transgenic (TOT) mouse. Freshly isolated cardiom yocytes from both strains are characterized by a more irregular shape compa red with wild-type cells. Alterations are observed at the intercalated disk s, the specialized areas of mechanical coupling between cardiomyocytes, whe reas the subcellular organization of contractile proteins in the sarcomeres of MLP knock-out mice appears unchanged. Distinct parts of the intercalate d disks are affected differently. Components from the adherens junctions ar e upregulated, desmosomal proteins are unchanged, and gap junction proteins are: downregulated. In addition, the expression of N-RAP, a LIM domain- co ntaining protein located at the intercalated disks, is upregulated in MLP k nockout as well as in TOT mice. Detailed analysis of intercalated disk comp osition during postnatal development reveals that an upregulation of N-RAP expression might serve as an early marker for the development of DCM. Alter ed expression levels of cytoskeletal proteins (either the lack of MLP or an increased expression of tropomodulin) apparently lead to impaired function of the myofibrillar apparatus and to physiological stress that ultimately results in DCM and is accompanied by an altered appearance and composition of the intercalated disks.