The Cardiac Mechanical Stretch Sensor Machinery Involves a Z Disc Complex that Is Defective in a Subset of Human Dilated Cardiomyopathy

Abstract

Muscle cells respond to mechanical stretch stimuli by triggering downstream signals for myocyte growth and survival. The molecular components of the muscle stretch sensor are unknown, and their role in muscle disease is unclear. Here, we present biophysical/biochemical studies in muscle LIM protein (MLP) deficient cardiac muscle that support a selective role for this Z disc protein in mechanical stretch sensing. MLP interacts with and colocalizes with telethonin (T-cap), a titin interacting protein. Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization. We propose that a Z disc MLP/T-cap complex is a key component of the in vivo cardiomyocyte stretch sensor machinery, and that defects in the complex can lead to human DCM and associated heart failure.

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

“…As a number of missense mutations in genes encoding for titin and titin-associated proteins have recently been reported to be responsible for DCM, 3,[12][13][14][15][19][20][21][22][23][24][25] we searched in a well-characterized sample of DCM patients for unknown SNPs and/or mutations in the human MYPN and ANKRD1 genes. In order to extend our knowledge on disease-causing mutations in these two proteins expressed in heart tissue, we screened the coding sequences and corresponding intron flanks of the two genes and found two novel non-synonymous mutations in the MYPN gene and only one rare synonymous SNP in the coding region of the ANKRD1 gene.…”

Molecular mechanisms of mechanosensing in muscle development

“…Titin's N-terminus is coupled via telethonin (T-cap) to MLP, which is believed to be central to Zdisk-based mechanosensing (Knöll et al, 2002) (Fig. 1).…”

“…In the Drosophila heart, Mlp84B acts as a stress sensor, which, when disrupted, causes diastolic interval prolongation, heart rhythm abnormalities, and reduced lifespan, while showing no obvious structural phenotypes (Mery et al, 2008). Likewise, cardiomyocytes of neonatal MLP null mice exhibit defects in stretch sensing (Knöll et al, 2002). This may be due to the selective loss of T-cap from the Z-disk since direct interaction of T-cap with MLP is required for the stabilization of T-cap at the Z-disk.…”

Remodelage précoce du ventricule gauche après un accident coronarien aigu

“…Ces deux voies aboutissent à l'activation de facteurs de transcription qui déclenchent, de façon additive ou non selon le gène considéré, le processus hypertrophique et la réexpression du programme foetal, mais qui peuvent aussi favoriser l'apoptose des myocytes. Une troisième voie, de découverte récente [10], est également activée par l'étirement des myocytes: elle fait intervenir des signaux qui trouvent leur origine au niveau de la ligne Z du sarcomère et des protéines d'ancrage de la ligne Z à la membrane cellulaire (costamère), et sont transmis au noyaux par une cascade de protéines en cours d'identification, dont, peut-être, la Tcap/téléthonine, la calsarcine et la calcineurine.…”