Plakoglobin is essential for myocardial compliance but dispensable for myofibril insertion into adherens junctions

Abstract

Plakoglobin (gamma-catenin), a member of the armadillo family of proteins, is a constituent of the cytoplasmic plaque of cardiac junctions and is involved in anchorage of cytoskeletal filaments to specific cadherins. Its genetic inactivation leads to an embryonic lethal phenotype due to heart dysfunction related to an impairment in the architecture of intercalated discs and in the stability of the heart tissue. To elucidate the functional consequences of the loss of plakoglobin for myofibrillar function, we monitored passive stress-strain relationship and contractility parameters of demembranated embryonic fibers. Heart fibers obtained from plakoglobin-deficient embryonic mice were significantly less compliant than were fibers from wild-type embryos. This difference was especially pronounced at lower fiber extension levels: at 120% of slack length, compliance was 2.5-fold lower in plakoglobin-deficient mice than in the corresponding wild-type group. Contractile paramenters (force per cross-section; Ca2+ sensitivity of isometric force and shortening velocity at near-zero load) were comparable in all experimental groups. Therefore, we suggest that plakoglobin is important for cardiac compliance but not necessary for the attachment of the myofibrillar apparatus to adherens junctions. Thus, we conclude that the loss of function of desmosomes and the profound disarrangement of junctional components in plakoglobin null embryos is associated with a decreased passive compliance, which may explain the ventricular rupture and consequent pericardial tamponade in embryos lacking plakoglobin.

Requirement of plakophilin 2 for heart morphogenesis and cardiac junction formation

“…Our work also shows that both plakophilin 2 and desmoplakin are not required for the anchorage of myofibrils to adhering junctions of cardiomyocytes (see Fig. 5, a and b), as this has also been shown for plakoglobin (Isac et al, 1999). By contrast, the IF arrays normally interspersed between the myofibrils and enriched at the intercalated disks (e.g., Kartenbeck et al, 1983;Milner et al, 1996) are often displaced in the mutant, but still display associations with desmoplakin, including formations of swirls around the desmoplakin aggregates.…”

Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

“…LIMP-2 stands out among ID proteins. Complete loss of other major constituents of the ID (cadherin, β-catenin, and plakoglobin) is lethal due to the developmental cardiac derangements (3)(4)(5)(6), suggesting that these components of the ID are essential for normal cardiac development. In contrast, cardiac development is normal in LIMP-2 null mice, and loss of LIMP-2 only aff ects postnatal cardiac remodeling upon hypertension.…”

In Vivo Function of Desmosomes

“…Desmosomes are normally found in the intercalated discs of the myocardium. The Birchmeier laboratory showed that desmosomes were not formed in the intercalated discs of the pg null myocardium (127, 128). Interestingly, these authors found extended adherens junctions that contained desmoplakin and β‐catenin.…”