Abstract
Dystonin is a giant cytoskeletal protein belonging to the plakin protein family and is believed to crosslink the major filament systems in contractile cells. Previous work has demonstrated skeletal muscle defects in dystonin-deficient dystonia musculorum (dt) mice. In this study, we show that the dystonin muscle isoform is localized at the Z-disc, the H zone, the sarcolemma and intercalated discs in cardiac tissue. Based on this localization pattern, we tested whether dystonin-deficiency leads to structural defects in cardiac muscle. Desmin intermediate filament, microfilament, and microtubule subcellular organization appeared normal in dt hearts. Nevertheless, increased transcript levels of atrial natriuretic factor (ANF, 66%) β-myosin heavy chain (beta-MHC, 95%) and decreased levels of sarcoplasmic reticulum calcium pump isoform 2A (SERCA2a, 26%), all signs of cardiac muscle stress, were noted in dt hearts. Hearts from two-week old dt mice were assessed for the presence of morphological and histological alterations. Heart to body weight ratios as well as left ventricular wall thickness and left chamber volume measurements were similar between dt and wild-type control mice. Hearts from dt mice also displayed no signs of fibrosis or calcification. Taken together, our data provide new insights into the intricate structure of the sarcomere by situating dystonin in cardiac muscle fibers and suggest that dystonin does not significantly influence the structural organization of cardiac muscle fibers during early postnatal development.
Highlights
Plakin crosslinking proteins such as dystonin and plectin have been implicated in regulating the cytoskeletal organization and function of muscle
To investigate the effects of dystonin-deficiency on cardiac muscle, we identified the sarcomeric localization of dystonin isoform-b, the predominant muscle isoform of dystonin in cardiac tissue
Our results show that the primary cytoskeletal components, namely microfilaments, desmin intermediate filaments, and microtubules remain intact in dt hearts
Summary
Plakin crosslinking proteins such as dystonin and plectin have been implicated in regulating the cytoskeletal organization and function of muscle (recently reviewed in [1,2]). While a number of recent studies have further defined the role of plectin in muscle tissue [3,4,5,6], much less progress has been made in elucidating the functions of dystonin in contractile cells. The muscle and neuronal isoforms can be further characterized by three unique Nterminal regions (dystonin-b1, b2, b3/a1, a2, a3) that influence the subcellular localization of these proteins [13,14,15,16]. The dystonin-b muscle isoforms are the largest (834 kDa) and consist of several domains: an N-terminal actin-binding domain (ABD), a plakin domain, a spectrin repeat containing rod domain, a centrally located intermediate filament binding domain (IFBD2) and a microtubule-binding domain (MTBD) at the C-terminus [8]
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