The Extracellular Matrix Protein ABI3BP in Cardiovascular Health and Disease

ABI3BP is a relatively newly identified protein whose general biological functions are not yet fully defined. It is implicated in promoting cellular senescence and cell-extracellular matrix interactions, both of which are of vital importance in the cardiovascular system. ABI3BP has been shown in multiple studies to be expressed in the heart and vasculature, and to have a role in normal cardiovascular function and disease. However, its precise role in the cardiovascular system is not known. Because ABI3BP is present in the cardiovascular system and is altered in cardiovascular disease states, further investigation into ABI3BP's biological and biochemical importance in cardiovascular health and disease is warranted

Improvement of cardiac contractile function by peptide-based inhibition of NF-κB in the utrophin/dystrophin-deficient murine model of muscular dystrophy

<p>Abstract</p> <p>Background</p> <p>Duchenne muscular dystrophy (DMD) is an inherited and progressive disease causing striated muscle deterioration. Patients in their twenties generally die from either respiratory or cardiac failure. In order to improve the lifespan and quality of life of DMD patients, it is important to prevent or reverse the progressive loss of contractile function of the heart. Recent studies by our labs have shown that the peptide NBD (Nemo Binding Domain), targeted at blunting Nuclear Factor κB (NF-κB) signaling, reduces inflammation, enhances myofiber regeneration, and improves contractile deficits in the diaphragm in dystrophin-deficient <it>mdx </it>mice.</p> <p>Methods</p> <p>To assess whether cardiac function in addition to diaphragm function can be improved, we investigated physiological and histological parameters of cardiac muscle in mice deficient for both dystrophin and its homolog utrophin (double knockout = dko) mice treated with NBD peptide. These dko mice show classic pathophysiological hallmarks of heart failure, including myocyte degeneration, an impaired force-frequency response and a severely blunted β-adrenergic response. Cardiac contractile function at baseline and frequencies and pre-loads throughout the in vivo range as well as β-adrenergic reserve was measured in isolated cardiac muscle preparations. In addition, we studied histopathological and inflammatory markers in these mice.</p> <p>Results</p> <p>At baseline conditions, active force development in cardiac muscles from NBD treated dko mice was more than double that of vehicle-treated dko mice. NBD treatment also significantly improved frequency-dependent behavior of the muscles. The increase in force in NBD-treated dko muscles to β-adrenergic stimulation was robustly restored compared to vehicle-treated mice. However, histological features, including collagen content and inflammatory markers were not significantly different between NBD-treated and vehicle-treated dko mice.</p> <p>Conclusions</p> <p>We conclude that NBD can significantly improve cardiac contractile dysfunction in the dko mouse model of DMD and may thus provide a novel therapeutic treatment for heart failure.</p

Cholesterol Regulation of PIP2: Why Cell Type is So Important

A commentary on how cholesterol regulates endothelial biomechanics

Lengthening-contractions in isolated myocardium impact force development and worsen cardiac contractile function in the mdx mouse model of muscular dystrophy

Lengthening-contractions exert eccentric stress on myofibers in normal myocardium. In congestive heart failure caused by a variety of diseases, the impact of lengthening-contractions of myocardium likely becomes more prevalent and severe. The present study introduces a method to investigate the role of stretching imposed by repetitive lengthening-contractions in myocardium under near-physiological conditions. By exerting various stretch-release ramps while the muscle is contracting, consecutive lengthening-contractions and their potential detrimental effect on cardiac function can be studied. We tested our model and hypothesis in age-matched (young and adult) mdx and wild-type mouse right ventricular trabeculae. These linear and ultrathin muscles possess all major cardiac cell types, and their contractile behavior very closely mimics that of the whole myocardium. In the first group of experiments, 10 lengthening-contractions at various magnitudes of stretch were performed in trabeculae from 10-wk-old mdx and wild-type mice. In the second group, 100 lengthening-contractions at various magnitudes were conducted in trabeculae from 10- and 20-wk-old mice. The peak isometric active developed tension (Fdev, in mN/mm2) and kinetic parameters time to peak tension (TTP, in ms) and time from peak tension to half-relaxation (RT50, in ms) were measured. Our results indicate lengthening-contractions significantly impact contractile behavior, and that dystrophin-deficient myocardium in mdx mice is significantly more susceptible to these damaging lengthening-contractions. The results indicate that lengthening-contractions in intact myocardium can be used in vitro to study this emerging contributor to cardiomyopathy

Metabolic dysfunction and altered mitochondrial dynamics in the utrophin-dystrophin deficient mouse model of duchenne muscular dystrophy.

The utrophin-dystrophin deficient (DKO) mouse model has been widely used to understand the progression of Duchenne muscular dystrophy (DMD). However, it is unclear as to what extent muscle pathology affects metabolism. Therefore, the present study was focused on understanding energy expenditure in the whole animal and in isolated extensor digitorum longus (EDL) muscle and to determine changes in metabolic enzymes. Our results show that the 8 week-old DKO mice consume higher oxygen relative to activity levels. Interestingly the EDL muscle from DKO mouse consumes higher oxygen per unit integral force, generates less force and performs better in the presence of pyruvate thus mimicking a slow twitch muscle. We also found that the expression of hexokinase 1 and pyruvate kinase M2 was upregulated several fold suggesting increased glycolytic flux. Additionally, there is a dramatic increase in dynamin-related protein 1 (Drp 1) and mitofusin 2 protein levels suggesting increased mitochondrial fission and fusion, a feature associated with increased energy demand and altered mitochondrial dynamics. Collectively our studies point out that the dystrophic disease has caused significant changes in muscle metabolism. To meet the increased energetic demand, upregulation of metabolic enzymes and regulators of mitochondrial fusion and fission is observed in the dystrophic muscle. A better understanding of the metabolic demands and the accompanied alterations in the dystrophic muscle can help us design improved intervention therapies along with existing drug treatments for the DMD patients

Transmission electron microscopic images show mitochondrial localization is altered in DKO EDL muscle.

<p>A) WT EDL B) DKO EDL at 14000X magnification. C) WT and D) DKO at 34000x magnification. The arrows point to the localization of mitochondria (M) which are at the I band on either side of the Z disc in WT, but this tight localization is reduced in the DKO EDL.</p

Increased potentiation of force by pyruvate in DKO EDL.

<p>A). Effect of substrate on force production showing an increase in force production using pyruvate as a substrate at lower frequencies in DKO mice. B) B) Specific force produced by WT EDL is significantly higher (p<0.05) than DKO EDL when glucose is used as a substrate at 50 Hz. In the presence of pyruvate the specific force produced by WT EDL is not significantly different from DKO EDL at 50Hz. There is a significant increase in force production in DKO EDL when pyruvate is used as a substrate compared to glucose (p<0.05). However, the force produced by WT EDL in the presence of pyruvate is not significantly different from the force produced in presence of glucose. C) % Increase in force using pyruvate as a substrate relative to glucose is significantly higher in DKO EDL compared to WT at 30Hz (p = 0.0033) and D) 50Hz (p = 0.0011). p< 0.05 is significant. * = p<0.05, ** = p<0.01.</p

DKO mice weigh less but consume similar amount of food when compared to WT controls.

<p>A) DKO mice weigh significantly less than WT (p = 0.0298). B) Food consumption between WT and DKO mice is not significantly different.</p

Increased oxygen consumption relative to integral force.

<p>A) The fatigue profile of WT and DKO EDL during the 10 minutes fatigue shows that DKO EDL generates lesser force and fatigues less. B) The % of initial force after the 10 minute fatigue is higher in DKO EDL indicating less fatigue (p = 0.0019). C) The quantified force time integral over the entire 10 minutes fatigue protocol is significantly reduced in the DKO EDL compared to WT (p = 0.0097). D) Oxygen consumption over 10 minutes fatigue is not significantly different in WT and DKO EDL muscle. E). Oxygen consumed per unit integral force produced is significantly higher in DKO EDL compared to WT (p = 0.0110). p< 0.05 is significant. * = p<0.05, ** = p<0.01.</p

Whole body energy expenditure of WT and DKO mice.

<p>A) Rate of oxygen consumption in DKO mice is not significantly different from WT at both night and B) day. Respiratory exchange ratio (F) is similar in WT and DKO mice both at C) night and D) day. Activity counts measured in WT and DKO mice during E) night and F) day. Activity counts are significantly reduced (p = 0.0060) in DKO mice at night compared to WT. Oxygen consumption per unit activity is significantly higher in the DKO mice both during G) night (p = 0.0023) and H) day (p = 0.0463) p<0.05 = significant. * = p<0.05, ** = p<.01.</p