Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity.

Doxorubicin (DOX) is a commonly used life-saving antineoplastic agent that also causes dose-dependent cardiotoxicity. Because ATP is absolutely required to sustain normal cardiac contractile function and because impaired ATP synthesis through creatine kinase (CK), the primary myocardial energy reserve reaction, may contribute to contractile dysfunction in heart failure, we hypothesized that impaired CK energy metabolism contributes to DOX-induced cardiotoxicity. We therefore overexpressed the myofibrillar isoform of CK (CK-M) in the heart and determined the energetic, contractile and survival effects of CK-M following weekly DOX (5 mg/kg) administration using in vivo (31)P MRS and (1)H MRI.

Skeletal muscle ATP kinetics are impaired in frail mice.

The interleukin-10 knockout mouse (IL10(tm/tm)) has been proposed as a model for human frailty, a geriatric syndrome characterized by skeletal muscle (SM) weakness, because it develops an age-related decline in SM strength compared to control (C57BL/6J) mice. Compromised energy metabolism and energy deprivation appear to play a central role in muscle weakness in metabolic myopathies and muscular dystrophies. Nonetheless, it is not known whether SM energy metabolism is altered in frailty.

Creatine kinase overexpression improves ATP kinetics and contractile function in postischemic myocardium.

Reduced myofibrillar ATP availability during prolonged myocardial ischemia may limit post-ischemic mechanical function. Because creatine kinase (CK) is the prime energy reserve reaction of the heart and because it has been difficult to augment ATP synthesis during and after ischemia, we used mice that overexpress the myofibrillar isoform of creatine kinase (CKM) in cardiac-specific, conditional fashion to test the hypothesis that CKM overexpression increases ATP delivery in ischemic-reperfused hearts and improves functional recovery. Isolated, retrograde-perfused hearts from control and CKM mice were subjected to 25 min of global, no-flow ischemia and 40 min of reperfusion while cardiac function [rate pressure product (RPP)] was monitored.

Use of perfluorocarbon nanoparticles for non-invasive multimodal cell tracking of human pancreatic islets.

In vivo imaging of engraftment and immunorejection of transplanted islets is critical for further clinical development, with (1)H MR imaging of superparamagnetic iron oxide-labeled cells being the current premier modality. Using perfluorocarbon nanoparticles, we present here a strategy for non-invasive imaging of cells using other modalities. To this end, human cadaveric islets were labeled with rhodamine-perfluorooctylbromide (PFOB) nanoparticles, rhodamine-perfluoropolyether (PFPE) nanoparticles or Feridex as control and tested in vitro for cell viability and c-peptide secretion for 1 week.

Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging.

Purpose: To develop novel immunoprotective alginate microcapsule formulations containing perfluorocarbons (PFCs) that may increase cell function, provide immunoprotection for xenografted cells, and simultaneously enable multimodality imaging.

Materials And Methods: All animal experiments were approved by an Institutional Animal Care and Use Committee. Cadaveric human islet cells were encapsulated with alginate, poly-l-lysine, and perfluorooctyl bromide (PFOB) or perfluoropolyether (PFPE).

Impaired ATP kinetics in failing in vivo mouse heart.

Background: The hypothesis that the failing heart may be energy-starved is supported in part by observations of reduced rates of adenosine 5'-triphosphate (ATP) synthesis through the creatine kinase (CK) reaction, the primary myocardial energy reservoir, in patients with heart failure (HF). Although murine models have been used to probe HF pathophysiology, it has not been possible to noninvasively measure the rate of ATP synthesis through CK in the in vivo mouse heart. The purpose of this work was to exploit noninvasive spatially localized magnetic resonance spectroscopy techniques to measure ATP flux through CK in in vivo mouse hearts and determine the extent of any reductions in murine HF.

In vivo "hot spot" MR imaging of neural stem cells using fluorinated nanoparticles.

To optimize (19)F MR tracking of stem cells, we compared cellular internalization of cationic and anionic perfluoro-15-crown-5-ether (PFCE) nanoparticles using cell culture plates with different surface coatings. The viability and proliferation of anionic and cationic PFCE-labeled neural stem cells (NSCs) did not differ from unlabeled cells. Cationic PFCE nanoparticles ((19)F T1/T2 = 580/536 ms at 9.

Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts.

After myocardial infarction, ventricular geometry and function, as well as energy metabolism, change markedly. In nonischemic heart failure, inhibition of xanthine oxidase (XO) improves mechanoenergetic coupling by improving contractile performance relative to a reduced energetic demand. However, the metabolic and contractile effects of XO inhibitors (XOIs) have not been characterized in failing hearts after infarction.

Hepatic ATP reserve and efficiency of replenishing: comparison between obese and nonobese normal individuals.

Objective: Although obesity-associated fatty liver disease is emerging as one of the most common diseases in hepatology practice, it is unclear why liver disease prevalence increases with obesity. Because impaired energy homeostasis enhances the susceptibility of hepatocytes to injury, the aim of this study was to determine whether increased body mass index (BMI) is associated with decreased basal hepatic adenosine triphosphate (ATP) stores or impaired recovery from fructose-induced hepatic ATP depletion.

Methods: Hepatic ATP stores were assessed by nuclear magnetic resonance spectroscopy in 19 healthy subjects with varying BMI.