Wen Zhang

Supranormal Myocardial Creatine and Phosphocreatine Concentrations Lead to Cardiac Hypertrophy and Heart Failure Insights From Creatine Transporter–Overexpressing Transgenic Mice

Background— Heart failure is associated with deranged cardiac energy metabolism, including reductions of creatine and phosphocreatine. Interventions that increase myocardial high-energy phosphate stores have been proposed as a strategy for treatment of heart failure. Previously, it has not been possible to increase myocardial creatine and phosphocreatine concentrations to supranormal levels because they are subject to tight regulation by the sarcolemmal creatine transporter (CrT). Methods and Results— We therefore created 2 transgenic mouse lines overexpressing the myocardial creatine transporter (CrT-OE). Compared with wild-type (WT) littermate controls, total creatine (by high-performance liquid chromatography) was increased in CrT-OE hearts (66±6 nmol/mg protein in WT versus 133±52 nmol/mg protein in CrT-OE). Phosphocreatine levels (by 31P magnetic resonance spectroscopy) were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed left ventricular (LV) dilatation (LV end-diastolic volume: 21.5±4.3 &mgr;L in WT versus 33.1±9.6 &mgr;L in CrT-OE; P=0.002), substantial LV dysfunction (ejection fraction: 64±9% in WT versus 49±13% in CrT-OE; range, 22% to 70%; P=0.003), and LV hypertrophy (by 3-dimensional echocardiography and magnetic resonance imaging). Myocardial creatine content correlated closely with LV end-diastolic volume (r=0.51, P=0.02), ejection fraction (r=−0.74, P=0.0002), LV weight (r=0.59, P=0.006), LV end-diastolic pressure (r=0.52, P=0.02), and dP/dtmax (r=−0.69, P=0.0008). Despite increased creatine and phosphocreatine levels, CrT-OE hearts showed energetic impairment, with increased free ADP concentrations and reduced free-energy change levels. Conclusions— Overexpression of the CrT leads to supranormal levels of myocardial creatine and phosphocreatine, but the heart is incapable of keeping the augmented creatine pool adequately phosphorylated, resulting in increased free ADP levels, LV hypertrophy, and dysfunction. Our data demonstrate that a disturbance of the CrT-mediated tight regulation of cardiac energy metabolism has deleterious functional consequences. These findings caution against the uncritical use of creatine as a therapeutic agent in heart disease.

Metabolomics of the interaction between PPAR-α and age in the PPAR-α-null mouse

Regulation between the fed and fasted states in mammals is partially controlled by peroxisome proliferator‐activated receptor‐α (PPAR‐α). Expression of the receptor is high in the liver, heart and skeletal muscle, but decreases with age. A combined 1H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography‐mass spectrometry metabolomic approach has been used to examine metabolism in the liver, heart, skeletal muscle and adipose tissue in PPAR‐α‐null mice and wild‐type controls during ageing between 3 and 13 months. For the PPAR‐α‐null mouse, multivariate statistics highlighted hepatic steatosis, reductions in the concentrations of glucose and glycogen in both the liver and muscle tissue, and profound changes in lipid metabolism in each tissue, reflecting known expression targets of the PPAR‐α receptor. Hepatic glycogen and glucose also decreased with age for both genotypes. These findings indicate the development of age‐related hepatic steatosis in the PPAR‐α‐null mouse, with the normal metabolic changes associated with ageing exacerbating changes associated with genotype. Furthermore, the combined metabolomic and multivariate statistics approach provides a robust method for examining the interaction between age and genotype.

Abnormal cardiac morphology, function and energy metabolism in the dystrophic mdx mouse: an MRI and MRS study.

Patients with muscular dystrophy have abnormal cardiac function and decreased high-energy phosphate metabolism. Here, we have determined whether the 8 month old mdx mouse, an animal model of muscular dystrophy, also has abnormal cardiac function and energetics. In vivo cardiac MRI revealed 33% and 104% larger right ventricular end-diastolic and end-systolic volumes, respectively, and 17% lower right ventricular ejection fractions in mdx mice compared with controls. Evidence of left ventricular diastolic dysfunction included 18% lower peak filling rates in mdx mouse hearts. Abnormal cardiac function was accompanied by necrosis and lower citrate synthase activity in the mdx mouse heart, suggesting decreased mitochondrial content. Decreased mitochondrial numbers were associated with 38% lower phosphocreatine concentration, 22% lower total creatine, 36% higher cytosolic free ADP concentration and 1.3 kJ/mol lower free-energy available from ATP hydrolysis in whole isolated, perfused mdx mouse hearts than in controls. Transsarcolemmal creatine uptake was 12% lower in mdx mouse hearts. We conclude that the absence of dystrophin in adult mdx mouse heart, as in the heart of human patient, is associated with right ventricular dilatation, left ventricular diastolic dysfunction and abnormal energy metabolism.

Data on triiodothyronine treated peroxisome proliferator-activated receptor-alpha-null mouse hearts using magnetic resonance imaging and magnetic resonance spectroscopy

This data contain left ventricular end-diastolic volumes, end-systolic volumes, stroke volumes, ejection fractions, cardiac outputs, heart rates, phosphocreatine concentrations, adenosine 5’-triphosphate (ATP) concentrations, total creatine concentrations, citrate synthase activities and heart weights for wild-type and peroxisome proliferator-activated receptor-alpha-null mouse hearts without and with triiodothyronine treatment.

Data on uncoupling protein-3 levels, hypoxia, low flow ischemia, and insulin stimulation in dystrophin-deficient mdx mouse hearts

The data contain body weights, plasma free fatty acids concentrations and cardiac uncoupling protein-3 protein levels for wild-type and mdx mice. The data provide heart rates, left ventricular contractile functions, coronary flow, phosphocreatine concentrations, and adenosine 5’-triphosphate (ATP) concentrations throughout hypoxia in mdx mouse hearts. This data article also provides left ventricular contractile functions after low flow ischemia with and without glucose, glycogen levels before ischemia or hypoxia, glucose uptake rates during low flow ischemia and insulin stimulation, and insulin-stimulated phospho-Akt protein levels, a protein in insulin signaling, in mdx mouse hearts.