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High-capacity mitochondrial ATP production is essential for normal function of the adult heart, and evidence is emerging that mitochondrial derangements occur in common myocardial diseases. Previous overexpression studies have shown that the inducible transcriptional coactivator peroxisome proliferator-activated receptor-[gamma] coactivator (PGC)-l[alpha] is capable of activating postnatal cardiac myocyte mitochondrial biogenesis. Recently, we generated mice deficient in PGC-1[alpha] ([PGC-1[alpha].sup.-/-] mice), which survive with modestly blunted postnatal cardiac growth. To determine if PGC-1[alpha] is essential for normal cardiac energy metabolic capacity, mitochondrial function experiments were performed on saponin-permeabilized myocardial fibers from PGC-l[[alpha].sup.-/-] mice. These experiments demonstrated reduced maximal (state 3) palmitoyl-L-carnitine respiration and increased maximal (state 3) pyruvate respiration in [PGC-l[alpha].sup.-/-] mice compared with PGC-1[[alpha].sup.+/+] controls. ATP synthesis rates obtained during maximal (state 3) respiration in permeabilized myocardial fibers were reduced for PGC-1[[alpha].sup.-/-] mice, whereas ATP produced per oxygen consumed (ATP/O), a measure of metabolic efficiency, was decreased by 58% for PGC-l[[alpha].sup.-/-] fibers. Ex vivo isolated working heart experiments demonstrated that PGC-l[[alpha].sup.-/-] mice exhibited lower cardiac power, reduced palmitate oxidation, and increased reliance on glucose oxidation, with the latter likely a compensatory response. [sup.13]C NMR revealed that hearts from PGC-l[[alpha].sup.-/-] mice exhibited a limited capacity to recruit triglyceride as a source for lipid oxidation during [beta]-adrenergic challenge. Consistent with reduced mitochondrial fatty acid oxidative enzyme gene expression, the total triglyceride content was greater in hearts of PGC-1[[alpha].sup.-/-] mice relative to PGC-l[[alpha].sup.+/+] following a fast. Overall, these results demonstrate that PGC-l[alpha] is essential for the maintenance of maximal, efficient cardiac mitochondrial fatty acid oxidation, ATP synthesis, and myocardial lipid homeostasis. nuclear receptors; ATP; cardiac energetics; heart failure; left ventricular hypertrophy; peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha]

In the diabetic heart, chronic activation of the PPAR[alpha] pathway drives excessive fatty acid (FA) oxidation, lipid accumulation, reduced glucose utilization, and cardiomyopathy. The related nuclear receptor, PPAR[beta]/[delta], is also highly expressed in the heart, yet its function has not been fully delineated. To address its role in myocardial metabolism, we generated transgenic mice with cardiac-specific expression of PPAR[beta]/[delta], driven by the myosin heavy chain (MHC-PPAR[beta]/[delta] mice). In striking contrast to MHC-PPAR[alpha] mice, MHC-PPAR[beta]/[delta] mice had increased myocardial glucose utilization, did not accumulate myocardial lipid, and had normal cardiac function. Consistent with these observed metabolic phenotypes, we found that expression of genes involved in cellular FA transport were activated by PPAR[alpha] but not by PPAR[beta]/[delta]. Conversely, cardiac glucose transport and glycolytic genes were activated in MHC-PPAR[beta]/[delta] mice, but repressed in MHC-PPAR[alpha] mice. In reporter assays, we showed that PPAR[beta]/[delta] and PPAR[alpha] exerted differential transcriptional control of the GLUT4 promoter, which may explain the observed isotype-specific effects on glucose uptake. Furthermore, myocardial injury due to ischemia/reperfusion injury was significantly reduced in the MHC-PPAR[beta]/[delta] mice compared with control or MHC-PPAR[alpha] mice, consistent with an increased capacity for myocardial glucose utilization. These results demonstrate that PPAR[alpha] and PPAR[beta]/[delta] drive distinct cardiac metabolic regulatory programs and identify PPAR[beta]/[delta] as a potential target for metabolic modulation therapy aimed at cardiac dysfunction caused by diabetes and ischemia., Introduction We are witnessing a pandemic of obesity-related diabetes (1). Diabetes predisposes to heart failure, particularly in combination with other comorbid conditions such as hypertension and coronary artery disease (2), [...]

High fatty acid oxidation (FAO) rates contribute to ischemia-reperfusion injury of the myocardium. Because peroxisome proliferator-activated receptor (PPAR)[alpha] regulates transcription of several FAO enzymes in the heart, we examined the response of mice with cardiac-restricted overexpression of PPAR[alpha] (MHC-PPAR[alpha]) or whole body PPAR[alpha] deletion including the heart (PPAR[[alpha].sup.-/-]) to myocardial ischemia-reperfusion injury. Isolated working hearts from MHC-PPAR[alpha] and nontransgenic (NTG) littermates were subjected to no-flow global ischemia followed by reperfusion. MHC-PPAR[alpha] hearts had significantly higher FAO rates during aerobic and postischemic reperfusion (aerobic 1,479 [+ or -] 171 vs. 699 [+ or -] 117, reperfusion 1,062 [+ or -] 214 vs. 601 [+ or -] 70 nmol x g dry [wt.sup.-1] x [min.sup.-1]; P < 0.05) and significantly lower glucose oxidation rates compared with NTG hearts (aerobic 225 [+ or -] 36 vs. 1,563 [+ or -] 165, reperfusion 402 [+ or -] 54 vs. 1,758 [+ or -] 165 nmol x g dry [wt.sup.-1] x [min.sup.-1]; p < 0.05). In hearts from PPAR[[alpha].sup.-/-] mice, FAO was significantly lower during aerobic and reperfusion (aerobic 235 [+ or -] 36 vs. 442 [+ or -] 75, reperfusion 205 [+ or -] 25 vs. 346 [+ or -] 38 nmol x g dry [wt.sup.-1] x [min.sup.-1]; P < 0.05) whereas glucose oxidation was significantly higher compared with wild-type (WT) hearts (aerobic 2,491 [+ or -] 631 vs. 901 [+ or -] 119, reperfusion 2,690 [+ or -] 562 vs. 1,315 [+ or -] 172 nmol x g dry [wt.sup.-1] x [min.sup.-1]; P < 0.05). Increased FAO rates in MHC-PPAR[alpha] hearts were associated with a markedly lower recovery of cardiac power (45 [+ or -] 9% vs. 71 [+ or -] 6% of preischemic levels in NTG hearts; P < 0.05). In contrast, the percent recovery of cardiac power of PPAR[[alpha].sup.-/-] hearts was not significantly different from that of WT hearts (80 [+ or -] 8% vs. 75 [+ or -] 9%). This study demonstrates that chronic activation of PPAR[alpha] is detrimental to the cardiac recovery during reperfusion after ischemia. myocardial ischemia; reperfusion; peroxisome proliferator-activated receptor [alpha]; fatty acid oxidation; acetyl-CoA carboxylase

An optical waveguide MEMS switch fabricated on an indium phosphide (InP) substrate for operation at 1550 nm wavelength is presented. Compared to other MEMS optical switches, which typically use relatively large mirrors or long end-coupled waveguides, our device uses a parallel switching mechanism. The device utilizes evanescent coupling between two closely-spaced waveguides fabricated side by side. Coupling is controlled by changing the gap and the coupling length between the two waveguides via electrostatic pull-in. This enables both optical switching and variable optical coupling at voltages below 10 V. Channel isolation as high as -47 dB and coupling efficiencies of up to 66% were obtained with switching losses of less than 0.5 dB. We also demonstrate voltage-controlled variable optical coupling over a 17.4 dB dynamic range. The devices are compact with 2 [micro]m x 2 [micro]m core cross section and active area as small as 500 [micro]m x 5 [micro]m. Due to the small travel range of the waveguides, fast operation is obtained with switching times as short as 4 [micro]s. Future devices can be scaled down to less than 1 [micro]m x 1 [micro]m waveguide cross-sectional area and device length less than 100 [micro]m without significant change in device design. [1372] Index Terms--Directional coupler, indium phosphide (InP), integrated waveguides, optical MEMS switches.

Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator-activated receptor-[alpha] (PPAR-[alpha]) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr[sup.-/-]), with (Ppara[sup.+/+]) or without (Ppara[sup.-/-]) PPAR-[alpha], were treated chronically with dexamethasone. Ppara[sup.+/+], but not Ppara[sup.-/-], mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using C57BL/6 mice. Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara[sup.+/+] mice. Adenoviral reconstitution of PPAR-[alpha] in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara[sup.-/-] mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression. It also increased blood pressure, renin activity, sympathetic nervous activity and renal sodium retention. Human hepatocytes treated with dexamethasone and the PPAR-[alpha] agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR-[alpha] as a mechanism underlying glucocorticoid-induced insulin resistance., Author(s): Carlos Bernal-Mizrachi [1, 2]; Sherry Weng [1, 2]; Chu Feng [1, 2]; Brian N Finck [1, 5]; Russell H Knutsen [3]; Teresa C Leone [1, 5]; Trey Coleman [1, [...]

While some clinical advances in cartilage repair have occurred, osteochondral (OC) defect repair remains a significant challenge, with current scaffold-based approaches failing to recapitulate the complex, hierarchical structure of native articular cartilage (AC). To address this need, we fabricated bilayered extracellular matrix (ECM)-derived scaffolds with aligned pore architectures. By modifying the freeze-drying kinetics and controlling the direction of heat transfer during freezing, it was possible to produce anisotropic scaffolds with larger pores which supported homogenous cellular infiltration and improved sulfated glycosaminoglycan deposition. Neo-tissue organization in vitro could also be controlled by altering scaffold pore architecture, with collagen fibres aligning parallel to the long-axis of the pores within scaffolds containing aligned pore networks. Furthermore, we used in vitro and in vivo assays to demonstrate that AC and bone ECM derived scaffolds could preferentially direct the differentiation of mesenchymal stromal cells (MSCs) towards either a chondrogenic or osteogenic lineage respectively, enabling the development of bilayered ECM scaffolds capable of spatially supporting unique tissue phenotypes. Finally, we implanted these scaffolds into a large animal model of OC defect repair. After 6 months in vivo , scaffold implantation was found to improve cartilage matrix deposition, with collagen fibres preferentially aligning parallel to the long axis of the scaffold pores, resulting in a repair tissue that structurally and compositionally was more hyaline-like in nature. These results demonstrate how scaffold architecture and composition can be spatially modulated to direct the regeneration of complex interfaces such as the osteochondral unit, enabling their use as cell-free, off-the-shelf implants for joint regeneration. The architecture of the extracellular matrix, while integral to tissue function, is often neglected in the design and evaluation of regenerative biomaterials. In this study we developed a bilayered scaffold for osteochondral defect repair consisting of tissue-specific extracellular matrix (ECM)-derived biomaterials to spatially direct stem/progenitor cell differentiation, with a tailored pore microarchitecture to promote the development of a repair tissue that recapitulates the hierarchical structure of native AC. The use of this bilayered scaffold resulted in improved tissue repair outcomes in a large animal model, specifically the ability to guide neo-tissue organization and therefore recapitulate key aspects of the zonal structure of native articular cartilage. These bilayer scaffolds have the potential to become a new therapeutic option for osteochondral defect repair. [Display omitted] [ABSTRACT FROM AUTHOR]

The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was targeted in mice. PGC-1alpha null (PGC-1alpha-/-) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1alpha-/- mice. With age, the PGC-1alpha-/- mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1alpha-/- mice, leading to reduced muscle performance and exercise capacity. PGC-1alpha-/- mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1alpha-/- mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1alpha-/- mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1alpha-/- mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1alpha-/- mice. These results demonstrate that PGC-1alpha is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor [Alpha] (PPAR[Alpha]), plays a pivotal role in the cellular metabolic response to fasting. Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPAR[Alpha] (PPAR[[Alpha].sup.-/-]), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPAR[[Alpha].sup.+/+] mice, fasting induced the hepatic and cardiac expression of PPAR[Alpha] target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome P450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPAR[Alpha] target genes was not induced by fasting in PPAR[[Alpha].sup.-/-] mice. These results define a critical role for PPAR[Alpha] in a transcriptional regulatory response to fasting and identify the PPAR[[Alpha].sup.-/-] mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.