Physiology - Research Publications
Now showing items 1-12 of 373
High-fructose diet elevates myocardial superoxide generation in mice in the absence of cardiac hypertrophy
(ELSEVIER SCIENCE INC, 2010-07-01)
OBJECTIVE: Dietary fructose intake has increased considerably in recent decades and this has been paralleled by an increase in the incidence of insulin resistance, especially in children and adolescents. The impact of a high-fructose diet on the myocardium is not fully understood. The aims of this study were to characterize the murine metabolic and cardiac phenotypes associated with a high-fructose diet and to determine whether this diet imparts differential effects with age. METHODS: Juvenile (4 wk) and adult (14 wk) C57Bl/6 mice were fed a 60% fructose diet or isoenergetic control (starch) diet for 6 wk. RESULTS: At completion of the dietary intervention (at ages 10 and 20 wk), fructose-fed mice were normotensive; hyperinsulinemia and cardiac hypertrophy were not evident. Interestingly, fructose-fed mice exhibited lower blood glucose levels (10 wk: 4.81+/-0.28 versus 5.42+/-0.31 mmol/L; 20 wk: 4.88+/-0.30 versus 5.96+/-0.42 mmol/L, P<0.05) compared with controls. Nicotinamide adenosine dinucleotide phosphate-driven myocardial superoxide production was significantly increased in fructose-fed mice at both ages (by approximately 29% of control at 10 wk of age and 16% at 20 wk, P<0.01). No increase in aortic superoxide production was observed. Fructose feeding did not alter gene expression of the antioxidant thioredoxin-2, suggesting an imbalance between myocardial reactive oxygen species generation and antioxidant induction. CONCLUSION: These findings indicate that increased myocardial superoxide production may represent an early and primary cardiac pathologic response to the metabolic challenge of excess dietary fructose in juveniles and adults that can be detected in the absence of cardiac hypertrophy and hypertension.
Control of sympathetic vasomotor tone by catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata
(OXFORD UNIV PRESS, 2011-09-01)
AIMS: Increased sympathetic tone in obstructive sleep apnoea results from recurrent episodes of systemic hypoxia and hypercapnia and might be an important contributor to the development of cardiovascular disease. In this study, we re-evaluated the role of a specific population of sympathoexcitatory catecholaminergic C1 neurones of the rostral ventrolateral medulla oblongata in the control of sympathetic vasomotor tone, arterial blood pressure, and hypercapnia-evoked sympathetic and cardiovascular responses. METHODS AND RESULTS: In anaesthetized rats in vivo and perfused rat working heart brainstem preparations in situ, C1 neurones were acutely silenced by application of the insect peptide allatostatin following cell-specific targeting with a lentiviral vector to express the inhibitory Drosophila allatostatin receptor. In anaesthetized rats with denervated peripheral chemoreceptors, acute inhibition of 50% of the C1 neuronal population resulted in ∼50% reduction in renal sympathetic nerve activity and a profound fall in arterial blood pressure (by ∼25 mmHg). However, under these conditions systemic hypercapnia still evoked vigorous sympathetic activation and the slopes of the CO(2)-evoked sympathoexcitatory and cardiovascular responses were not affected by inhibition of C1 neurones. Inhibition of C1 neurones in situ resulted in a reversible fall in perfusion pressure and the amplitude of respiratory-related bursts of thoracic sympathetic nerve activity. CONCLUSION: These data confirm a fundamental physiological role of medullary catecholaminergic C1 neurones in maintaining resting sympathetic vasomotor tone and arterial blood pressure. However, C1 neurones do not appear to mediate sympathoexcitation evoked by central actions of CO(2).
Hsp72 preserves muscle function and slows progression of severe muscular dystrophy
(NATURE PUBLISHING GROUP, 2012-04-19)
Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca(2+), which activates inflammatory and muscle degenerative pathways. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies.
Effect of Pregnancy for Females Born Small on Later Life Metabolic Disease Risk
(PUBLIC LIBRARY SCIENCE, 2012-09-13)
There is a strong inverse relationship between a females own birth weight and her subsequent risk for gestational diabetes with increased risk of developing diabetes later in life. We have shown that growth restricted females develop loss of glucose tolerance during late pregnancy with normal pancreatic function. The aim of this study was to determine whether growth restricted females develop long-term impairment of metabolic control after an adverse pregnancy adaptation. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham surgery (Control) in late pregnancy (E18) in F0 female rats. F1 Control and Restricted female offspring were mated with normal males and allowed to deliver (termed Ex-Pregnant). Age-matched Control and Restricted Virgins were also studied and glucose tolerance and insulin secretion were determined. Pancreatic morphology and hepatic glycogen and triacylglycerol content were quantified respectively. Restricted females were born lighter than Control and remained lighter at all time points studied (p<0.05). Glucose tolerance, first phase insulin secretion and liver glycogen and triacylglycerol content were not different across groups, with no changes in β-cell mass. Second phase insulin secretion was reduced in Restricted Virgins (-34%, p<0.05) compared to Control Virgins, suggestive of enhanced peripheral insulin sensitivity but this was lost after pregnancy. Growth restriction was associated with enhanced basal hepatic insulin sensitivity, which may provide compensatory benefits to prevent adverse metabolic outcomes often associated with being born small. A prior pregnancy was associated with reduced hepatic insulin sensitivity with effects more pronounced in Controls than Restricted. Our data suggests that pregnancy ameliorates the enhanced peripheral insulin sensitivity in growth restricted females and has deleterious effects for hepatic insulin sensitivity, regardless of maternal birth weight.
Insulin-like growth factor-1 overexpression in cardiomyocytes diminishes ex vivo heart functional recovery after acute ischemia
(ELSEVIER SCIENCE INC, 2012-01-01)
BACKGROUND: Acute insulin-like growth factor-1 administration has been shown to have beneficial effects in cardiac pathological conditions. The aim of the present study was to assess the structural and ex vivo functional impacts of long-term cardiomyocyte-specific insulin-like growth factor-1 overexpression in hearts of transgenic αMHC-IGF-1 Ea mice. METHODS: Performance of isolated transgenic αMHC-IGF-1 Ea and littermate wild-type control hearts was compared under baseline conditions and in response to 20-min ischemic insult. Cardiac desmin and laminin expression patterns were determined histologically, and myocardial hydroxyproline was measured to assess collagen content. RESULTS: Overexpression of insulin-like growth factor-1 did not modify expression patterns of desmin or laminin but was associated with a pronounced increase (∼30%) in cardiac collagen content (from ∼3.7 to 4.8 μg/mg). Baseline myocardial contractile function and coronary flow were unaltered by insulin-like growth factor-1 overexpression. In contrast to prior evidence of acute cardiac protection, insulin-like growth factor-1 overexpression was associated with significant impairment of acute functional response to ischemia-reperfusion. Insulin-like growth factor-1 overexpression did not modify ischemic contracture development, but postischemic diastolic dysfunction was aggravated (51±5 vs. 22±6 mmHg in nontransgenic littermates). Compared with wild-type control, recovery of pressure development and relaxation indices relative to baseline performance were significantly reduced in transgenic αMHC-IGF-1 Ea after 60-min reperfusion (34±7% vs. 62±7% recovery of +dP/dt; 35±11% vs. 57±8% recovery of -dP/dt). CONCLUSIONS: Chronic insulin-like growth factor-1 overexpression is associated with reduced functional recovery after acute ischemic insult. Collagen deposition is elevated in transgenic αMHC-IGF-1 Ea hearts, but there is no change in expression of the myocardial structural proteins desmin and laminin. These findings suggest that sustained cardiac elevation of insulin-like growth factor-1 may not be beneficial in the setting of an acute ischemic insult.
Uteroplacental Insufficiency and Lactational Environment Separately Influence Arterial Stiffness and Vascular Function in Adult Male Rats
(LIPPINCOTT WILLIAMS & WILKINS, 2012-08-01)
Early life environmental influences can have lifelong consequences for health, including the risk of cardiovascular disease. Uteroplacental insufficiency causes fetal undernutrition and impairs fetal growth. Previously we have shown that uteroplacental insufficiency is associated with impaired maternal mammary development, compromising postnatal growth leading to hypertension in male rat offspring. In this study we investigated the roles of prenatal and postnatal nutritional environments on endothelial and smooth muscle reactivity and passive wall stiffness of resistance arteries of male rat offspring. Fetal growth restriction was induced by maternal bilateral uterine vessel ligation (restricted) on day 18 of pregnancy. Control offspring were from mothers that had sham surgery (control) and another group from mothers with their litter size reduced (reduced; litter size reduced to 5 at birth, equivalent to the restricted group). On postnatal day 1, offspring (control, restricted, and reduced) were cross-fostered onto control or restricted mothers. At 6 months, mesenteric and femoral arteries were studied using wire and pressure myography. In restricted-on-restricted rats, wall stiffness was increased, and sensitivity to phenylephrine and relaxation evoked by endothelium-derived hyperpolarizing factor and sodium nitroprusside were impaired in mesenteric arteries. In femoral arteries, relaxation to sodium nitroprusside was reduced, whereas wall stiffness was unaltered. Cross-fostering restricted offspring onto control mothers alleviated deficits in vascular stiffness and reactivity. Control or reduced offspring who suckled a restricted mother had marked vascular stiffening. In conclusion, prenatal and early postnatal environments separately influence vascular function and stiffness. Furthermore, the early postnatal lactational environment is a determinant of later cardiovascular function.
Cardiomyocyte Mineralocorticoid Receptors Are Essential for Deoxycorticosterone/Salt-Mediated Inflammation and Cardiac Fibrosis
(LIPPINCOTT WILLIAMS & WILKINS, 2012-12-01)
Because the role of mineralocorticoid receptors in specific cell types in cardiac remodeling remains unknown, we have compared cardiac responses with deoxycorticosterone/salt in cardiomyocyte mineralocorticoid receptor-null (MyoMRKO) and wild-type (WT) mice at 8 days and 8 weeks. No differences in cardiac function between untreated WT and MyoMRKO mice were found, whereas profibrotic markers were reduced in MyoMRKO hearts at baseline. At 8 days, MyoMRKO showed monocyte/macrophage recruitment equivalent to WT mice in response to deoxycorticosterone/salt but a suppression of markers of fibrosis compared with WT. At 8 weeks, MyoMRKO mice showed no deoxycorticosterone/salt-induced increase in inflammatory cell infiltration and collagen deposition or in proinflammatory gene expression. Although some profibrotic markers were equivalently increased in both genotypes, MyoMRKO mice also showed increased baseline levels of mRNA and protein for the transforming growth factor-β/connective tissue growth factor inhibitor decorin compared with WT that was accompanied by higher levels of matrix metalloproteinase 2/matrix metalloproteinase 9 activity. These data point to a direct role for cardiomyocyte mineralocorticoid receptor in both deoxycorticosterone/salt-induced tissue inflammation and remodeling and suggest potential mechanisms for the cardioprotective effects of selective mineralocorticoid receptor blockade in cardiomyocytes that may involve regulation of matrix metalloproteinase 2/matrix metalloproteinase 9 activity and the transforming growth factor-β-connective tissue growth factor profibrotic pathway.
Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin
(ROCKEFELLER UNIV PRESS, 2012-06-25)
Follistatin is essential for skeletal muscle development and growth, but the intracellular signaling networks that regulate follistatin-mediated effects are not well defined. We show here that the administration of an adeno-associated viral vector expressing follistatin-288aa (rAAV6:Fst-288) markedly increased muscle mass and force-producing capacity concomitant with increased protein synthesis and mammalian target of rapamycin (mTOR) activation. These effects were attenuated by inhibition of mTOR or deletion of S6K1/2. Furthermore, we identify Smad3 as the critical intracellular link that mediates the effects of follistatin on mTOR signaling. Expression of constitutively active Smad3 not only markedly prevented skeletal muscle growth induced by follistatin but also potently suppressed follistatin-induced Akt/mTOR/S6K signaling. Importantly, the regulation of Smad3- and mTOR-dependent events by follistatin occurred independently of overexpression or knockout of myostatin, a key repressor of muscle development that can regulate Smad3 and mTOR signaling and that is itself inhibited by follistatin. These findings identify a critical role of Smad3/Akt/mTOR/S6K/S6RP signaling in follistatin-mediated muscle growth that operates independently of myostatin-driven mechanisms.