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Loss of muscle mass occurs in a variety of diseases, including cancer, chronic heart failure, aquired immunodeficiency syndrome, diabetes, and renal failure, often aggravating pathological progression. Preventing muscle wasting by promoting muscle growth has been proposed as a possible therapeutic approach. Myostatin is an important negative modulator of muscle growth during myogenesis, and myostatin inhibitors are attractive drug targets. However, the role of the myostatin pathway in adulthood and the transcription factors involved in the signaling are unclear. Moreover, recent results confirm that other transforming growth factor-[beta] (TGF-[beta]) members control muscle mass. Using genetic tools, we perturbed this pathway in adult myofibers, in vivo, to characterize the downstream targets and their ability to control muscle mass. Smad2 and Smad3 are the transcription factors downstream of myostatin/TGF-[beta] and induce an atrophy program that is muscle RING-finger protein 1 (MuRF1) independent. Furthermore, Smad2/3 inhibition promotes muscle hypertrophy independent of satellite cells but partially dependent of mammalian target of rapamycin (mTOR) signaling. Thus myostatin and Akt pathways cross-talk at different levels. These findings point to myostatin inhibitors as good drugs to promote muscle growth during rehabilitation, especially when they are combined with IGF-1-Akt activators. muscle atrophy; hypertrophy; Akt; myostatin

Blood pressure (BP) is more salt sensitive in men than in premenopausal women. In Dahl salt-sensitive rats (DS), high-salt (HS) diet increases BP more in males than females. In contrast to the systemic renin-angiotensin system, which is suppressed in response to HS in male DS, intrarenal angiotensinogen expression is increased, and intrarenal levels of ANG II are not suppressed. In this study, the hypothesis was tested that there is a sexual dimorphism in HS-induced upregulation of intrarenal angiotensinogen mediated by testosterone that also causes increases in BP and renal injury. On a low-salt (LS) diet, male DS had higher levels of intrarenal angiotensinogen mRNA than females. HS diet for 4 wk increased renal cortical angiotensinogen mRNA and protein only in male DS, which was prevented by castration. Ovariectomy of female DS had no effect on intrarenal angiotensinogen expression on either diet. Radiotelemetric BP was similar between males and castrated rats on LS diet. HS diet for 4 wk caused a progressive increase in BP, protein and albumin excretion, and glomerular sclerosis in male DS rats, which were attenuated by castration. Testosterone replacement in castrated DS rats increased BP, renal injury, and upregulation of renal angiotensinogen associated with HS diet. Testosterone contributes to the development of hypertension and renal injury in male DS rats on HS diet possibly through upregulation of the intrarenal renin-angiotensin system. androgens; hypertension; renal injury; glomerular sclerosis; angiotensinogen

Women with systemic lupus erythematosus (SLE) exhibit a high prevalence of hypertension and renal injury. Rosiglitazone (Rosi), a peroxisome proliferator activator receptor gamma ([PPAR.sub.[gamma]]) agonist, has renal protective and antihypertensive effects. We tested whether Rosi ameliorates hypertension and renal injury in a female mouse model of SLE (NZBWF1). Thirty-week-old SLE and control (NZW/LacJ) mice (n [greater than or equal to] 6/group) were fed Rosi (5 mg x [kg.sup.-1] x [day.sup.-1] in standard chow) or standard chow for 4 wk. SLE mice had increased blood pressure (BP in mmHg) compared with controls (139 [+ or -] 4 vs. 111 [+ or -] 4, P < 0.05). Rosi treatment lowered BP in SLE mice (127 [+ or -] 4, P < 0.05) but not in controls (111 [+ or -] 4). Urinary albumin ([micro]g/mg creatinine) was increased in SLE mice compared with controls (12,396 [+ or -] 6,525 vs. 50 [+ or -] 6) and reduced with Rosi treatment (148 [+ or -] 117). Glomerulosclerosis (% of glomeruli with sclerosis) was reduced in Rosi-treated SLE mice (4.2 [+ or -] 1.6 vs. 0.4 [+ or -] 0.3, P < 0.05). Renal monocyte/ macrophage numbers (cell number/1,320 points counted) were reduced in SLE mice treated with Rosi (32.6 [+ or -] 11.0 vs. 10.6 [+ or -] 3.6, P < 0.05) but unchanged in controls (3.7 [+ or -] 1.6 vs. 3.7 [+ or -] 2.0). Renal osteopontin expression, a cytokine-regulating macrophage recruitment, was reduced in Rosi-treated SLE mice. Urinary endothelin (in pg/mg creatinine) was increased in SLE mice compared with controls (1.9 [+ or -] 0.59 vs. 0.6 [+ or -] 0.04, P < 0.05) and reduced in SLE mice treated with Rosi (0.8 [+ or -] 0.11, P < 0.05). [PPAR.sup.[gamma]]/protein expression in the renal cortex was significantly lower in SLE mice compared with controls and was unaffected by Rosi. These data suggest that Rosi may be an important therapeutic option for the treatment of SLE hypertension and renal injury. lupus; inflammation; endothelin; glomerulosclerosis; proliferator activated receptor gamma

In general, blood pressure is higher in normotensive men than in age-matched women, and the prevalence of hypertension in men is also higher until after menopause, when the prevalence of hypertension increases for women. It is likely then that the mechanisms by which blood pressure increases in men and women with aging may be different. Although clinical trials to reduce blood pressure with antioxidants have typically not been successful in human cohorts, studies in male rats suggest that oxidative stress plays an important role in mediating hypertension. The exact mechanisms by which oxidative stress increases blood pressure have not been completely elucidated. There may be several reasons for the discrepancies between clinical and animal studies. In this review, the data obtained in selected clinical and animal studies are discussed, and the hypothesis is put forward that oxidative stress may not be as important in mediating hypertension in females as has been shown previously in male rats. Furthermore, it is likely that differences in genetics, age, length of time with hypertension, endothelial dysfunction, and sex are all factored in to modulate the responses to antioxidants in humans. As such, future clinical trials should be designed and powered to evaluate the effects of oxidative stress on blood pressure separately in men and women. [F.sub.2]-isoprostanes

Impaired epithelial sodium channel function predisposes to delayed resorption of pulmonary edema and more severe experimental lung injury, whereas even a small fraction of the normal Na-K-ATPase activity is thought to be sufficient to maintain normal ion transport. However, direct proof is lacking. Therefore, we studied baseline and cAMP stimulated alveolar fluid clearance (AFC) in mice with a 50% decrease in lung protein expression of the [[alpha].sub.1]- and/or [[alpha].sub.2]-subunit of the Na-K-ATPase. There was no difference in basal and stimulated AFC in [[alpha].sub.1.sup.+/-]or [[alpha].sub.2.sup.+/-] mice compared with wild-type littermates. Also, the compound heterozygous mice ([[alpha].sub.1.sup.+/-]/[[alpha].sub.2].sup.+/-]) had normal basal AFC. However, the combined [[alpha].sub.1.+/-]/[[alpha].sub.2.sup.+/-] [[alpha].sub.2.sup.+/-] mice showed a significant decrease in cAMP-stimulated AFC compared with wild-type littermates (11.1 [+ or -] 1.0 vs. 14.9 [+ or -] 1.8%/30 min, P < 0.001). When exposed to 96 h of >95% hyperoxia, the decrease in stimulated AFC in the [[alpha].sub.1.sup.+/-]/[[alpha].sub.2.sup.+/-] mice was not associated with more lung edema compared with wild-type littermates (lung wet-to-dry weight ratio 6.6 [+ or -] 0.9 vs. 5.9 [+ or -] 1.1, respectively; P = not significant). Thus a 50% decrease in protein expression of the [[alpha].sub.1]- or [[alpha].sub.2]-subunits of the Na-K-ATPase does not impair basal or stimulated AFC. However, a 50% protein reduction in both the [[alpha].sub.1] and [[alpha].sub.2]-subunits of the Na-K-ATPase produces a submaximal stimulated AFC, suggesting a synergistic role for [[alpha].sub.1]- and [[alpha].sub.2]-subunits in cAMP-dependent alveolar epithelial fluid clearance. pulmonary edema; acute lung injury; cAMP; sodium transport; alveolar epithelium

In pulmonary hypertension right ventricular pressure overload leads to abnormal left ventricular (LV) diastolic function. Acute high-altitude exposure is associated with hypoxia-induced elevation of pulmonary artery pressure particularly in the setting of high-altitude pulmonary edema. Tissue Doppler imaging (TDI) allows assessment of LV diastolic function by direct measurements of myocardial velocities independently of cardiac preload. We hypothesized that in healthy mountaineers, hypoxia-induced pulmonary artery hypertension at high altitude is quantitatively related to LV diastolic function as assessed by conventional and TDI Doppler methods. Forty-one healthy subjects (30 men and 11 women; mean age 41 [+ or -] 12 yr) underwent transthoracic echocardiography at low altitude (550 m) and after a rapid ascent to high altitude (4,559 m). Measurements included the right ventricular to right atrial pressure gradient ([DELTA][P.sub.RV-RA]), transmitral early (E) and late (A) diastolic flow velocities and mitral annular early ([E.sub.m]) and late ([A.sub.m]) diastolic velocities obtained by TDI at four locations: septal, inferior, lateral, and anterior. At a high altitude, [DELTA][P.sub.RV-RA] increased from 16 [+ or -] 7 to 44 [+ or -] 15 mmHg (P < 0.0001), whereas the transmittal E-to-A ratio (E/A ratio) was significantly lower (1.11 [+ or -] 0.27 vs. 1.41 [+ or -] 0.35; P < 0.0001) due to a significant increase of A from 52 [+ or -] 15 to 65 [+ or -] 16 cm/s (P = 0.0001). [DELTA][P.sub.RV-RA] and transmittal E/A ratio were inversely correlated ([r.sup.2] = 0.16; P = 0.0002) for the whole spectrum of measured values (low and high altitude). Diastolic mitral annular motion interrogation showed similar findings for spatially averaged (four locations) as well as for the inferior and septal locations: [A.sub.m] increased from low to high altitude (all P < 0.01); consequently, [E.sub.m]/[A.sub.m] ratio was lower at high versus low altitude (all P < 0.01). These intraindividual changes were reflected interindividually by an inverse correlation between [DELTA][P.sub.RV-RA] and [E.sub.m/[A.sub.m] (all P < 0.006) and a positive association between [DELTA][P.sub.RV-RA] and [A.sub.m] (all P < 0.0009). In conclusion, high-altitude exposure led to a two- to threefold increase in pulmonary artery pressure in healthy mountaineers. This acute increase in pulmonary artery pressure led to a change in LV diastolic function that was directly correlated with the severity of pulmonary hypertension. However, in contrast to patients suffering from some form of cardiopulmonary disease and pulmonary hypertension, in these healthy subjects, overt LV diastolic dysfunction was not observed because it was prevented by augmented atrial contraction. We propose the new concept of compensated diastolic (dys)function. edema; tissue Doppler imaging; right ventricular pressure overload

Surfactant protein (SP) phospholipids SP-A, SP-B and SP-C are secreted by lamellar vessels in the fetus, with new subtypes developing as the breathing of the fetus starts. Degradation of alveolar surfactant into a remnant type having a SP-A containing lavage fluid occurs during breathing. The turn-over rate of SP phospholipids during breathing is more than that of phosphatidylcholine.

Partial restoration of defective chloride conductance in [Delta]F508 CF mice by trimethylamine oxide. Am J Physiol Lung Cell Mol Physiol 281: L52-L57, 2001.--This study was designed to test the in vivo efficacy of the chemical chaperone trimethylamine oxide (TMAO) in correcting the [Cl.sup.-] transport defect in a mouse model of cystic fibrosis (CF). Rectal potential difference (RPD) measurements were done in matched wild-type and [Delta]F508 CF mice. Mice were treated by subcutaneous injections of TMAO. Wild-type mice demonstrated a forskolin-stimulated, [Cl.sup.-]-dependent hyperpolarization of -6.4 [+ or -] 0.8 mV (n = 11), which was significantly increased to -13.1 [+ or -] 1.4 mV after treatment with TMAO. [Delta]F508 CF mice showed no significant responses to forskolin. Treatment with TMAO recovered a forskolin-activated RPD in [Delta]F508 CF mice (-1.1 [+ or -] 0.2 mV; n = 17) but not in CFTR null mice. The effects of TMAO were dose dependent, resulting in a slope of -0.4 [+ or -] 0.1 m V [multiplied by] [g.sup.-1] [multiplied by] [kg.sup.-1] in [Delta]F508 CF mice. The forskolin-stimulated RPD in TMAO-treated [Delta]F508 CF mice was partially blocked by glibenclamide and further stimulated by apigenin. The total response to forskolin plus apigenin was -2.5 [+ or -] 0.45 mV (n = 6 mice), corresponding to 39% of the response evoked by forskolin only in wild-type mice. apigenin; [Delta]F508 cystic fibrosis transmembrane conductance regulator; cystic fibrosis transmembrane conductance regulator knockout; glibenclamide; rectum; epithelia

Allemann, Yves, Claudio Sartori, Mattia Lepori, Sebastien Pierre, Christian Melot, Robert Naeije, Urs Scherrer, and Marco Maggiorini. Echocardiographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude. Am J Physiol Heart Circ Physiol 279: H2013-H2016, 2000.--Exaggerated hypoxia-induced pulmonary hypertension is a hallmark of high-altitude pulmonary edema (HAPE) and plays a major role in its pathogenesis. Many studies of HAPE have estimated systolic pulmonary arterial pressure (SPAP) with Doppler echocardiography. Whereas at low altitude, Doppler echocardiographic estimation of SPAP correlates closely with its invasive measurement, no such evidence exists for estimations obtained at high altitude, where alterations of blood viscosity may invalidate the simplified Bernoulli equation. We measured SPAP by Doppler echocardiography and invasively in 14 mountaineers prone to HAPE and in 14 mountaineers resistant to this condition at 4,559 m. Mountaineers prone to HAPE had more pronounced pulmonary hypertension (57 [+ or -] 12 and 58 [+ or -] 10 mmHg for noninvasive and invasive determination, respectively; means [+ or -] SD) than subjects resistant to HAPE (37 [+ or -] 8 and 37 [+ or -] 6 mmHg, respectively), and the values measured in the two groups as a whole covered a wide range of pulmonary arterial pressures (30-83 mmHg). Spearman test showed a highly significant correlation (r = 0.89, P [is less than] 0.0001) between estimated and invasively measured SPAP values. The mean difference between invasively measured and Doppler-estimated SPAP was 0.5 [+ or -] 8 mmHg. At high altitude, estimation of SPAP by Doppler echocardiography is an accurate and reproducible method that correlates closely with its invasive measurement. Doppler echocardiography; right heart catheterization; high-altitude pulmonary edema

We investigated the relation between swimming exercise and fear memory extinction. Rats that performed regular swimming exercise over 6 wk underwent fear conditioning. Twenty-eight days later, they were submitted to extinction tests. Swimming rats had enhanced extinction process throughout the 5 days of the extinction test compared with sedentary rats. This suggests that the swimming exercise accelerated the process of aversive memory extinction, reducing the expression of conditioned fear behavior. These results encourage further studies addressing the anxiolytic effects of exercise, with potential implications for anxiety disorders such as posttraumatic stress disorder. NEW & NOTEWORTHY We have shown that rats that performed regular swimming exercise over 6 wk had enhanced extinction process compared with sedentary animals. The swimming exercise may accelerate the process of aversive memory extinction, reducing the expression of conditioned fear behavior. [ABSTRACT FROM AUTHOR]

Pulmonary vascular disease (PVD) represents an underestimated and increasing clinical burden not only in the neonatal period but also later in life, when exercise tolerance is decreased. Animal models performing long-term followup after a perinatal insult are lacking. This study aimed to develop and characterize a neonatal swine model with hypoxia-induced PVD during long-term followup after reexposure to normoxia and to investigate the exercise response in this model. Piglets were exposed to a normoxic (n = 10) or hypoxic environment (n = 9) for 4 wk. Neonatal hypoxia exposure resulted in pulmonary hypertension. Mean pulmonary artery pressure was elevated 1 day after reexposure to normoxia (30.2 ± 3.3 vs. 14.3 ± 0.9 mmHg) and remained significantly higher in the second week (32.8 ± 3.8 vs. 21.4 ± 1.2 mmHg), accompanied by decreased exercise tolerance. Exercise resulted in a trend toward an exaggerated increase of pulmonary artery pressure in hypoxia-exposed animals (week 6, P = 0.086). Although pulmonary hypertension was transient, thickening of pulmonary arterioles was found at the end of followup. Furthermore, right ventricular dilation, lower right ventricular fractional area change (week 8, 40.0 ± 2.7% vs. 29.5 ± 4.7%), and tricuspid annular plane systolic excursion (week 8, 27.0 ± 2.5 vs. 22.9 ± 2.1 mm) persisted during followup. Male animals showed more severe PVD than female animals. In conclusion, we developed a neonatal swine model that allows examination of the long-term sequelae of damage to the developing neonatal lung, the course of the disease and the effect of therapy on long-term outcome. [ABSTRACT FROM AUTHOR]

da Silva, Mirian M., Adriano Sartori, Eduardo Belisle, and Alicia J. Kowaltowski. Ischemic preconditioning inhibits mitochondrial respiration, increases [H.sub.2][O.sub.2] release, and enhances [K.sup.+] transport. Am J Physiol Heart Circ Physiol 285: H154-H162, 2003. First published March 6, 2003; 10.1152/ajpheart.00955.2002.--Ischemic preconditioning, or the protective effect of short ischemic episodes on a longer, potentially injurious, ischemic period, is prevented by antagonists of mitochondrial ATP-sensitive [K.sup.+] channels (mito[K.sub.ATP]) and involves changes in mitochondrial energy metabolism and reactive oxygen release after ischemia. However, the effects of ischemic preconditioning itself on mitochondria are still poorly understood. We determined the effects of ischemic preconditioning on isolated heart mitochondria and found that two brief (5 min) ischemic episodes are sufficient to induce a small but significant decrease (~25%) in mitochondrial NADH-supported respiration. Preconditioning also increased mitochondrial [H.sub.2][O.sub.2] release, an effect related to respiratory inhibition, because it is not observed in the presence of succinate plus rotenone and can be mimicked by chemically inhibiting complex I in the presence of NADH-linked substrates. In addition, preconditioned mitochondria presented more substantial ATP-sensitive [K.sup.+] transport, indicative of higher mito[K.sub.ATP] activity. Thus we directly demonstrate that preconditioning leads to mitochondrial respiratory inhibition in the presence of NADH-linked substrates, increased reactive oxygen release, and activation of mito[K.sub.ATP]. heart; ischemia-reperfusion; free radicals; NADH dehydrogenase; [K.sub.ATP] channel

Impaired epithelial sodium channel function predisposes to delayed resorption of pulmonary edema and more severe experimental lung injury, whereas even a small fraction of the normal Na-K-ATPase activity is thought to be sufficient to maintain normal ion transport. However, direct proof is lacking. Therefore, we studied baseline and cAMP stimulated alveolar fluid clearance (AFC) in mice with a 50% decrease in lung protein expression of the α1- and/or α2-subunit of the Na-K-ATPase. There was no difference in basal and stimulated AFC in α1+/- or α2+/- mice compared with wild-type littermates. Also, the compound heterozygous mice (α1+/-/α2+/-) had normal basal AFC. However, the combined α1+/-/α2+/- mice showed a significant decrease in cAMPstimulated AFC compared with wild-type littermates (11.1 ± 1.0 vs. 14.9 ± 1.8%/30 min, P < 0.001). When exposed to 96 h of >95% hyperoxia, the decrease in stimulated AFC in the α1+/-/α2+/- mice was not associated with more lung edema compared with wild-type littermates (lung wet-to-dry weight ratio 6.6 ± 0.9 vs. 5.9 ± 1.1, respectively; P = not significant). Thus a 50% decrease in protein expression of the α1 or α2-subunits of the Na-K-ATPase does not impair basal or stimulated AFC. However, a 50% protein reduction in both the α1- and α2-subunits of the Na-K-ATPase produces a submaximal stimulated AFC, suggesting a synergistic role for α1- and α2-subunits in cAMP-dependent alveolar epithelial fluid clearance. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning, or the protective effect of short ischemic episodes on a longer, potentially injurious, ischemic period, is prevented by antagonists of mitochondrial ATP-sensitive K[sup +] channels (mitoK[sub ATP]) and involves changes in mitochondrial energy metabolism and reactive oxygen release after ischemia. However, the effects of ischemic preconditioning itself on mitochondria are still poorly understood. We determined the effects of ischemic preconditioning on isolated heart mitochondria and found that two brief (5 min) ischemic episodes are sufficient to induce a small but significant decrease (∼25%) in mitochondrial NADH-supported respiration. Preconditioning also increased mitochondrial H[sub 2]O[sub 2] release, an effect related to respiratory inhibition, because it is not observed in the presence of succinate plus rotenone and can be mimicked by chemically inhibiting complex I in the presence of NADH-linked substrates. In addition, preconditioned mitochondria presented more substantial ATP-sensitive K[sup +] transport, indicative of higher mitoK[sub ATP] activity. Thus we directly demonstrate that preconditioning leads to mitochondrial respiratory inhibition in the presence of NADH-linked substrates, increased reactive oxygen release, and activation of mitoK[sub ATP]. [ABSTRACT FROM AUTHOR]

Examines the partial restoration of defective chloride conductance in the deletion of phenylalanine in mice with cystic fibrosis (CF). Efficacy of trimethylamine oxide in correcting chloride ion transport defect; Measurement of rectal potential difference in CF mice; Response of the mice to forskolin.