Cancer catecholamine conundrum.

Exercise, psychosocial stress, and drugs such as adrenergic agonists and antagonists increase the concentrations of catecholamines and/or alter adrenergic signaling. Intriguingly, exercise studies universally suggest that catecholamines are cancer-inhibiting whereas cancer stress studies typically report the opposite, whereas ß-blocker studies show variable effects. Here, we term variable effects of catecholamines in cancer the cancer catecholamine conundrum. Variable effects of catecholamines can potentially be explained by variable expression of nine adrenergic receptor isoforms and by other factors including catecholamine effects on cancer versus immune or endothelial cells. Future studies on catecholamines and cancer should seek to understand the mechanisms that explain variable effects of catecholamines in cancer to utilize beneficial or block detrimental effects of catecholamines in cancer patients.

Serum concentrations of myostatin and myostatin-interacting proteins do not differ between young and sarcopenic elderly men.

Sarcopenia is the loss of muscle size and function during ageing. The aim of this study was to test whether serum concentrations of myostatin and interacting proteins (GASP-1, FLRG, and follistatin) differed between young and elderly sarcopenic men. Isometric knee extensor maximal voluntary contraction and quadriceps cross-sectional area (magnetic resonance imaging measurement) were significantly higher in young (22 ± 2 years; 266 ± 54 N/m; 8,686 ± 1,154 mm(2)) than in mildly sarcopenic (69 ± 3 years; 183 ± 17 N/m; 6,621±718 mm(2)) and severely sarcopenic men (76 ± 6 years; 127 ± 23 N/m; 5,846 ± 591 mm(2)), respectively (p ≤ .01 for all comparisons). There was a trend (p = .06) toward higher FLRG in young (20 ± 8 ng/mL) than in mildly (15 ± 6 ng/mL) and severely sarcopenic men (17 ± 8 ng/mL). Myostatin, follistatin, GASP-1, tumor necrosis factor α, and interleukin-6 did not differ significantly. Insulin-like growth factor-1 and free testosterone were both significantly lower in sarcopenic men (p < .001). This suggests that altered serum concentrations of myostatin and myostatin-interacting proteins are not contributing to sarcopenia with the possible exception of FLRG.

Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle.

We determined the effects of intravenous infusion of amino acids (AA) at serum insulin of 5, 30, 72, and 167 mU/l on anabolic signaling, expression of ubiquitin-proteasome components, and protein turnover in muscles of healthy young men. Tripling AA availability at 5 mU/l insulin doubled incorporation of [1-(13)C]leucine [i.e., muscle protein synthesis (MPS), P < 0.01] without affecting the rate of leg protein breakdown (LPB; appearance of d(5)-phenylalanine). While keeping AA availability constant, increasing insulin to 30 mU/l halved LPB (P < 0.05) without further inhibition at higher doses, whereas rates of MPS were identical to that at 5 mU/l insulin. The phosphorylation of PKB Ser(473) and p70(S6k) Thr(389) increased concomitantly with insulin, but whereas raising insulin to 30 mU/l increased the phosphorylation of mTOR Ser(2448), 4E-BP1 Thr(37/46), or GSK3beta Ser(9) and decreased that of eEF2 Thr(56), higher insulin doses to 72 and 167 mU/l did not augment these latter responses. MAFbx and proteasome C2 subunit proteins declined as insulin increased, with MuRF-1 expression largely unchanged. Thus increasing AA and insulin availability causes changes in anabolic signaling and amounts of enzymes of the ubiquitin-proteasome pathway, which cannot be easily reconciled with observed effects on MPS or LPB.

Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation.

Endurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6x10 repetitions of 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3- and 2.7-fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by approximately 2-fold and increased PGC-1alpha protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3beta at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E-BP1, eIF-2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK-PGC-1alpha signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB-TSC2-mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the "AMPK-PKB switch." We hypothesize that the AMPK-PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.

Momordica charantia fruit juice stimulates glucose and amino acid uptakes in L6 myotubes.

The fruit of Momordica charantia (family: Cucurbitacea) is used widely as a hypoglycaemic agent to treat diabetes mellitus (DM). The mechanism of the hypoglycaemic action of M. charantia in vitro is not fully understood. This study investigated the effect of M. charantia juice on either 3H-2-deoxyglucose or N-methyl-amino-a-isobutyric acid (14C-Me-AIB) uptake in L6 rat muscle cells cultured to the myotube stage. The fresh juice was centrifuged at 5000 rpm and the supernatant lyophilised. L6 myotubes were incubated with either insulin (100 nM), different concentrations (1-10 microg ml(-1)) of the juice or its chloroform extract or wortmannin (100 nM) over a period of 1- 6 h. The results were expressed as pmol min(-1) (mg cell protein)(-1), n = 6-8 for each value. Basal 3H-deoxyglucose and 14C-Me-AIB uptakes by L6 myotubes after 1 h of incubation were (means +/- S.E.M.) 32.14 +/- 1.34 and 13.48 +/- 1.86 pmol min(-1) (mg cell protein)(-1), respectively. Incubation of L6 myotubes with 100 nM insulin for 1 h resulted in significant (ANOVA, p < 0.05) increases in 3H-deoxyglucose and 14C-Me-AIB uptakes. Typically, 3H-deoxyglucose and 14C-Me-AIB uptakes in the presence of insulin were 58.57 +/- 4.49 and 29.52 +/- 3.41 pmol min(-1) (mg cell protein(-1)), respectively. Incubation of L6 myotubes with three different concentrations (1, 5 and 10 microg ml(-1)) of either the lyophilised juice or its chloroform extract resulted in time-dependent increases in 3H-deoxy-D-glucose and 14C-Me-AIB uptakes, with maximal uptakes occurring at a concentration of 5 microg ml(-1). Incubation of either insulin or the juice in the presence of wortmannin (a phosphatidylinositol 3-kinase inhibitor) resulted in a marked inhibition of 3H-deoxyglucose by L6 myotubes compared to the uptake obtained with either insulin or the juice alone. The results indicate that M. charantia fruit juice acts like insulin to exert its hypoglycaemic effect and moreover, it can stimulate amino acid uptake into skeletal muscle cells just like insulin.

Cardiac output, leg blood flow and oxygen uptake during foot plantar flexions.

When studying the adjustment of muscle perfusion during exercise, the influence of central factors (e.g. blood volume, central blood pressure and venous return) can be reduced by choosing small muscle groups. In the present study parallel determinations of cardiac output (CO), leg blood flow (LBF) and pulmonary oxygen (VO2) uptake were performed in 9 healthy male subjects at the onset and cessation of dynamic foot plantar flexions. The volunteers exercised with both feet for 5 minutes at 3 different resistances corresponding to 6%, 18% and 30% of the mean maximal voluntary contraction. Doppler measurements at the aortic root and in the femoral artery were utilized to estimate CO and LBF. Oxygen uptake was analyzed breath-by-breath as the difference between inspired and expired oxygen volumes. Within the first 10 s of exercise LBF increased from 400 ml x min(-1) to about 1,000 ml x min(-1) at all exercises intensities. During the subsequent 5 minutes of exercise, LBF decreased to about 800 ml x min(-1) at the lowest intensity. By contrast, it increased to about 1,900 ml x min(-1) at the highest intensity. The changes in CO during exercise were quantitatively identical with the changes in LBF. The present results suggest that the fine adjustment of muscle blood flow and muscle metabolism starts only after a fast and uniform circulatory on response. The second component may lead to leg perfusion values above, at or below the initial peak perfusion levels. The off-transients of LBF displayed no comparable fast responses. They were slower than the recovery kinetics of any cardiovascular parameter measured in the present study.

Recovery of free ADP, Pi, and free energy of ATP hydrolysis in human skeletal muscle.

We measured significant undershoots of the concentrations of free ADP ([ADP]) and Pi ([Pi]) and the free energy of ATP hydrolysis (DeltaGATP) below initial resting levels during recovery from severe ischemic exercise with 31P-nuclear magnetic resonance spectroscopy in 11 healthy sports students. Undershoots of the rate of oxidative phosphorylation would be predicted if the rate of oxidative phosphorylation would depend solely on free [ADP], [Pi], or DeltaGATP. However, undershoots of the rate of oxidative phosphorylation have not been reported in the literature. Furthermore, undershoots of the rate of oxidative phosphorylation are unlikely because there is evidence that a balance between ATP production and consumption cannot be achieved if an undershoot of the rate of oxidative phosphorylation actually occurs. Therefore, oxidative phosphorylation seems to depend not only on free [ADP], [Pi], or DeltaGATP. An explanation is that acidosis-related or other factors control oxidative phosphorylation additionally, at least under some conditions.

Leg blood flow during slow head-down tilt with and without leg venous congestion.

The effects of slow changes in body position on leg blood flow (LBF) were studied in nine healthy male subjects. Using a tilt table, sitting volunteers were tilted about 60 degrees backwards to a supine position within 40 s. To modify the venous filling in the legs, the tilt manoeuvre was repeated with congestion of the leg veins induced by two thigh cuffs inflated to a subdiastolic pressure of 60 mmHg. Doppler measurements in the femoral artery were used to estimate LBF. Additional Doppler measurements at the aortic root in five of the subjects were taken for the determination of cardiac output. The LBF was influenced by body position. In the control experiment it increased from 500 ml x min(-1) in the upright to 780 ml x min(-1) after 15 min in the supine position. A mean maximal value of 950 ml x min(-1) was observed 20 s after the tilt. Heart rate remained almost constant during the tilt phase, whereas stroke volume increased from 90 ml to 120 ml and it remained at that level after the cessation of the tilt. Congestion of the leg veins had no significant effect on heart rate, stroke volume and mean blood pressure. However, it increased vascular resistance of the leg during and after the tilt. After 15 min in the tilted position LBF amounted to 600 ml x min(-1). The results suggest that the filling of the leg veins is inversely related to leg blood flow. The most likely mechanism underlying this observation is a local effect of venous filling on vasomotor tone.

Effects of chronically increased ambient CO2 concentrations on aerobic capacity.

As part of a joint NASA-ESA-DARA study on the effects of chronically increased CO2 concentrations in ambient air, changes in parameters indicating aerobic capacity were investigated by cycle ergometry. Two potential sources for reductions of aerobic capacities were hypothesized: 1) the adaptations to CO2 such as reduction in H(+)-buffer capacities which may influence muscle metabolism; 2) the reduced physical activities which may lead to a detraining effect. Four subjects were exposed to 0.7% and 1.2% CO2 concentration in a confined compartment for 23 d each with 3 mo in between the two campaigns. A combined exercise test was applied before, during (on days 5, 11, and 22) and after CO2 exposure. Comparing steady-states at 30 W and 80 W power, elevated ventilation was found increased during CO2 exposure with significant differences between the two campaigns. Peak oxygen uptake decreased over the period of CO2 exposure, but was found not significantly different on day 5 compared to pre-exposure measurements. This decrease was not dependent on the CO2 concentration. The lactate concentration at low exercise intensities was found elevated during CO2 exposure. A shift in reverse direction was observed after the CO2 exposure. Since peak oxygen uptake did not differ on day 5 and the lactate concentration was found increased, it was concluded that the potential changes in muscle metabolism by adaptation to elevated CO2 concentrations did not influence the aerobic capacities. Therefore, it was concluded that the changes in aerobic capacities are the result of the reduced physical activities of the subjects while living in the confined compartment.

Glycolytic ATP production estimated from 31P magnetic resonance spectroscopy measurements during ischemic exercise in vivo.

In an oxygen-depleted muscle, glycolytically produced ATP is inversely related to the ([ATP]+ creatine phosphate [PCr]) decrease because ATP, PCr, and glycolysis are virtually the only energy sources under these conditions. In particular, the onset of glycolysis or any appreciable increase in the rate of glycolytic ATP production will lead to a slower rate of ([ATP]+ [PCr]) breakdown at a given energy consumption. To quantify this relationship, endurance athletes performed isometric foot plantar flexion (20% of a test force [TF], n = 10; 50% TF, n = 5) during local arterial occlusion. Parameters of energy metabolism were measured with 31P magnetic resonance spectroscopy (31P-MRS). During exercise, [PCr] decreased to 80 +/- 10 (20% TF) and 11 +/- 4% (50% TF) of its resting concentration, and pH dropped from 7.04 +/- 0.01 to 6.98 +/- 0.10 (20% TF) and from 7.03 +/- 0.02 to 6.70 +/- 0.10 (50% TF). In both experiments, two phases of ([ATP]+ [PCr]) decrease were observed: an initial faster decrease was followed by a slower decline. The latter phase started at about the time when the pH began to drop. The difference between a line extrapolated from the slope of the initial phase and the measured ([ATP]+[PCr]) decrease was used as an estimate for glycolytically produced ATP. This estimate and pH were significantly correlated with r = -0.97 (20% TF) and r = -0.99 (50% TF). These results indicate that glycolytically produced ATP can be estimated from the ([ATP]+ [PCr]) decrease during exercise.