Plasma sodium-osmotic dissociation and hormonal interaction with drinking-induced hypervolemia at 2800 m altitude.

PURPOSE: To study hormonal factors that may account for the dissociation between beverage-induced plasma sodium p[Na+] and osmotic p[Osm] concentrations that appear to refute the high theoretical correlation between p[Na+] and p[Osm]. METHODS: Ten men (24 +/- SD 3 yr of age) sat reclining (head up) for 12 h in a chamber (21-23 degrees C dry bulb, 25-33% relative humidity) at 2800 m (9184 ft, 539 mm Hg) altitude (ALT), and at 321 m (1053 ft, 732 mm Hg) on the ground (GND). During 1000-1030 hours they consumed 3 fluids (12 ml x kg(-1),X = 948 ml x d(-1)) with large differences in sodium and osmotic contents: AstroAde (AA) with 185 mEq x L(-1) Na+ and 283 mOsm x kg(-1), Performance 1 (Shaklee) (P1) with 22 mEq x L(-1) Na+ and 365 mOsm kg(-1), or H2O at ALT; and only H2O on the GND. RESULTS: After drinking: plasma volume (PV) increased at 1200 hours by 8.3% (p < 0.05) with AA but was not significantly (NS) changed in the other sessions (Xdelta = +0.9%, range -0.9 to 2.8%); p[Na+] and p[Osm] were unchanged. Urinary rates and free-water clearances were attenuated with AA and P1 vs. those with H2O. Correlations between and among p[Na+] and p[Osm] suggest that the pNa+ ion is more tightly controlled than pOsm; and that there was no clear hormonal response that could account for this dissociation from theoretical considerations. CONCLUSIONS: There is significant dissociation between plasma sodium and osmotic concentrations after fluid intake. Induction and maintenance of hypervolemia requires increased (near isotonic) drink Na+ osmols rather than increased non-ionic osmols.

Immunization against IGF-I prevents increases in protein synthesis in diabetic rats after resistance exercise.

These studies examined whether passive immunization against insulin-like growth factor I (IGF-I) would prevent increases in rates of protein synthesis in skeletal muscle of diabetic rats after resistance exercise. Male Sprague-Dawley rats were pancreatectomized and randomly assigned to either an exercise or a sedentary group. Animals in each of these groups received either an IGF-I antibody or a nonspecific IgG from a subcutaneous osmotic pump. Exercise did not change plasma or gastrocnemius IGF-I concentrations in nondiabetic rats. However, plasma and muscle IGF-I concentrations were higher in IgG-treated diabetic rats that exercised compared with respective sedentary groups (P < 0.05). Passively immunized diabetic rats did not exhibit the same exercise-induced increase in IGF-I concentrations. In nondiabetic rats, protein synthesis rates were higher after exercise in both control and immunized groups. In diabetic rats, exercise increased protein synthesis in the IgG-treated animals but not in those treated with IGF-I antibody. There was also a significant positive correlation between both plasma and gastrocnemius IGF-I concentrations and rates of protein synthesis in diabetic (P < 0.01), but not nondiabetic, rats. These results suggest that IGF-I is compensatory for insulin in hypoinsulinemic rats by facilitating an anabolic response after acute resistance exercise.

Selected Contribution: IGF-I antibody prevents increases in protein synthesis in epitrochlearis muscles from refed, diabetic rats.

The purpose of this study was to examine whether immune neutralization of muscle-produced insulin-like growth factor I (IGF-I) would prevent an appropriate anabolic response to refeeding in diabetic rats. Male Sprague-Dawley rats were made diabetic by partial pancreatectomy and were randomly assigned to be either control-fed, fasted, or fasted-refed (n = 7-8 per group). Diabetes decreased rates of protein synthesis and increased rates of protein degradation in incubated epitrochlearis muscles (P < 0.05). In both groups of rats, fasting lowered protein synthesis and increased proteolysis and subsequent refeeding returned both parameters to near basal values (P < 0.05). Neutralization of muscle IGF-I by the addition of IGF-I antibody to the incubation medium reduced protein synthesis an average of 22% for all groups (P < 0.05). However, rates of protein degradation were not affected. In nondiabetic rats, refeeding increased protein synthesis in both control and antibody-treated muscles (P < 0.05). Refeeding also increased protein synthesis in the control muscles from diabetic rats (P < 0.01). In contrast, muscles from diabetic rats that were incubated with anti-IGF-I did not increase protein synthesis in response to refeeding. These data suggest that immune neutralization of muscle IGF-I in hypoinsulinemic rats negated the ability of endogenous IGF-I to promote protein synthesis and thereby prevented an appropriate anabolic response.

Eukaryotic initiation factors and protein synthesis after resistance exercise in rats.

Translational control of protein synthesis depends on numerous eukaryotic initiation factors (eIFs) and we have previously shown (Am. J. Physiol. Endocrinol. Metab. 276: E721-E727, 1999) that increases in one factor, eIF2B, are associated with increases in rates of protein synthesis after resistance exercise in rats. In the present study we investigated whether the eIF4E family of initiation factors is also involved with an anabolic response to exercise. Male Sprague-Dawley rats either remained sedentary (n = 6) or performed acute resistance exercise (n = 6), and rates of protein synthesis were assessed in vivo 16 h after the last session of resistance exercise. eIF4E complexed to eIF4G (eIF4E x eIF4G), eIF4E binding protein 1 (4E-BP1) complexed to eIF4E, and phosphorylation state of eIF4E and 4E-BP1 (gamma-form) were assessed in gastrocnemius. Rates of protein synthesis were higher in exercised rats compared with sedentary rats [205 +/- 8 (SE) vs. 164 +/- 5.5 nmol phenylalanine incorporated x g muscle(-1) x h(-1), respectively; P < 0.05]. Arterial plasma insulin concentrations were not different between the two groups. A trend (P = 0.09) for an increase in eIF4E x eIF4G with exercise was noted; however, no statistically significant differences were observed in any of the components of the eIF4E family in response to resistance exercise. These new data, along with our previous report on eIF2B, suggest that the regulation of peptide chain initiation after exercise is more dependent on eIF2B than on the eIF4E system.

Time course evaluation of protein synthesis and glucose uptake after acute resistance exercise in rats.

The temporal pattern for changes in rates of protein synthesis and glucose uptake after resistance exercise, especially relative to each other, is not known. Male Sprague-Dawley rats performed acute resistance exercise (n = 7) or remained sedentary (n = 7 per group), and the following were assessed in vivo 1, 3, 6, 12 and 24 h later: rates of protein synthesis, rates of glucose uptake, phosphatidylinositol 3-kinase (PI3-kinase) activity, and p70(S6k) activity. Rates of protein synthesis in mixed gastrocnemius muscle did not increase until 12 h after exercise (e.g., at 12 h, sedentary = 138 +/- 4 vs. exercised = 178 +/- 6 nmol phenylalanine incorporated x g muscle(-1) x h(-1), mean +/- SE, P < 0.05), whereas at 6 h after exercise rates of glucose uptake were significantly elevated (sedentary = 0.18 +/- 0.020 vs. exercised = 0.38 +/- 0.024 micromol glucose 6-phosphate incorporated x kg muscle(-1) x min(-1), P < 0.05). At 24 h after exercise, rates of protein synthesis were still elevated, whereas glucose uptake had returned to basal levels. Arterial insulin concentrations were not different between groups at any time. Non-insulin-stimulated activities of PI3-kinase and p70(S6k) were higher at 6, 12, and 24 h after exercise (P < 0.05), and, generally, these occurred when rates of protein synthesis (12 and 24 h) and glucose uptake were elevated (6 and 12 but not 24 h) by exercise. These data suggest that regulators of protein synthesis and glucose uptake may respond to the same contraction-generated signals with different kinetics or that they respond to different intra- or extracellular signals that are generated by exercise.

Severe diabetes prohibits elevations in muscle protein synthesis after acute resistance exercise in rats.

This study determined whether rates of protein synthesis increase after acute resistance exercise in skeletal muscle from severely diabetic rats. Previous studies consistently show that postexercise rates of protein synthesis are elevated in nondiabetic and moderately diabetic rats. Severely diabetic rats performed acute resistance exercise (n = 8) or remained sedentary (n = 8). A group of nondiabetic age-matched rats served as controls (n = 9). Rates of protein synthesis were measured 16 h after exercise. Plasma glucose concentrations were >500 mg/dl in the diabetic rats. Rates of protein synthesis (nmol phenylalanine incorporated. g muscle(-1). h(-1), means +/- SE) were not different between exercised (117 +/- 7) and sedentary (106 +/- 9) diabetic rats but were significantly (P < 0.05) lower than in sedentary nondiabetic rats (162 +/- 9) and in exercised nondiabetic rats (197 +/- 7). Circulating insulin concentrations were 442 +/- 65 pM in nondiabetic rats and 53 +/- 11 and 72 +/- 19 pM in sedentary and exercised diabetic rats, respectively. Plasma insulin-like growth factor I concentrations were reduced by 33% in diabetic rats compared with nondiabetic rats, and there was no difference between exercised and sedentary diabetic rats. Muscle insulin-like growth factor I was not affected by resistance exercise in diabetic rats. The results show that there is a critical concentration of insulin below which rates of protein synthesis begin to decline in vivo. In contrast to previous studies using less diabetic rats, severely diabetic rats cannot increase rates of protein synthesis after acute resistance exercise.

Hypertrophy of skeletal muscle in diabetic rats in response to chronic resistance exercise.

This study had the following objectives: 1) to determine whether diabetic rats could increase muscle mass due to a physiological manipulation (chronic resistance exercise), 2) to determine whether exercise training status modifies the effect of the last bout of exercise on elevations in rates of protein synthesis, and 3) to determine whether chronic resistance exercise alters basal glycemia. Groups consisted of diabetic or nondiabetic rats that performed progressive resistance exercise for 8 wk, performed acute resistance exercise, or remained sedentary. Arterial plasma insulin in diabetic groups was reduced by about one-half (P < 0.05) compared with nondiabetic groups. Soleus and gastrocnemius-plantaris complex muscle wet weights were lower because of diabetes, but in response to chronic exercise these muscles hypertrophied in diabetic (0.028 +/- 0.003 vs. 0.032 +/- 0.0015 g/cm for sedentary vs. exercised soleus and 0.42 +/- 0.068 vs. 0.53 +/- 0.041 g/cm for sedentary vs. exercised gastrocnemius-plantaris, both P < 0.05) but not in nondiabetic (0.041 +/- 0.0026 vs. 0.042 +/- 0.003 g/cm for sedentary vs. exercised soleus and 0.72 +/- 0.015 vs. 0.69 +/- 0.013 g/cm for sedentary vs. exercised gastrocnemius-plantaris) rats when muscle weight was expressed relative to tibial length or body weight (data not shown). Another group of diabetic rats that lifted heavier weights showed muscle hypertrophy. Rates of protein synthesis were higher in red gastrocnemius in chronically exercised than in sedentary rats: 155 +/- 11 and 170 +/- 7 nmol phenylalanine incorporated x g muscle(-1) x h(-1) in exercised diabetic and nondiabetic rats vs. 110 +/- 14 and 143 +/- 7 nmol phenylalanine incorporated x g muscle(-1) x h(-1) in sedentary diabetic and nondiabetic rats. These elevations, however, were lower than in acutely exercised (but untrained) rats: 176 +/- 15 and 193 +/- 8 nmol phenylalanine incorporated x g muscle(-1) x h(-1) in diabetic and nondiabetic rats. Finally, chronic exercise training in diabetic rats was associated with reductions in basal glycemia, and such reductions did not occur in sedentary diabetic groups. These data demonstrate that, despite lower circulating insulin concentrations, diabetic rats can increase muscle mass in response to a physiological stimulus.

Regulation of protein synthesis after acute resistance exercise in diabetic rats.

These studies determined whether insulin-like growth factor-I (IGF-I) involvement in exercise-stimulated anabolic processes becomes more evident during hypoinsulinemia. Male Sprague-Dawley rats (n = 6-12/group) were made diabetic (blood glucose congruent with 300 mg/dl) by partial pancreatectomy (PPX) or remained nondiabetic (glucose congruent with 144 mg/dl). Rats performed acute resistance exercise by repetitive standing on the hindlimbs with weighted backpacks (ex), or they remained sedentary (sed). Resistance exercise caused increases in rates of protein synthesis (nmol Phe incorporated. g muscle-1. h-1, measured for gastrocnemius muscle in vivo 16 h after exercise) for both nondiabetic [sed = 154 +/- 6 (SE) vs. ex = 189 +/- 7] and diabetic rats (PPXsed = 152 +/- 11 vs. PPXex = 202 +/- 14, P < 0.05). Arterial plasma insulin concentrations in diabetic rats, congruent with180 pM, were less than one-half those found in nondiabetic rats, congruent with444 pM, (P < 0.05). The activity of eukaryotic initiation factor 2B (eIF2B; pmol GDP exchanged/min) was higher (P < 0.05) in ex rats (sed = 0.028 +/- 0.006 vs. ex = 0.053 +/- 0.015; PPXsed = 0.033 +/- 0.013 vs. PPXex = 0.047 +/- 0.009) regardless of diabetic status. Plasma IGF-I concentrations were higher in ex compared with sed diabetic rats (P < 0.05). In contrast, plasma IGF-I was not different in nondiabetic ex or sed rats. Muscle IGF-I (ng/g wet wt) was similar in ex and sed nondiabetic rats, but in diabetic rats was 2- to 3-fold higher in ex (P < 0.05) than in sed rats. In conclusion, moderate hypoinsulinemia that is sufficient to alter glucose homeostasis does not inhibit an increase in rates of protein synthesis after acute moderate-intensity resistance exercise. This preserved response may be due to a compensatory increase in muscle IGF-I content and a maintained ability to activate eIF2B.

Effects of intensity of acute-resistance exercise on rates of protein synthesis in moderately diabetic rats.

These studies determined whether increases in rates of protein synthesis observed in skeletal muscle after moderate or severe acute-resistance exercise were blunted by insulinopenia. Rats (n = 6-9 per group) were made insulin deficient by partial pancreatectomy or remained nondiabetic. Groups either remained sedentary or performed acute-resistance exercise 16 h before rates of protein synthesis were measured in vivo. Exercise required 50 repetitions of standing on the hindlimbs with either 0.6 g backpack wt/g body wt (moderate exercise) or 1.0 g backpack wt/g body wt (severe exercise). Insulin-deficient rats had a mean blood glucose concentration >15 mM and reduced insulin concentrations in the plasma. Rates of protein synthesis in gastrocnemius muscle were not different in all sedentary groups. The moderate-exercised nondiabetic group (192 +/- 12 nmol phenylalanine incorporated. g muscle-1. h-1) and moderate-exercised diabetic group (215 +/- 18) had significantly (P < 0.05, ANOVA) higher rates of protein synthesis than did respective sedentary groups. In contrast, diabetic rats that performed severe-resistance exercise had rates of protein synthesis (176 +/- 12) that were not different (P > 0.05) from diabetic sedentary rats (170 +/- 9), whereas nondiabetic rats that performed severe exercise had higher (212 +/- 24) rates compared with nondiabetic sedentary rats (178 +/- 10) P < 0.05. The present data in combination with previous studies [J. D. Fluckey, T. C. Vary, L. S. Jefferson, and P. A. Farrell. Am. J. Physiol. 270 (Endocrinol. Metab. 33): E313-E319, 1996] show that the amount of insulin required for an in vivo permissive effect of insulin on rates of protein synthesis can be quite low after moderate-intensity resistance exercise. However, severe exercise in combination with low insulin concentrations can ablate an anabolic response.

Sodium chloride-citrate beverages attenuate hypovolemia in men resting 12 h at 2800 m altitude.

BACKGROUND: The mechanism for reduction and restoration of total body water and plasma volume (PV) during initial exposure to acute altitude (ALT) is not clear but may involve involuntary dehydration; i.e., delayed voluntary fluid intake. METHOD: Ten men (24 +/- SD 3 yr, 180.8 +/- 8.1 cm height, 78.8 +/- 12.8 kg weight, 1.99 +/- 0.19 m2 surface area, and 12.2 +/- 4.0% body fat) were in a semi-reclining position for 12 h in a chamber at 2800 m (539 mmHg) ALT or at 321 m (732 mmHg; ground). They ate a controlled breakfast (450 kcal + 3 ml x kg(-1) H2O) on the ground, and lunch and dinner at ALT (or on the ground) for a total daily intake of 2850 kcal (14% PRO, 67% CHO, 16% fat, 2.6g NaCl). At hour 10 they consumed fluid-electrolyte beverages or water (12 ml x kg(-1), 948 ml x d(-1)) in 4 sessions at weekly intervals. Beverage compositions were: a) 185 mEq x L(-1) Na+, 283 mOsm x kg(-1); b) 21.6 mEq x L(-1) Na+, 365 mOsm x kg(-1); c) water at ALT; and d) water on the ground. RESULTS: After 10 h at ALT % deltaPV (Hb-Hct) decreased (p < 0.05) by: a) 9.0 +/- SE 1.5%; b) 6.2 +/- 1.7%; c) 7.4 +/- 2.2%; and d) by 9.0 +/- 2.4%, respectively. After drinking from 1000-1030 h, PV at 1200 h changed by: a) +8.3 +/- SE 2.0% (p < 0.05); b) +2.8 +/- 2.7% (NS); c) -0.9 +/- 1.5% (NS); and d) by +0.8 +/- 3.5% (NS), respectively. The similar ground-induced hypovolemia suggests a response to confinement rather than an ALT effect and involuntary dehydration does not appear to be implicated. CONCLUSION: The significant increase in PV after consuming the (a) NaCl-NaCitrate beverage indicates that drink ionic composition appears to be more important than its osmolality for restoring PV in these conditions. Practical considerations: Because this hypovolemia was probably due to the confinement rather that reduced ambient pressure, appropriate countermeasures could be consumption of isotonic beverages, elastic stockings, leg exercise, and leg elevation.