Skeletal muscle protein and function decline with advancing age but the underlying pathophysiology is poorly understood. To test the hypothesis that the catabolic cytokine tumor necrosis factor alpha (TNF-alpha) contributes to this process, we studied the effects of aging and resistance exercise on TNF-alpha expression in human muscle. Using in situ hybridization, TNF-alpha message was localized to myocytes in sections of skeletal muscle from elderly humans. Both TNF-alpha mRNA and protein levels were elevated in skeletal muscle from frail elderly (81+/-1 year) as compared to healthy young (23+/-1 year) men and women. To determine whether resistance exercise affects TNF-alpha expression, frail elderly men and women were randomly assigned to a training group or to a nonexercising control group. Muscle biopsies were performed before and after 3 months. Muscle TNF-alpha mRNA and protein levels decreased in the exercise group but did not change in the control group. Muscle protein synthesis rate in the exercise group was inversely related to levels of TNF-alpha protein. These data suggest that TNF-alpha contributes to age-associated muscle wasting and that resistance exercise may attenuate this process by suppressing skeletal muscle TNF-alpha expression.

Many clinical studies have been carried out to determine the health benefits of soy protein and the isoflavones contained in soy. S-equol is not present in soybeans but is produced naturally in the gut of certain individuals, particularly Asians, by the bacterial biotransformation of daidzein, a soy isoflavone. In those intervention studies in which plasma S-equol levels were determined, a concentration of >5-10 ng/mL has been associated with a positive outcome for vasomotor symptoms, osteoporosis (as measured by an increase in bone mineral density), prostate cancer, and the cardiovascular risk biomarkers low-density lipoprotein cholesterol and C-reactive protein. These studies suggest that S-equol may provide therapeutic benefits for a number of medical needs.

Amino acids and insulin have anabolic effects in skeletal muscle, but the mechanisms are poorly understood. To test the hypothesis that leucine and insulin stimulate translation initiation in human skeletal muscle by phosphorylating 70-kDa ribosomal protein S6 kinase (p70(S6k)), we infused healthy adults with leucine alone (n = 6), insulin alone (n = 6), or both leucine and insulin (n = 6) for 2 h. p70(S6k) and protein kinase B (PKB) serine(473) phosphorylation were measured in vastus lateralis muscles. Plasma leucine increased from approximately 116 to 343 micromol/l during the leucine-alone and leucine + insulin infusions. Plasma insulin increased to approximately 400 pmol/l during the insulin-alone and leucine + insulin infusions and was unchanged during the leucine-alone infusion. Phosphorylation of p70(S6k) increased 4-fold in response to leucine alone, 8-fold in response to insulin alone, and 18-fold after the leucine + insulin infusion. Insulin-alone and leucine + insulin infusions increased PKB phosphorylation, but leucine alone had no effect. These results show that physiological concentrations of leucine and insulin activate a key mediator of protein synthesis in human skeletal muscle. They suggest that leucine stimulates protein synthesis through a nutrient signaling mechanism independent of insulin, raising the possibility that administration of branched-chain amino acids may improve protein synthesis in insulin-resistant states.

The purpose of this investigation was to determine whether endurance exercise training increases the ability of human skeletal muscle to accumulate glycogen after exercise. Subjects (4 women and 2 men, 31 +/- 8 yr old) performed high-intensity stationary cycling 3 days/wk and continuous running 3 days/wk for 10 wk. Muscle glycogen concentration was measured after a glycogen-depleting exercise bout before and after endurance training. Muscle glycogen accumulation rate from 15 min to 6 h after exercise was twofold higher (P < 0.05) in the trained than in the untrained state: 10.5 +/- 0.2 and 4.5 +/- 1.3 mmol. kg wet wt(-1). h(-1), respectively. Muscle glycogen concentration was higher (P < 0.05) in the trained than in the untrained state at 15 min, 6 h, and 48 h after exercise. Muscle GLUT-4 content after exercise was twofold higher (P < 0.05) in the trained than in the untrained state (10.7 +/- 1.2 and 4.7 +/- 0.7 optical density units, respectively) and was correlated with muscle glycogen concentration 6 h after exercise (r = 0.64, P < 0.05). Total glycogen synthase activity and the percentage of glycogen synthase I were not significantly different before and after training at 15 min, 6 h, and 48 h after exercise. We conclude that endurance exercise training enhances the capacity of human skeletal muscle to accumulate glycogen after glycogen-depleting exercise.

Previous studies have demonstrated that frail octogenarians have an attenuated capacity for cardiovascular adaptations to endurance exercise training. In the present study, we determined the magnitude of cardiovascular and metabolic adaptations to high-intensity endurance exercise training in healthy, nonfrail elderly subjects. Ten subjects [8 men, 2 women, 80.3 yr (SD2.5)] completed 10-12 mo (108 exercise sessions) of a supervised endurance exercise training program consisting of 2.5 sessions/wk (SD 0.2), 58 min/session (SD 6), at an intensity of 83% (SD 5) of peak heart rate. Primary outcomes were maximal attainable aerobic power [peak aerobic capacity (Vo(2peak))]; serum lipids, oral glucose tolerance, and insulin action during a hyperglycemic clamp; body composition by dual-energy X-ray absorptiometry, and energy expenditure using doubly labeled water and indirect calorimetry. The training program resulted in an increase in Vo(2peak) of 15% (SD 7) [22.9 (SD 3.3) to 26.2 ml.kg(-1).min(-1) (SD 4.0); P < 0.0001]. Favorable lipid changes included reductions in total cholesterol (-8%; P = 0.002) and LDL cholesterol (-10%; P = 0.003), with no significant change in HDL cholesterol or triglycerides. Insulin action improved, as evidenced by a 29% increase in glucose disposal rate relative to insulin concentration during the hyperglycemic clamp. Fat mass decreased by 1.8 kg (SD 1.4) (P = 0.003); lean mass did not change. Total energy expenditure increased by 400 kcal/day because of an increase in physical activity. No change occurred in resting metabolism. In summary, healthy nonfrail octogenarians can adapt to high-intensity endurance exercise training with improvements in aerobic power, insulin action, and serum lipid and lipoprotein risk factors for coronary heart disease; however, the adaptations in aerobic power and insulin action are attenuated compared with middle-aged individuals.

Exercise increases the expression of lipoprotein lipase (LPL) and GLUT-4 in skeletal muscle. Intense exercise increases catecholamines, and catecholamines without exercise can affect the expression of both LPL and GLUT-4. To test the hypothesis that adrenergic-receptor signaling is central to the induction of LPL and GLUT-4 by exercise, six untrained individuals [age 28 +/- 4 (SD) yr, peak oxygen uptake 3.6 +/- 0.3 l/min] performed two exercise bouts within 12 days. Exercise consisted of cycling at approximately 65% peak oxygen uptake for 60 min with (block trial) and without (control trial) adrenergic-receptor blockade. Exercise intensity was the same during the block and control trials. Plasma catecholamine concentrations were significantly higher and heart rates were significantly lower during the block trial compared with the control trial, consistent with known effects of adrenergic-receptor blockade. However, blockade did not prevent the induction of either LPL or GLUT-4 proteins assayed in biopsies of skeletal muscle. LPL was significantly increased by 170-240% and GLUT-4 was significantly increased by 32-51% at 22 h after exercise compared with before exercise during both the control and block trials. These findings provide evidence that exercise increases muscle LPL and GLUT-4 protein content via signals generated by alterations in cellular homeostasis and not by adrenergic-receptor stimulation.

It is well documented that endurance exercise training results in a blunted norepinephrine (NE) response to exercise of a given absolute exercise intensity. However, it is not clear what effect training has on the catecholamine response to exercise of the same relative intensity because previous studies have provided conflicting results. The purpose of the present study was, therefore, to determine the catecholamine response to exercise of the same relative exercise intensity before and after endurance exercise training. Six women and three men [age 28 +/- 8 (SD) yr] performed 10 wk of training. Maximal O2 uptake (VO2 max) was determined during treadmill exercise. Fifteen-minute treadmill exercise bouts were performed at 60, 65, 70, 75, 80, and 85% of VO2 max before and after training. VO2 max was increased by 20% (from 39.2 +/- 7.7 to 46.9 +/- 8.1 ml. kg-1. min-1; P < 0.05) in response to training. Plasma NE concentrations were higher (P < 0.05) during exercise at the same relative intensity after, compared with before, training at 65-85% of VO2 max. Differences between heart rates and plasma epinephrine concentrations after, compared with before, training were not statistically significant. These results provide evidence that the NE response to exercise is dependent on the absolute as well as the relative intensity of the exercise.

To examine the effects of rapid dehydration on isometric muscular strength and endurance, seven men were tested at baseline (control) and after a dehydration (dHST) and a euhydration (eHST) heat stress trial. The dHST consisted of intermittent sauna exposure until 4% of body mass was lost, whereas the eHST consisted of intermittent sauna exposure (same duration as dHST) with water replacement. Peak torque was determined for the knee extensors and elbow flexors during three isometric maximal voluntary contractions. Time to fatigue was determined by holding a maximal voluntary contraction until torque dropped below 50% peak torque for 5 s. Strength and endurance were assessed 3.5 h after the HSTs (no food or water intake). Body mass was decreased 3.8+/-0.4% post dHST and 0.4+/-0.3% post eHST. Plasma volume was decreased 7.5+/-4.6% and 5.7+/-4.4%, 60 and 120 min post dHST, respectively. A small (1.6 mEq x L[-1]) but significant increase was found for serum Na+ concentration 60 min post dHST but had returned to predehydration level 120 min post dHST. Serum K+ and myoglobin concentrations were not affected by HSTs. Peak torque was not different (P > 0.05) among control, dHST, and eHST for the knee extensors (Mean (Nm)+/-SD, 285+/-79, 311+/-113, and 297+/-79) and elbow flexors (79+/-12, 83+/-15, and 80+/-12). Time to fatigue was not different (P > 0.05) among control, dHST and eHST for the knee extensors (Mean (s)+/-SD. 42.4+/-11.5, 45.3+/-7.6, and 41.8+/-6.0) and elbow flexors (48.2+/-8.9, 44.0+/-9.4, and 46.0+/-6.4). These results provide evidence that isometric strength and endurance are unaffected 3.5 h after dehydration of approximately 4% body mass.