Robert C. Hickner

Prolonged exercise decreases serum leptin concentrations

Serum leptin and free fatty acid concentrations were determined in two groups of subjects undergoing strenuous exercise: 12 men who fasted overnight and then pedaled a stationary ergometer for 2 hours, and 14 nonfasting ultramarathon runners. Blood samples were collected before exercise, immediately after cessation of exercise, and 6 to 24 hours after the end of the exercise period. Two hours of strenuous pedaling following an overnight fast significantly reduced mean leptin levels by 8.3%; free fatty acids were highly increased and correlated well with the decrease in serum leptin (r = .737, P = .01). After 6 hours of rest and refeeding, leptin concentrations recovered to preexercise levels and free fatty acid concentrations were decreased to less than preexercise levels. A similar decrease in serum leptin levels (12.3%) occurred in subjects who fasted overnight and then for a period corresponding to the cycle exercise period. The prolonged exercise of an ultramarathon significantly reduced leptin concentrations by 32% in comparison to prerace levels; free fatty acid concentrations were highly increased, but did not correlate with the change in serum leptin concentrations (r = .366, P = .20). Leptin and free fatty acid concentrations all trended toward prerace levels in blood samples collected 18 to 24 hours after cessation of racing. The results suggest that the negative energy balance of exercise can reduce serum leptin concentrations, but that the significant decrease occurs only at extremes of severity/duration of the exercise-induced negative balance. The possible physiological role of reduced leptin concentrations in response to energy balance and the role of free fatty acids in mediating the response are discussed.

Effect of exercise intensity and volume on persistence of insulin sensitivity during training cessation.

The purpose of this study was to determine whether exercise prescriptions differing in volume or intensity also differ in their ability to retain insulin sensitivity during an ensuing period of training cessation. Sedentary, overweight/obese subjects were assigned to one of three 8-mo exercise programs: 1) low volume/moderate intensity [equivalent of approximately 12 miles/wk, 1,200 kcal/wk at 40-55% peak O(2) consumption (Vo(2peak)), 200 min exercise/wk], 2) low volume/vigorous intensity ( approximately 12 miles/wk, 1,200 kcal/wk at 65-80% Vo(2peak), 125 min/wk), and 3) high volume/vigorous intensity ( approximately 20 miles/wk, 2,000 kcal/wk at 65-80% Vo(2peak), 200 min/wk). Insulin sensitivity (intravenous glucose tolerance test, S(I)) was measured when subjects were sedentary and at 16-24 h and 15 days after the final training bout. S(I) increased with training compared with the sedentary condition (P < or = 0.05) at 16-24 h with all of the exercise prescriptions. S(I) decreased to sedentary, pretraining values after 15 days of training cessation in the low-volume/vigorous-intensity group. In contrast, at 15 days S(I) was significantly elevated compared with sedentary (P < or = 0.05) in the prescriptions utilizing 200 min/wk (low volume/moderate intensity, high volume/vigorous intensity). In the high-volume/vigorous-intensity group, indexes of muscle mitochondrial density followed a pattern paralleling insulin action by being elevated at 15 days compared with pretraining; this trend was not evident in the low-volume/moderate-intensity group. These findings suggest that in overweight/obese subjects a relatively chronic persistence of enhanced insulin action may be obtained with endurance-oriented exercise training; this persistence, however, is dependent on the characteristics of the exercise training performed.

Long-term Exercise Training in Overweight Adolescents Improves Plasma Peptide YY and Resistin

The objective of this study was to investigate the effect of long‐term exercise training on concentrations of five hormones related to appetite and insulin resistance in overweight adolescents. In addition, we were interested in the relationships of these hormones with each other and with anthropometric and/or cardiovascular disease marker changes. Participants were ≥ the 85th percentile for BMI for age and sex and participated in an 8‐month supervised aerobic training program. Anthropometrics, cardiovascular fitness assessment, and fasting blood samples were taken pre‐ and post‐training. Glucose, insulin, total cholesterol (TC), high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, triglycerides, leptin, active ghrelin, total peptide YY (PYY), adiponectin, and resistin concentrations were measured. The participants increased their time to exhaustion on an incremental treadmill test and decreased both percent body fat and blood triglyceride concentrations. Total PYY concentration increased and resistin concentration decreased after long‐term exercise training, which are favorable outcomes. Leptin concentrations were related to weight, percent body fat, waist circumference, and triglyceride concentrations pre‐ and post‐training. The changes in resistin concentrations were related to the changes in triglyceride concentrations. We conclude that long‐term exercise training has beneficial effects for overweight adolescents with respect to PYY and resistin, hormones related to appetite and insulin sensitivity.

Training-induced alterations in fat and carbohydrate metabolism during exercise in elderly subjects

Compared with young adults, fat oxidation is lower in elderly persons during endurance exercise performed at either the same absolute or relative intensity. We evaluated the effect of 16 wk of endurance training on fat and glucose metabolism during 60 min of moderate intensity exercise [50% of pretraining peak oxygen consumption (VO2peak)] in six elderly men and women (74 +/- 2 yr). Training caused a 21% increase in mean VO2peak. The average rate of fat oxidation during exercise was greater after (221 +/- 28 mumol/min) than before (166 +/- 17 mumol/min) training (P = 0.002), and the average rate of carbohydrate oxidation during exercise was lower after (3,180 +/- 461 mumol/min) than before (3,937 +/- 483 mumol/min) training (P = 0.003). Training did not cause a significant change in glycerol rate of appearance (Ra), free fatty acid (FFA) Ra, and FFA rate of disappearance during exercise. However, glucose Ra during exercise was lower after (1,027 +/- 95 mumol/min) than before (1,157 +/- 69 mumol/min) training (P = 0.01). These results demonstrate that a 16-wk period of endurance training increases fat oxidation without a significant change in lipolysis (glycerol Ra) or FFA availability (FFA Ra) during exercise in elderly subjects. Therefore, the training-induced increase in fat oxidation during exercise is likely related to alterations in skeletal muscle fatty acid metabolism.Compared with young adults, fat oxidation is lower in elderly persons during endurance exercise performed at either the same absolute or relative intensity. We evaluated the effect of 16 wk of endurance training on fat and glucose metabolism during 60 min of moderate intensity exercise [50% of pretraining peak oxygen consumption (V˙o 2 peak)] in six elderly men and women (74 ± 2 yr). Training caused a 21% increase in meanV˙o 2 peak. The average rate of fat oxidation during exercise was greater after (221 ± 28 μmol/min) than before (166 ± 17 μmol/min) training ( P = 0.002), and the average rate of carbohydrate oxidation during exercise was lower after (3,180 ± 461 μmol/min) than before (3,937 ± 483 μmol/min) training ( P = 0.003). Training did not cause a significant change in glycerol rate of appearance (Ra), free fatty acid (FFA) Ra, and FFA rate of disappearance during exercise. However, glucose Ra during exercise was lower after (1,027 ± 95 μmol/min) than before (1,157 ± 69 μmol/min) training ( P = 0.01). These results demonstrate that a 16-wk period of endurance training increases fat oxidation without a significant change in lipolysis (glycerol Ra) or FFA availability (FFA Ra) during exercise in elderly subjects. Therefore, the training-induced increase in fat oxidation during exercise is likely related to alterations in skeletal muscle fatty acid metabolism.

Influence of age and resistance exercise on human skeletal muscle proteolysis: a microdialysis approach

We combined the interstitial sampling method of microdialysis with the natural tracer qualities (i.e. non‐recyclability) of the amino acid 3‐methylhistidine (3MH) to uniquely study in vivo degradation of the two most abundant skeletal muscle proteins, myosin and actin. Interstitial 3MH concentration was measured before and for 24 h following a single bout of resistance exercise in eight young (27 ± 2 years) and eight old (75 ± 4 years) men. The exercise bout consisted of four exercises (3 sets of 8 repetitions at 80% one‐repetition maximum (1RM) per exercise) emphasizing the quadriceps. Interstitial 3MH concentration was calculated using the internal reference method from microdialysate samples that were obtained from two microdialysis probes placed in the vastus lateralis. Resting interstitial 3MH concentration was 44% higher (P < 0.05) in the old (6.16 ± 0.56 nmol ml−1) as compared with the young (4.28 ± 0.27 nmol ml−1). Interstitial 3MH was not different (P > 0.05) from preexercise at any time point within the 24 h following exercise in both the young and the old. Leg arteriovenous exchange measurements in a separate group of young subjects also showed no increase in 3MH release during the 4 h following a resistance exercise bout compared with a non‐exercised control leg (control leg: –28 ± 6, exercise leg: –28 ± 11 nmol min−1). These results suggest that myosin and actin proteolysis are not increased in the first 24 h following a standard bout of resistance exercise, and this response is not altered with ageing. The higher interstitial 3MH concentration in the old suggests an increased proteolysis of the two main contractile proteins in the rested and fasted state, which is consistent with a decrease in muscle mass with ageing. Microdialysis is an appropriate methodology for use in ageing individuals and is compatible with high‐intensity resistance exercise.

No difference in the skeletal muscle angiogenic response to aerobic exercise training between young and aged men

Ischaemia‐induced skeletal muscle angiogenesis is impaired in aged compared with young mice. In humans, vascular endothelial growth factor (VEGF) mRNA and protein following an acute exercise bout are lower in aged compared with young untrained men. We hypothesized that exercise‐induced skeletal muscle angiogenesis would be attenuated in aged compared with young men. In eight aged (mean age: 64 years) and six young (mean age: 25 years) sedentary men, muscle biopsies were obtained from the vastus lateralis prior to (Pre), after 1 week and after 8 weeks of an aerobic exercise training program for the measurement of capillarization and VEGF mRNA. Dialysate VEGF protein collected from the muscle interstitial space was measured at rest and during submaximal exercise at Pre, 1 week and 8 weeks. Exercise training increased capillary contacts (CC) and capillary‐to‐fibre perimeter exchange index (CFPE) of type I and IIA fibres similarly in young and aged. The CC of type IIA and IIB fibres was lower in aged compared with young independent of training status. Exercise‐induced interstitial VEGF protein was lower in aged compared with young independent of training status. In untrained, greater exercise‐induced interstitial VEGF protein during exercise was associated with greater type I, IIA and IIB CC. Exercise training increased VEGF mRNA similarly in young and aged. These results demonstrate that the angiogenic response to aerobic exercise training is not altered during the ageing process in humans. In addition, muscular activity‐associated increases in interstitial VEGF protein may play an important role in the maintenance of skeletal muscle capillarization across the life span.

Acute resistance exercise increases skeletal muscle angiogenic growth factor expression

Aims:  Both aerobic and resistance exercise training promote skeletal muscle angiogenesis. Acute aerobic exercise increases several pro‐angiogenic pathways, the best characterized being increases in vascular endothelial growth factor (VEGF). We hypothesized that acute resistance exercise also increases skeletal muscle angiogenic growth factor [VEGF and angiopoietin (Ang)] expression.

Regulation of fat metabolism during resistance exercise in sedentary lean and obese men

The effect of acute resistance exercise (RE) on whole body energy expenditure (EE) and alpha(2)-adrenergic receptor (alpha(2)-AR) regulation of lipolysis in subcutaneous abdominal adipose tissue (SCAAT) was determined in sedentary lean (LN) and obese (OB) men. Lipolysis was monitored using microdialysis in 10 LN [body mass index (BMI) 20.9 +/- 0.6] and 10 OB (BMI 36.2 +/- 2.7) men before, during, and for 24 h after RE. EE was measured before and immediately after RE for 40 min. Changes in interstitial glycerol were measured in SCAAT with three microdialysis probes perfused with a control solution, phentolamine (alpha(2)-AR antagonist), or propranolol (beta-AR antagonist). EE and fat oxidation (FOX) were significantly (P < 0.001) elevated immediately post-RE compared with pre-RE in LN and OB subjects, with no differences between groups. RE-induced increases in SCAAT glycerol concentrations from rest to peak exercise were greater in LN than in OB men in the control (LN 142.1 +/- 30.8 vs. OB 65.4 +/- 14.2%, P = 0.03) and phentolamine probes (LN 187.2 +/- 29.6 vs. OB 66.7 +/- 11.0%, P = 0.002). Perfusion of propranolol had no effect on interstitial glycerol concentrations over the time course of the experiment in either group. Plasma insulin concentrations were significantly lower (P = 0.002) and plasma growth hormone (GH) was significantly higher (P = 0.03) in LN compared with OB men. The mechanism behind RE contributing to improved body composition may in part be due to enhanced SCAAT lipolysis and improved EE and FOX in response to RE in LN and OB men. The blunted SCAAT lipolytic response to RE in OB compared with LN men is unrelated to RE-induced catecholamine activation of the antilipolytic alpha(2)-ARs and may be due to depressed GH in OB subjects.

Age-related anabolic resistance after endurance-type exercise in healthy humans

Age‐related skeletal muscle loss is thought to stem from suboptimal nutrition and resistance to anabolic stimuli. Impaired microcirculatory (nutritive) blood flow may contribute to anabolic resistance by reducing delivery of amino acids to skeletal muscle. In this study, we employed contrast‐enhanced ultrasound, microdialysis sampling of skeletal muscle interstitium, and stable isotope methodology, to assess hemodynamic and metabolic responses of older individuals to endurance type (walking) exercise during controlled amino acid provision. We hypothesized that older individuals would exhibit reduced microcirculatory blood flow, interstitial amino acid concentrations, and amino acid transport when compared with younger controls. We report for the first time that aging induces anabolic resistance following endurance exercise, manifested as reduced (by ∼40%) efficiency of muscle protein synthesis. Despite lower (by ∼40–45%) microcirculatory flow in the older than in the younger participants, circulating and interstitial amino acid concentrations and phenylalanine transport into skeletal muscle were all equal or higher in older individuals than in the young, comprehensively refuting our hypothesis that amino acid availability limits postexercise anabolism in older individuals. Our data point to alternative mediators of age‐related anabolic resistance and importantly suggest correction of these impairments may reduce requirements for, and increase the efficacy of, dietary protein in older individuals. Durham, W. J., Casperson, S. L., Dillon, E. L., Keske, M. A., Paddon‐Jones, D., Sanford, A. P., Hickner, R. C., Grady, J. J., Sheffield‐Moore, M. Age‐related anabolic resistance after endurance‐type exercise in healthy humans. FASEB J. 24, 4117–4127 (2010). www.fasebj.org

NO-mediated alterations in skeletal muscle nutritive blood flow and lactate metabolism in fibromyalgia.

Abstract The purpose of these investigations was to determine if differences exist in skeletal muscle nutritive blood flow and lactate metabolism in women with fibromyalgia (FM) compared to healthy women (HC); furthermore, to determine if differences in nitric oxide‐mediated systems account for any detected alterations in blood flow and lactate metabolism and contribute to exertional fatigue in FM. FM (n=8) and HC (n=8) underwent a cycle ergometry test of aerobic capacity, a muscle biopsy for determination of nitric oxide synthase (eNOS, nNOS, iNOS) content, and microdialysis for investigation of muscle nutritive blood flow and lactate metabolism. During prolonged (3 h) resting conditions, the ethanol outflow/inflow ratio (inversely related to blood flow) increased in FM over time compared to HC (P<0.05). FM also exhibited a reduced nutritive blood flow response to aerobic exercise (P<0.05). There was an increase in dialysate lactate in response to acetylcholine in FM, and to sodium nitroprusside in both groups, with a greater rise in dialysate lactate in FM (P<0.05). The iNOS protein content was higher in FM and was negatively correlated with total exercise time (r2=0.462, P<0.05). In conclusion: (1) There is reduced nutritive flow response to aerobic exercise and reduced maximal exercise time in FM that might relate to higher iNOS protein content and contribute to exertional fatigue in FM; (2) The increased dialysate lactate in FM in response to stimulation of NOS or a nitric oxide donor suggest that FM may be more sensitive than HC to the suppressive effect of nitric oxide on oxidative phosphorylation.