Effect of elevated FFA on carbohydrate and lipid oxidation during prolonged exercise in humans

Increased availability of circulating free fatty acids (FFA) inhibits the rate of glycolysis in heart and resting skeletal muscle (Randle effect). Whether elevated FFA may play a role in decreasing carbohydrate oxidation during prolonged exercise in humans is more controversial. Using respiratory exchange measurements, we measured substrate utilization during 2.5 h of exercise at approximately 44 +/- 1% maximal O2 uptake (VO2 max) in the presence or absence of elevated FFA levels. After 30 min of base-line determinations, 1,000 U heparin was given intravenously and a 3-h constant infusion of Intralipid 10% (150 g/h) and heparin (500 U/h) was started. After an additional 30 min of rest, subjects exercised for 2.5 h (study 1, n = 6). In another five subjects (study 2) 100 g glucose was ingested after 30 min of exercise. The same protocols (studies 1 and 2) were also performed during a 0.9%-saline infusion. During exercise, without glucose ingestion, higher FFA concentrations prevailed during the Intralipid infusion (1,122 +/- 40 vs. 782 +/- 65 mumol/l), but the relative contributions of carbohydrate (49 +/- 4 vs. 50 +/- 4%) or lipid (49 +/- 4 vs. 47 +/- 6%) oxidation to the total energy expenditure were different only during the first 30 min of exercise. Similarly, higher FFA levels (1,032 +/- 62 vs. 568 +/- 46 mumol/l) did not alter the relative contributions of carbohydrate (62 +/- 4 vs. 69 +/- 2%) or lipid (36 +/- 4 vs. 29 +/- 2%) oxidation to the total energy expenditure after glucose feeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

No effect of menstrual cycle phase on glucose kinetics and fuel oxidation during moderate-intensity exercise

Resting and exercise fuel metabolism was assessed in three different phases of the menstrual cycle, characterized by different levels of estrogen relative to progesterone: early follicular (EF, low estrogen and progesterone), midfollicular (MF, elevated estrogen, low progesterone), and midluteal (ML, elevated estrogen and progesterone). It was hypothesized that exercise glucose utilization and whole body carbohydrate oxidation would decrease sequentially from the EF to the MF to the ML phase. Normal-weight healthy females, experiencing a regular menstrual cycle, were recruited. Subjects were moderately active but not highly trained. Testing occurred after 3 days of diet control and after an overnight fast (12-13 h). Resting (2 h) and exercise (50% maximal O(2) uptake, 90 min) measurements of whole body substrate oxidation, tracer-determined glucose flux, and substrate and hormone concentrations were made. No significant difference was observed in whole body fuel oxidation during exercise in the three phases (nonprotein respiratory exchange ratio: EF 0.84 +/- 0.01, MF 0.85 +/- 0.01, ML 0.85 +/- 0.01) or in rates of glucose appearance or disappearance. There were, however, significantly higher glucose (P < 0.05) and insulin (P < 0.001) concentrations during the first 45 min of exercise in the ML phase vs. EF and MF phases. In conclusion, whole body substrate oxidation and glucose utilization did not vary significantly across the menstrual cycle in moderately active women, either at rest or during 90 min of moderate-intensity exercise. During the ML phase, however, this similar pattern of substrate utilization was associated with greater glucose and insulin concentrations. Both estrogen and progesterone are elevated during the ML phase of the menstrual cycle, suggesting that one or both of these sex steroids may play a role in this response.     

Effect of glucose on plasma glucagon and free fatty acids during prolonged exercise

The effects of glucose ingestion on the changes in blood glucose, FFA, insulin and glucagon levels induced by a prolonged exercise at about 50% of maximal oxygen uptake were investigated. Healthy volunteers were submitted to the following procedures: 1. a control test at rest consisting of the ingestion of 100 g glucose, 2. an exercise test without, or 3. with ingestion of 100 g of glucose. Exercise without glucose induced a progressive decrease in blood glucose and plasma insulin; plasma glucagon rose significantly from the 60th min onward (+45 pg/ml), the maximal increase being recorded during the 4th h of exercise (+135 pg/ml); plasma FFA rose significantly from the 60th min onward and reached their maximal values during the 4th h of exercise (2177 +/- 144 muEq/l, m +/- SE). Exercise with glucose ingestion blunted almost completely the normal insulin response to glucose. Under these conditions, exercise did not increase plasma glucagon before the 210th min; similarly, the exercise-induced increase in plasma FFA was markedly delayed and reduced by about 60%. It is suggested that glucose availability reduces exercise-induced glucagon secretion and, possibly consequently, FFA mobilization.     

Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts

After myocardial infarction, ventricular geometry and function, as well as energy metabolism, change markedly. In nonischemic heart failure, inhibition of xanthine oxidase (XO) improves mechanoenergetic coupling by improving contractile performance relative to a reduced energetic demand. However, the metabolic and contractile effects of XO inhibitors (XOIs) have not been characterized in failing hearts after infarction. After undergoing permanent coronary ligation, mice received a XOI (allopurinol or oxypurinol) or matching placebo in the daily drinking water. Four weeks later, 1H MRI and 31P magnetic resonance spectroscopy (MRS) were used to quantify in vivo functional and metabolic changes in postinfarction remodeled mouse myocardium and the effects of XOIs on that process. End-systolic (ESV) and end-diastolic volumes (EDV) were increased by more than sixfold after infarction, left ventricle (LV) mass doubled (P < 0.005), and the LV ejection fraction (EF) decreased (14 +/- 9%) compared with control hearts (59 +/- 8%, P < 0.005) at 1 mo. The myocardial phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) was also significantly decreased in infarct remodeled hearts (1.4 +/- 0.6) compared with control animals (2.1 +/- 0.5, P < 0.02), in agreement with prior studies in larger animals. The XOIs allopurinol and oxypurinol did not change LV mass but limited the increase in ESV and EDV of infarct hearts by 50%, increased EF (23 +/- 9%, P = 0.01), and normalized cardiac PCr/ATP (2.0 +/- 0.5, P < 0.04). We conclude that XOIs improve ventricular function after infarction and normalize high-energy phosphate ratio in heart failure. Thus XOI therapy offers a new and potentially complementary approach to limit the adverse contractile and metabolic consequences after infarction.     

Effects of sprint training on maximal stroke volume of rats with a chronic myocardial infarction.

The hemodynamic response to maximal exercise was determined in rats with a chronic myocardial infarction (MI) that were subjected to 6-8 wk of high-intensity sprint training (HIST) or limited exercise activity (sedentary control). Training was performed 6 days/wk and consisted of five 1-min bouts of treadmill running at work loads (15% grade, 97 m/min) in excess of the animal's maximal O2 uptake (VO2max). The left ventricular infarct size for the HIST and sedentary control rats was 35 +/- 4 and 34 +/- 3% of the total endocardial circumference, respectively. VO2max was significantly greater for MI rats subjected to the HIST paradigm than for sedentary control rats. This increase in VO2max was due to an increase in the maximal stroke volume that could be generated by the HIST rat during exercise, inasmuch as the maximal heart rate response and the ability to extract O2 from the blood were similar between the two groups of rats. Citrate synthase activities measured in the plantaris muscle of the HIST and sedentary control rats were similar. These results suggest that the increase in VO2max produced with HIST in MI rats may be linked to changes in central cardiac function, as indicated by the increase in maximal stroke volume that could be generated by the MI rat during maximal exercise conditions.     

Effect of Acute Hyperglycemia on Left Ventricular Contractile Function in Diabetic Patients with and without Heart Failure: Two Randomized Cross-Over Studies

Background

It is unknown whether changes in circulating glucose levels due to short-term insulin discontinuation affect left ventricular contractile function in type 2 diabetic patients with (T2D-HF) and without (T2D-nonHF) heart failure.

Materials and Methods

In two randomized cross-over-designed trials, 18 insulin-treated type 2 diabetic patients with (Ejection Fraction (EF) 36±6%, n = 10) (trial 2) and without systolic heart failure (EF 60±3%, n = 8) (trial 1) were subjected to hyper- and normoglycemia for 9–12 hours on two different occasions. Advanced echocardiography, bicycle exercise tests and 6-minute hall walk distance were applied.

Results

Plasma glucose levels differed between study arms (6.5±0.8 mM vs 14.1±2.6 mM (T2D-HF), 5.8±0.4 mM vs 9.9±2.1 mM (T2D-nonHF), p<0.001). Hyperglycemia was associated with an increase in several parameters: maximal global systolic tissue velocity (Vmax) (p<0.001), maximal mitral annulus velocity (S''max) (p<0.001), strain rate (p = 0.02) and strain (p = 0.05). Indices of increased myocardial systolic contractile function were significant in both T2D-HF (Vmax: 14%, p = 0.02; S''max: 10%, p = 0.04), T2D-nonHF (Vmax: 12%, p<0.01; S''max: 9%, p<0.001) and in post exercise S''max (7%, p = 0.049) during hyperglycemia as opposed to normoglycemia. LVEF did not differ between normo- and hyperglycemia (p = 0.17), and neither did peak exercise capacity nor catecholamine levels. Type 2 diabetic heart failure patients'' 6-minute hall walk distance improved by 7% (p = 0.02) during hyperglycemia as compared with normoglycemia.

Conclusions

Short-term hyperglycemia by insulin discontinuation is associated with an increase in myocardial systolic contractile function in type 2 diabetic patients with and without heart failure and with a slightly prolonged walking distance in type 2 diabetic heart failure patients. (Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT00653510","term_id":"NCT00653510"}}NCT00653510)     

Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes

Maximal dynamic exercise results in a postexercise hyperglycemia in healthy young subjects. We investigated the influence of maximal exercise on glucoregulation in non-insulin-dependent diabetic subjects (NIDDM). Seven NIDDM and seven healthy control males bicycled 7 min at 60% of their maximal O2 consumption (VO2max), 3 min at 100% VO2max, and 2 min at 110% VO2max. In both groups, glucose production (Ra) increased more with exercise than did glucose uptake (Rd) and, accordingly, plasma glucose increased. However, in NIDDM subjects the increase in Ra was hastened and Rd inhibited compared with controls, so the increase in glucose occurred earlier and was greater [147 +/- 21 to 169 +/- 19 (30 min postexercise) vs. 90 +/- 4 to 100 +/- 5 (SE) mg/dl (10 min postexercise), P less than 0.05]. Glucose levels remained elevated for greater than 60 min postexercise in both groups. Glucose clearance increased during exercise but decreased postexercise to or below (NIDDM, P less than 0.05) basal levels, despite increased insulin levels (P less than 0.05). Plasma epinephrine and glucagon responses to exercise were higher in NIDDM than in control subjects (P less than 0.05). By use of the insulin clamp technique at 40 microU.m-2.min-1 of insulin with plasma glucose maintained at basal levels, glucose disposal in NIDDM subjects, but not in controls, was enhanced 24 h after exercise. It is concluded that, because of exaggerated counter-regulatory hormonal responses, maximal dynamic exercise results in a 60-min period of postexercise hyperglycemia and hyperinsulinemia in NIDDM. However, this event is followed by a period of increased insulin effect on Rd that is present 24 h after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intramyocellular lipid content is increased after exercise in nonexercising human skeletal muscle.

Intramyocellular lipid (IMCL) content has been reported to decrease after prolonged submaximal exercise in active muscle and, therefore, seems to form an important local substrate source. Because exercise leads to a substantial increase in plasma free fatty acid (FFA) availability with a concomitant increase in FFA uptake by muscle tissue, we aimed to investigate potential differences in the net changes in IMCL content between contracting and noncontracting skeletal muscle after prolonged endurance exercise. IMCL content was quantified by magnetic resonance spectroscopy in eight trained cyclists before and after a 3-h cycling protocol (55% maximal energy output) in the exercising vastus lateralis and the nonexercising biceps brachii muscle. Blood samples were taken before and after exercise to determine plasma FFA, glycerol, and triglyceride concentrations, and substrate oxidation was measured with indirect calorimetry. Prolonged endurance exercise resulted in a 20.4 +/- 2.8% (P < 0.001) decrease in IMCL content in the vastus lateralis muscle. In contrast, we observed a substantial (37.9 +/- 9.7%; P < 0.01) increase in IMCL content in the less active biceps brachii muscle. Plasma FFA and glycerol concentrations were substantially increased after exercise (from 85 +/- 6 to 1450 +/- 55 and 57 +/- 11 to 474 +/- 54 microM, respectively; P < 0.001), whereas plasma triglyceride concentrations were decreased (from 1498 +/- 39 to 703 +/- 7 microM; P < 0.001). IMCL is an important substrate source during prolonged moderate-intensity exercise and is substantially decreased in the active vastus lateralis muscle. However, prolonged endurance exercise with its concomitant increase in plasma FFA concentration results in a net increase in IMCL content in less active muscle.     

Muscle glucose transport: interactions of in vitro contractions, insulin, and exercise

Exercise increases permeability of muscle to glucose. Normally, the effects of exercise and a maximal insulin stimulus on glucose transport are additive. However, the combined effect on rat epitrochlearis muscle permeability to 3-O-methylglucose (3-MG) of a maximal insulin stimulus followed by in vitro contractile activity of 1.24 +/- 0.06 mumol.10 min-1.ml intracellular water-1 was no greater than that of either stimulus alone. We found that this absence of an additive effect was caused by prolonged exposure to an unphysiologically high insulin concentration (20,000 microU/ml for 60 min), which, in addition to stimulating glucose transport, appears to prevent further increases in permeability to glucose. When the treatments were reversed and muscles were first stimulated to contract and then incubated with 20,000 microU/ml insulin, 3-MG uptake (mumol.10 min-1.ml intracellular water-1) increased from a control value of 0.26 +/- 0.03 to 1.80 +/- 0.15, compared with 1.04 +/- 0.06 for contractile activity alone, 1.21 +/- 0.08 for insulin, and 1.88 +/- 0.11 for exercise (swimming) plus insulin. Swimming plus in vitro contractile activity did not have a greater effect than contractile activity alone. Our results provide evidence that 1) the effect of exercise on muscle permeability to glucose is mediated solely by a process associated with contractile activity, and 2) it is advisable to avoid the use of unphysiologically high insulin concentrations in studies designed to elucidate in vivo actions of insulin.     

Influence of carnitine supplementation on muscle substrate and carnitine metabolism during exercise

We examined 1) the effect of L-carnitine supplementation on free fatty acid (FFA) utilization during exercise and 2) exercise-induced alterations in plasma levels and skeletal muscle exchange of carnitine. Seven moderately trained human male subjects serving as their own controls participated in two bicycle exercise sessions (120 min, 50% of VO2max). The second exercise was preceded by 5 days of oral carnitine supplementation (CS; 5 g daily). Despite a doubling of plasma carnitine levels, with CS, there were no effects on exercise-induced changes in arterial levels and turnover of FFA, the relation between leg FFA inflow and FFA uptake, or the leg exchange of other substrates. Heart rate during exercise after CS decreased 7-8%, but O2 uptake was unchanged. Exercise before CS induced a fall from 33.4 +/- 1.6 to 30.8 +/- 1.0 (SE) mumol/l in free plasma carnitine despite a release (2.5 +/- 0.9 mumol/min) from the leg. Simultaneously, acylated plasma carnitine rose from 5.0 +/- 1.0 to 14.2 +/- 1.4 mumol/l, with no evidence of leg release. Consequently, total plasma carnitine increased. We concluded that in healthy subjects CS does not influence muscle substrate utilization either at rest or during prolonged exercise and that free carnitine released from muscle during exercise is presumably acylated in the liver and released to plasma.     

The PPAR-alpha activator fenofibrate fails to provide myocardial protection in ischemia and reperfusion in pigs

Rodent studies suggest that peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation reduces myocardial ischemia-reperfusion (I/R) injury and infarct size; however, effects of PPAR-alpha activation in large animal models of myocardial I/R are unknown. We determined whether chronic treatment with the PPAR-alpha activator fenofibrate affects myocardial I/R injury in pigs. Domestic farm pigs were assigned to treatment with fenofibrate 50 mg.kg(-1).day(-1) orally or no drug treatment, and either a low-fat (4% by weight) or a high-fat (20% by weight) diet. After 4 wk, 66 pigs underwent 90 min low-flow regional myocardial ischemia and 120 min reperfusion under anesthetized open-chest conditions, resulting in myocardial stunning. The high-fat group received an infusion of triglyceride emulsion and heparin during this terminal experiment to maintain elevated arterial free fatty acid (FFA) levels. An additional 21 pigs underwent 60 min no-flow ischemia and 180 min reperfusion, resulting in myocardial infarction. Plasma concentration of fenofibric acid was similar to the EC50 for activation of PPAR-alpha in vitro and to maximal concentrations achieved in clinical use. Myocardial expression of PPAR-alpha mRNA was prominent but unaffected by fenofibrate treatment. Fenofibrate increased expression of carnitine palmitoyltransferase (CPT)-I mRNA in liver and decreased arterial FFA and lactate concentrations (each P < 0.01). However, fenofibrate did not affect myocardial CPT-I expression, substrate uptake, lipid accumulation, or contractile function during low-flow I/R in either the low- or high-fat group, nor did it affect myocardial infarct size. Despite expression of PPAR-alpha in porcine myocardium and effects of fenofibrate on systemic metabolism, treatment with this PPAR-alpha activator does not alter myocardial metabolic or contractile responses to I/R in pigs.     

Effects of exercise training on contractile function in myocardial trabeculae after ischemia-reperfusion.

Potential protective effects of aerobic exercise training on the myocardium, before an ischemic event, are not completely understood. The purpose of the study was to investigate the effects of exercise training on contractile function after ischemia-reperfusion (Langendorff preparation with 15-min global ischemia/30-min reperfusion). Trabeculae were isolated from the left ventricles of both sedentary control and 10- to 12-wk treadmill exercise-trained rats. The maximal normalized isometric force (force/cross-sectional area; Po/CSA) and shortening velocity (Vo) in isolated, skinned ventricular trabeculae were measured using the slack test. Ischemia-reperfusion induced significant contractile dysfunction in hearts from both sedentary and trained animals; left ventricular developed pressure (LVDP) and maximal rates of pressure development and relaxation (+/-dP/dtmax) decreased, whereas end-diastolic pressure (EDP) increased. However, this dysfunction (as expressed as percent change from the last 5 min before ischemia) was attenuated in trained myocardium [LVDP: sedentary -60.8 +/- 6.4% (32.0 +/- 5.5 mmHg) vs. trained -15.6 +/- 8.6% (64.9 +/- 6.6 mmHg); +dP/dtmax: sedentary -54.1 +/- 4.7% (1,058.7 +/- 124.2 mmHg/s) vs. trained -16.7 +/- 8.4% (1,931.9 +/- 188.3 mmHg/s); -dP/dtmax: sedentary -44.4 +/- 2.5% (-829.3 +/- 52.0 mmHg/s) vs. trained -17.9 +/- 7.2% (-1,341.3 +/- 142.8 mmHg/s); EDP: sedentary 539.5 +/- 147.6%; (41.3 +/- 6.0 mmHg) vs. trained 71.6 +/- 30.6%; 11.4 +/- 1.2 mmHg]. There was an average 26% increase in Po/CSA in trained trabeculae compared with sedentary controls, and this increase was not affected by ischemia-reperfusion. Ischemia-reperfusion reduced Vo by 39% in both control and trained trabeculae. The relative amount of the beta-isoform of myosin heavy chain (MHC-beta) was twofold greater in trained trabeculae as well as in the ventricular free walls. Despite a possible increase in the economy in the trained heart, presumed from a greater amount of MHC-beta, ischemia-reperfusion reduced Vo, to a similar extent in both control and trained animals. Nevertheless, the trained myocardium appears to have a greater maximum force-generating ability that may, at least partially, compensate for reduced contractile function induced by a brief period of ischemia.     

Effects of prolonged exercise in highly trained traumatic paraplegic men

This study investigated the cardiovascular and metabolic responses to prolonged wheelchair exercise in a group of highly trained, traumatic paraplegic men. Six endurance-trained subjects with spinal cord lesions from T10 to T12/L3 underwent a maximal incremental exercise test in which they propelled their own track wheelchairs on a motor-driven treadmill to exhaustion to determine maximal O2 uptake (VO2max) and related variables. One week later each subject exercised in the same wheelchair on a motorized treadmill at 60-65% of VO2max for 80 min in a thermoneutral environment (dry bulb 22 degrees C, wet bulb 17 degrees C). Approximately 10 ml of venous blood were withdrawn both 20 min and immediately before exercise (0 min), after 40 and 80 min of exercise, and 20 min postexercise. Venous blood was analyzed for hematocrit (Hct), hemoglobin (Hb), and lactate, and the separated plasma was analyzed for glucose, K+, Na+, Cl-, free fatty acid (FFA), and osmolality. VO2, CO2 production (VCO2), minute ventilation (VE), respiratory exchange ratio (R), net efficiency, and wheelchair strike rate were determined at four intervals throughout the exercise period. Data were analyzed with an analysis of variance repeated-measures design and a Scheffé post hoc test. VO2max was 47.5 +/- 1.8 (SE) ml.min-1.kg-1 with maximal VE BTPS and maximal heart rate (HR) being 100.1 +/- 3.8 l/min and 190 +/- 1 beats/min, respectively. During prolonged exercise there were no significant changes in VO2, VCO2, VE, R, net efficiency, wheelchair strike rate, and lactate, glucose, and Na+ concentrations. Significant increases occurred in HR, FFA, K+, Cl-, osmolality, Hb, and Hct throughout exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of metabolic substrates between exercise and cold exposure in skaters

To test the effect of a cold condition on metabolic substrate and possible development of muscle injuries, short track skaters (n=9) and inline skaters (n=10) took rest and submaximal cycled (65% V(.)O2max) in cold (ambient temperature: 5+/-1 degrees C, relative humidity: 41+/-8%) and warm conditions (ambient temperature: 21+/-1 degrees C, relative humidity: 35+/-5%), for 60 min, each. Blood glucose (BG), triglyceride (TG), free fatty acid (FFA), and total cholesterol (TC) were determined to investigate the effect on energy metabolism. To estimate possible muscle injury in the cold condition, creatine kinase (CK), lactate dehydrogenase (LDH), and myoglobin (Mb) were also measured. TG and FFA levels were increased during exercise in the cold condition, but were unaffected by the difference of skaters. Of the myocellular enzymes, CK was significantly higher during the transition from submaximal exercise to recovery phase in a short track skater compared with inline skater group, indicating a higher physical strain. Additionally, the level of Mb in the inline skater group significantly elevated during recovery phase in the cold compared with in the warm condition. It is concluded that exercise caused stress that was dependent on the ambient temperature. Therefore, exercise in the cold condition altered the circulating level of energy substrate and increased muscle injuries.     

Myocardial function defined by strain rate and strain during alterations in inotropic states and heart rate

For porcine myocardium, ultrasonic regional deformation parameters, systolic strain (epsilon(sys)) and peak systolic strain rate (SR(sys)), were compared with stroke volume (SV) and contractility [contractility index (CI)] measured as the ratio of end-systolic strain to end-systolic wall stress. Heart rate (HR) and contractility were varied by atrial pacing (AP = 120-180 beats/min, n = 7), incremental dobutamine infusion (DI = 2.5-20 microg. kg(-1). min(-1), n = 7), or continuous esmolol infusion (0.5 mg. kg(-1). min(-1)) + subsequent pacing (120-180 beats/min) (EI group, n = 6). Baseline SR(sys) and epsilon(sys) averaged 5.0 +/- 0.4 s(-1) and 60 +/- 4%. SR(sys) and CI increased linearly with DI (20 microg. kg(-1). min(-1); SR(sys) = 9.9 +/- 0.7 s(-1), P < 0.0001) and decreased with EI (SR(sys) = 3.4 +/- 0.1 s(-1), P < 0.01). During pacing, SR(sys) and CI remained unchanged in the AP and EI groups. During DI, epsilon(sys) and SV initially increased (5 microg. kg(-1). min(-1); epsilon(sys) = 77 +/- 6%, P < 0.01) and then progressively returned to baseline. During EI, SV and epsilon(sys) decreased (epsilon(sys) = 38 +/- 2%, P < 0.001). Pacing also decreased SV and epsilon(sys) in the AP (180 beats/min; epsilon(sys) = 36 +/- 2%, P < 0.001) and EI groups (180 beats/min; epsilon(sys) = 25 +/- 3%, P < 0.001). Thus, for normal myocardium, SR(sys) reflects regional contractile function (being relatively independent of HR), whereas epsilon(sys) reflects changes in SV.     

Effects of a 36-hour fast on human endurance and substrate utilization

To determine if prolonged fasting affects substrate utilization and endurance time, seven trained men exercised to exhaustion on a cycle ergometer at 50% maximum oxygen consumption (VO2max) in an overnight-fasted [postabsorptive (PA)] state and after a 36-h fast (F). Fasting produced significant elevations in the resting concentrations of blood free fatty acids (FFA; 1.16 +/- 0.05 vs. 0.56 +/- 0.06 mM, F vs. PA, respectively, a 107% increase), beta-hydroxybutyrate (beta-OH, 2.06 +/- 0.66 vs. 0.15 +/- 0.06 mM, a 1,270% increase), and glycerol (0.12 +/- 0.03 vs. 0.04 +/- 0.01 mM, a 200% increase), with a significant decline in glucose (79.79 +/- 2.12 vs. 98.88 +/- 3.11 mg/dl, a 19% decrease). Exercise in the F trial increased FFA, decreased glucose, and significantly elevated beta-OH and glycerol over the PA trial. There was no difference in blood glucose concentration between trials at exhaustion. However, F produced a significant decrement in exercise endurance time compared with the PA trial (88.9 +/- 18.3 vs. 144.4 +/- 22.6 min, F vs. PA, a 38% decrease). Based on the respiratory exchange ratio, fasting led to a greater utilization of lipids during rest and exercise. It was concluded that 1) a 36-h fast significantly altered substrate utilization at rest and throughout exercise to exhaustion, 2) glucose levels do not appear to be the single determinant of time to exhaustion in submaximal exercise, and 3) despite the apparent sparing of carbohydrate utilization with the 36-h fast, endurance performance was significantly decreased.     

Substrate metabolism during different exercise intensities in endurance-trained women.

We have studied eight endurance-trained women at rest and during exercise at 25, 65, and 85% of maximal oxygen uptake. The rate of appearance (R(a)) of free fatty acids (FFA) was determined by infusion of [(2)H(2)]palmitate, and fat oxidation rates were determined by indirect calorimetry. Glucose kinetics were assessed with [6,6-(2)H(2)]glucose. Glucose R(a) increased in relation to exercise intensity. In contrast, whereas FFA R(a) was significantly increased to the same extent in low- and moderate-intensity exercise, during high-intensity exercise, FFA R(a) was reduced compared with the other exercise values. Carbohydrate oxidation increased progressively with exercise intensity, whereas the highest rate of fat oxidation was during exercise at 65% of maximal oxygen uptake. After correction for differences in lean body mass, there were no differences between these results and previously reported data in endurance-trained men studied under the same conditions, except for slight differences in glucose metabolism during low-intensity exercise (Romijn JA, Coyle EF, Sidossis LS, Gastaldelli A, Horowitz JF, Endert E, and Wolfe RR. Am J Physiol Endocrinol Metab 265: E380-E391, 1993). We conclude that the patterns of changes in substrate kinetics during moderate- and high-intensity exercise are similar in trained men and women.     

Gadolinium prevents stretch-mediated contractile dysfunction in isolated papillary muscles

We tested the hypothesis that overstretching the myocardium could induce and/or exacerbate contractile dysfunction via stretch-activated (SA) ion channels. Maximum developed tension (T(max)), normalized to a control value, was compared in guinea pig papillary muscles held at one of three resting lengths (physiological stretch, overstretch, and unloaded) for 85 min. Overstretched muscles exhibited decreased contractile force (T(max) = 0.77 +/- 0.03) compared with physiological and unloaded muscles (T(max) = 0.93 +/- 0.05 and 1.03 +/- 0.07, respectively). Gd(3+), an SA channel antagonist, eliminated the adverse effect of overstretching (T(max) = 0.98 +/- 0.06), but nifedipine, a dihydropyridine (DHP) antagonist of L-type calcium channels, did not (T(max) = 0.82 +/- 0.04). Exposure to modified hypoxia-reoxygenation (MHR) during physiological stretch resulted in decreased contractility (T(max) = 0.63 +/- 0.07), an effect that was exacerbated by overstretching (T(max) = 0.44 +/- 0.04). Gd(3+) mitigated the effects of overstretch during MHR (T(max) = 0.64 +/- 0.05), but DHP did not (T(max) = 0.48 +/- 0.04). These data suggest that overstretching of the myocardium contributes to contractile abnormalities via SA channels that are distinct from L-type calcium channels.     

Eccentric exercise induces transient insulin resistance in healthy individuals.

Euglycemic-hyperinsulinemic clamps were performed on six healthy untrained individuals to determine whether exercise that induces muscle damage also results in insulin resistance. Clamps were performed 48 h after bouts of predominantly 1) eccentric exercise [30 min, downhill running, -17% grade, 60 +/- 2% maximal O2 consumption (VO2max)], 2) concentric exercise (30 min, cycle ergometry, 60 +/- 2% VO2max), or 3) without prior exercise. During the clamps, euglycemia was maintained at 90 mg/dl while insulin was infused at 30 mU.m-2.min-1 for 120 min. Hepatic glucose output (HGO) was determined using [6,6-2H]glucose. Eccentric exercise caused marked muscle soreness and significantly elevated creatine kinase levels (273 +/- 73, 92 +/- 27, 87 +/- 25 IU/l for the eccentric, concentric, and control conditions, respectively) 48 h after exercise. Insulin-mediated glucose disposal rate was significantly impaired (P less than 0.05) during the clamp performed after eccentric exercise (3.47 +/- 0.51 mg.kg-1.min-1) compared with the clamps performed after concentric exercise (5.55 +/- 0.94 mg.kg-1.min-1) or control conditions (5.48 +/- 1.0 mg.kg-1.min-1). HGO was not significantly different among conditions (0.77 +/- 0.26, 0.65 +/- 0.27, and 0.66 +/- 0.64 mg.kg-1.min-1 for the eccentric, concentric, and control clamps, respectively). The insulin resistance observed after eccentric exercise could not be attributed to altered plasma cortisol, glucagon, or catecholamine concentrations. Likewise, no differences were observed in serum free fatty acids, glycerol, lactate, beta-hydroxybutyrate, or alanine. These results show that exercise that results in muscle damage, as reflected in muscle soreness and enzyme leakage, is followed by a period of insulin resistance.     

Plasma FFA responses to prolonged walking in untrained men and women

Gender differences in plasma FFA responses to 90 min of treadmill walking at 35% VO2max were investigated in six men and six women following an overnight fast. The subjects represented average values for maximal oxygen uptake and body fat percentage for age and gender. Mean plasma FFA concentration at 45 and 90 min of exercise were significantly (P less than 0.05) higher for women (0.82 mmol X 1(-1), 0.88 mmol X 1(-1)) than men (0.42 mmol X 1(-1), 0.59 mmol X 1(-1)). Lower R values for women throughout the exercise period indicated a greater percentage fat in total metabolism than for men while the FFA/glycerol results supported greater lipolytic activity for women. The uniformity of percent fat in metabolism for women from rest to exercise showed that FFA release from adipose tissue increased rapidly with the onset of exercise which was not the case for men. Comparison of metabolic data as well as a statistical analysis (ANCOVA) controlling for the influence of VO2max and percentage body fat on FFA plasma concentration suggested that gender differences in FFA responses to prolonged submaximal exercise can be expected to occur in untrained subjects.