Maximum rate of oxygen consumption related to succinate dehydrogenase activity in skeletal muscle fibres of chronic heart failure patients and controls

Previous studies indicate that the low maximum rate of oxygen consumption (VO2max) of chronic heart failure (CHF) patients is not because of impaired pump function of the heart. We hypothesize that VO2 during maximum exercise is determined by the total oxidative capacity of skeletal muscle. VO2max of six controls and 14 CHF patients, New York Heart Association class I-III, was determined using an incremental bicycle ergometer test. Cryostat sections of a biopsy from the quadriceps femoris muscle were incubated for succinate dehydrogenase (SDH) using quantitative histochemistry. VO2max (range: 29 ml O2 kg muscle(-1) min(-1) in a class III patient to 118 ml O2 kg muscle(-1) min(-1) in a control subject) correlates with the mean SDH activity of skeletal muscle fibres (r=0.79 or r=0.81, including or excluding oxygen uptake at rest, respectively; P<0.001). The relationship between VO2max and SDH activity is similar to that determined previously using isolated single muscle fibres and myocardial trabeculae under hyperoxic conditions. From the product of SDH activity and the cross-sectional area of the fibre (i.e. spatially integrated SDH activity), it is possible to calculate the maximum oxygen uptake rate per unit muscle fibre length. This uptake rate is linearly related to the number of capillaries per fibre (r=0.76, P<0.001) in all subjects, suggesting that oxidative capacity of skeletal muscle fibres in CHF patients decreases in proportion to the oxygen supply capacity of the microcirculation.     

Muscle adaptations and glucose control after physical training in insulin-dependent diabetes mellitus

Summary. Six men and three women with insulin-dependent diabetes (without complications) participated in physical training three times a week for 20 weeks. Physical training did not change the concentration of fasting blood-glucose, glucose excretion in urine or glucosylated haemoglobin (Hb_A1). However, the glucose disposal rate during euglycaemic clamp increased after training. In two patients a minor reduction of insulin dosage was necessary to alleviate slight hypoglycaemic episodes. The training resulted in significant increases in quadriceps isometric and dynamic strength and endurance. Maximal oxygen uptake increased by 8%, the activity of glycolytic enzymes in vastus lateralis muscle by 47% for hexokinase, and 30% for tri-osephosphate dehydrogenase and 25% for lactic dehydrogenase, the activity of oxidative enzymes by 42% for citrate synthase and 46% for 3-hydroxy-acyl-CoA-dehydrogenase. The glycogen concentration in the vastus lateralis muscle did not change significantly. Lipoprotein lipase activity did not change in muscle, nor in adipose tissue. The mean muscle fibre area increased by 25% and the area of FTa fibres by 30%. The new formation of capillaries around different muscle fibres was significant for FTb fibres (26%). The proliferation of capillaries, however, appeared to be insufficient to cope with the increased area of muscle fibres. As a result, the mean area of muscle fibre supplied by one capillary (a measure of diffusion distance) significantly increased after training for FTa fibres. It is concluded that with the exception of deficient proliferation of capillaries, patients with insulin-dependent diabetes mellitus show a normal central and peripheral adaptation to physical training. Physical training does not apparently improve blood glucose control in most cases, despite an increased insulin sensitivity.     

Adaptation of human skeletal muscle to endurance training of long duration

Summary. The aim of this study was to examine the adaptive response of skeletal muscle to dynamic training of long duration and low intensity. The response of m. triceps brachii, (TB) and m. quadriceps femoris, vastus lateralis (VL) to training of long duration at an intensity corresponding to approximately 45% of V?O₂, max, has been studied in six subjects. Muscle specimens were taken during training (18.5 miles (30 km)), which involved skiing with a backpack, (6 daydweek, 8 weeks), as well as during a subsequent period of detraining (33 weeks). Increases in oxidative enzyme activities and capillarization during training were limited to the TB. There were parallel increases in citrate synthase (CS) and malate dehydrogenase (MDH) during the first 3 weeks of training (30%). CS then continued to rise (to 90% above pretraining level), while the increase in MDH levelled off. The activity of 3–hydroxyacyl-CoA-dehydrogenase (HAD) and the number of capillaries per fibre increased by 50 % and 40 % respectively. A selective decrease (12%) in area of fibre type IIA was noted during training after a 2-week period of energy deficiency. During the first 6 weeks of detraining, the decrease in CS and HAD (30%) was greater than the decrease in capillaries per fibre (14%). It is concluded that prolonged duration of training is not, in itself, sufficient to elicit an adaptive response in the leg muscles, while a modest training effect was seen for the arm muscles. The finding emphasizes the importance of adequate intensity in physical training programmes.     

Different alterations in the insulin-stimulated glucose uptake in the athlete's heart and skeletal muscle.

Physical training increases skeletal muscle insulin sensitivity. Since training also causes functional and structural changes in the myocardium, we compared glucose uptake rates in the heart and skeletal muscles of trained and untrained individuals. Seven male endurance athletes (VO2max 72 +/- 2 ml/kg/min) and seven sedentary subjects matched for characteristics other than VO2max (43 +/- 2 ml/kg/min) were studied. Whole body glucose uptake was determined with a 2-h euglycemic hyperinsulinemic clamp, and regional glucose uptake in femoral and arm muscles, and myocardium using 18F-fluoro-2-deoxy-D-glucose and positron emission tomography. Glucose uptake in the athletes was increased by 68% in whole body (P < 0.0001), by 99% in the femoral muscles (P < 0.01), and by 62% in arm muscles (P = 0.06), but it was decreased by 33% in the heart muscle (P < 0.05) as compared with the sedentary subjects. The total glucose uptake rate in the heart was similar in the athletes and control subjects. Left ventricular mass in the athletes was 79% greater (P < 0.001) and the meridional wall stress smaller (P < 0.001) as estimated by echocardiography. VO2max correlated directly with left ventricular mass (r = 0.87, P < 0.001) and inversely with left ventricular wall stress (r = -0.86, P < 0.001). Myocardial glucose uptake correlated directly with the rate-pressure product (r = 0.75, P < 0.02) and inversely with left ventricular mass (r = -0.60, P < 0.05) or with the whole body glucose disposal (r = -0.68, P < 0.01). Thus, in athletes, (a) insulin-stimulated glucose uptake is enhanced in the whole body and skeletal muscles, (b) whereas myocardial glucose uptake per muscle mass is reduced possibly due to decreased wall stress and energy requirements or the use of alternative fuels, or both.     

Exercise physiology and cardiovascular fitness

Endurance exercise training produces numerous metabolic and cardiovascular effects. Metabolic adaptations include an increase in oxidative capacity of skeletal muscle (greater number and size of mitochondria); an increase in skeletal muscle myoglobin concentration; a greater ability to oxidize fatty acids for energy; and an increase in stored glycogen. Cardiovascular effects of training include a decrease in resting heart rate and heart rate response to submaximal exercise; an increase in resting and exercise stroke volume; an increase in maximal cardiac output; an increase in VO2max; and an increase in arteriovenous oxygen difference. Aerobic exercise training contributes to cardiovascular fitness, because it beneficially alters the coronary artery disease risk profile. An inverse relationship exists between physical fitness and resting heart rate, body weight, percent body fat, serum cholesterol, triglycerides, glucose, and systolic blood pressure. In addition, exercise training increases the high-density lipoprotein fraction of total cholesterol. Endurance exercise is any activity that uses large muscle groups, can be performed continuously, and is rhythmic and aerobic in nature. To develop and maintain cardiovascular fitness, this exercise should be performed at a frequency of 3 to 5 days per week, an intensity of 60% to 90% HRmax or 50% to 85% HRmax reserve, and a duration of 20 to 60 minutes.     

Relationship between muscle morphology and metabolism in obese women: the effects of long-term physical training

To evaluate the relationships between changes in muscle morphology and metabolic adaptation to physical training in obesity, twenty obese women were subjected to a physical training programme with three sessions a week for 3 months. Physical training resulted in lowering of plasma insulin and improved glucose tolerance. Neither body weight nor body fat changed. With physical training the percentage distribution of fast twitch oxidative (FTa) muscle fibres (m vastus lateralis) increased (from 30.3 +/- 5.1% to 35.2 +/- 4.8%, P less than 0.05) and that of fast twitch glycolytic fibres decreased (from 18.3 +/- 6.6 to 5.8 +/- 4.8%, P less than 0.05). The number of capillaries increased, mainly around slow twitch (ST) fibres (from 4.5 +/- 0.6 to 5.8 +/- 0.8, P less than 0.01) and fast twitch oxidative (FTa) fibres (from 3.9 +/- 0.7 to 4.7 +/- 0.8, P less than 0.01). The activities of oxidative enzymes (cytochrome-c-oxidase and citrate synthase) increased (P less than 0.05) while those of glycolytic enzymes (phosphofructokinase and hexokinase) decreased after physical training (P less than 0.01). Significant negative correlations between plasma insulin and number of capillaries in contact with ST fibres (r = 0.80, P less than 0.001) and FTa fibres (r = 0.62, P less than 0.001) were found before training. The capillary density around those fibres could predict 80% of the explained variance of plasma insulin levels (P less than 0.001). The changes of glucose concentration after training could be predicted by observed changes in enzyme activities. The strong associations between muscle morphology and capillarization and enzyme activities and glucose and insulin concentrations and their changes after training suggest an important regulatory role of muscle which warrants further studies.     

Comparison of carbohydrate-containing and carbohydrate-restricted hypocaloric diets in the treatment of obesity. Endurance and metabolic fuel homeostasis during strenuous exercise.

Eight untrained, obese females (greater than 30% body fat), ages 25-33 yr, were studied before, at 1 wk, and after 6 wk while taking either of two 830-kcal/d diets: carbohydrate-containing (CC) group (n = 4): 35% protein, 29% fat, 36% carbohydrate-restricted (CR) group (n = 4): 35% protein, 64% fat, 1% carbohydrate. Endurance, at approximately 75% of VO2max (maximum oxygen uptake) on a cycle decreased from base line by 50% at 1 and 6 wk in the CR group, but there was no change in the CC group. Preexercise muscle glycogen (vastus lateralis) did not change significantly in the CC group, but was decreased by 49% in the CR group after 1 wk, and by 51% after 6 wk. There was a close correlation between percent decrease in resting muscle glycogen and percent decrease in endurance (r = 0.79, P less than 0.01). The mean fasting and exercise plasma glucose concentration was lower in the CR group than in the CC group after 6 wk, but no subject became hypoglycemic during exercise. Serum FFA, lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, insulin, and glucagon changed similarly in the two groups during exercise at base line, 1 and 6 wk. Glycerol concentration was higher in the CR group during exercise only after 6 wk. Increases in serum lactate concentrations, and a mean exercise respiratory quotient of 0.93 suggested that cycle exercise at approximately 75% VO2max used predominantly glucose as a fuel. Conclusions: Resting muscle glycogen and endurance, during cycle exercise at approximately 75% VO2max, were maintained during a 36% carbohydrate, 830-kcal/d diet. In contrast, significant decreases, occurred in resting muscle glycogen and endurance, during similar exercise, after 6 wk of a 1% carbohydrate, 830-kcal/d diet.     

Deletion of mitochondrial DNA in a case of early-onset diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome, MIM 222300).

The Wolfram syndrome (MIM 222300) is a disease of unknown origin consisting of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Here we report on a generalized deficiency of the mitochondrial respiratory enzyme activities in skeletal muscle and lymphocyte homogenate of a girl suffering from the Wolfram syndrome. In addition, we provide evidence for a 7.6-kilobase pair heteroplasmic deletion (spanning nucleotides 6465-14135) of the mitochondrial DNA in the two tissues and show that directly repeated sequences (11 bp) were present in the wild-type mitochondrial genome at the boundaries of the deletion. Neither of the patient's parents was found to bear rearranged molecules. This study supports the view that a respiratory chain defect can present with insulin-dependent diabetes mellitus as the onset symptom. It also suggests that a defect of oxidative phosphorylation should be considered when investigating other cases of Wolfram syndrome, especially because this syndrome fulfills the criteria for a genetic defect of the mitochondrial energy supply: (a) an unexplained association of symptoms (b) with early onset and rapidly progressive course, (c) involving seemingly unrelated organs and tissues.     

Long-term administration of L-carnitine to humans: effect on skeletal muscle carnitine content and physical performance

BACKGROUND: Long-term administration of high oral doses of L-carnitine on the skeletal muscle composition and the physical performance has not been studied in humans. METHODS: Eight healthy male adults were treated with 2 x 2 g of L-carnitine per day for 3 months. Muscle biopsies and exercise tests were performed before, immediately after, and 2 months after the treatment. Exercise tests were performed using a bicycle ergometer for 10 min at 20%, 40%, and 60% of the individual maximal workload (P(max)), respectively, until exhaustion. RESULTS: There were no significant differences between V(O(2)max), RER(max), and P(max) between the three time points investigated. At submaximal intensities, the only difference to the pretreatment values was a 5% increase in V(O(2)) at 20% and 40% of P(max) 2 months after the cessation of the treatment. The total carnitine content in the skeletal muscle was 4.10 +/- 0.82 micromol/g before, 4.79 +/- 1.19 micromol/g immediately after, and 4.19 +/- 0.61 micromol/g wet weight 2 months after the treatment (no significant difference). Activities of the two mitochondrial enzymes citrate synthase and cytochrome oxidase, as well as the skeletal muscle fiber composition also remained unaffected by the administration of L-carnitine. CONCLUSIONS: Long-term oral treatment of healthy adults with L-carnitine is not associated with a significant increase in the muscle carnitine content, mitochondrial proliferation, or physical performance. Beneficial effects of the long-term treatment with L-carnitine on the physical performance of healthy adults cannot be explained by an increase in the carnitine muscle stores.     

Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.

We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39 +/- 5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v O2 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7 +/- 2.1) despite normal oxygen carrying capacity and Hgb-O2 P50. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Qmax, patient = 303 ml/min per kg, normal men 238 +/- 36) and the slope of increase in Q relative to VO2 (i.e., delta Q/delta VO2) from rest to exercise was exaggerated (delta Q/delta VO2, patient = 29, normal men = 4.7 +/- 0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at the level of complex II of the mitochondrial respiratory chain. A defect in Complex II in skeletal muscle was confirmed by the finding of deficiency of succinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle.     

Effects of exercise training on oxygen uptake kinetic responses in women with type 2 diabetes.

OBJECTIVE: Women with uncomplicated type 2 diabetes have both a decreased maximal oxygen consumption (VO2max) and slowed oxygen uptake (VO2) kinetics at the onset of exercise compared with nondiabetic women. These abnormalities are seen not only at maximal workloads, but also at the onset of low-level exercise. To evaluate the hypothesis that VO2max and VO2 kinetics would improve with exercise training in untrained people with type 2 diabetes, we measured these parameters in premenopausal sedentary women before and after 3 months of supervised exercise training. RESEARCH DESIGN AND METHODS: A total of 8 women with type 2 diabetes, 9 overweight nondiabetic women, and 10 lean nondiabetic women were studied. At baseline and after 3 months of exercise training, subjects underwent bicycle ergometer testing to obtain VO2max and VO2 kinetics data. RESULTS: On entry, women with type 2 diabetes had the lowest VO2max and slowest VO2 kinetics of the three groups. After exercise training, the women with type 2 diabetes improved their VO2max more than the lean and overweight control women: 28 vs. 5 and 8%, respectively (P < 0.05 for the diabetic group vs. both control groups). In the group with diabetes, VO2 kinetics improved by 39 and 22% at 20 and 30 W, respectively. For the control subjects, VO2 kinetics did not improve at any workload in either group. CONCLUSIONS: Despite beginning with the lowest VO2max and slowest VO2 kinetics, subjects with type 2 diabetes benefited more from an exercise training program than did control subjects. These findings suggest that in addition to its known metabolic effects, exercise training in individuals with type 2 diabetes may be an effective therapy to improve the cardiovascular response to exercise and to overcome low-level exercise impairment as reflected by improved VO2max and VO2 kinetics. If the ability to make circulatory adjustments at the beginning of exercise at low workloads is improved by an exercise training program, as suggested by the VO2 kinetics data, the clinical significance of exercise for people with type 2 diabetes is clear.     

Ten-year experience with an exercise-based outpatient life-style modification program in the treatment of diabetes mellitus.

Exercise is frequently recommended in the treatment of diabetes mellitus. Nevertheless, its use has been limited in clinical practice, and concerns about safety and efficacy persist. We have reviewed a 10-yr experience with 255 patients enrolled in a comprehensive diabetes program that emphasized physical training. A low maximal oxygen uptake (VO2max) was found in patients with non-insulin-dependent diabetes mellitus compared with sedentary control subjects. This was not accounted for by autonomic neuropathy and is unlikely to be due to subtle differences in life-style. Exercise-related proteinuria was common and occurred in 29% of patients and was associated with higher blood pressure levels at rest and during exercise, impaired VO2max, and decreased R-R interval variation. Regular exercise was associated with a modest decrease in resting and exercise blood pressure. Glycosylated hemoglobin levels and plasma triglycerides improved only in patients with non-insulin-dependent diabetes mellitus. Insulin requirements were significantly reduced in patients with insulin-dependent diabetes mellitus. Compliance for up to 3 mo in the program was acceptable but longer-term compliance was poor. Serious complications during the program were rare. Our experience suggests a program of regular aerobic training can be safely and effectively used in an outpatient population with diabetes mellitus for up to 3 mo.     

Reduction of enzyme efflux from skeletal muscle by diethylstilbestrol.

We have previously shown that oral diethylstilbestrol (DES) lowers the high serum enzyme levels characteristic of Duchenne's muscular dystrophy (DMD). The present studies were undertaken to assess the effect of DES on the efflux of enzymes from isolated mouse skeletal muscle. Thirty-four male mice were used. Half received daily subcutaneous injections of 10 mug diethylstilbestrol-diphosphate (DES-DP) in saline for up to 3 wk and half daily saline injections. Left gastrocnemii were isolated from control and treated mice, and placed in separate incubation media at 37 degrees C. The efflux of creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) from each was compared over a 4- to 5-hr period. In 15 of 18 there was a reduction in efflux of both enzymes from muscles isolated from DES-DP-treated mice. The greatest effect was noted during the second hour, when the mean efflux of each enzyme was reduced about 30%. Minor differences in muscle weight, water content, and enzyme activities did not explain the reduced efflux. These results suggest that DES has either reduced the permeability of the sarcolemma or enhanced the intracytoplasmic stability of these enzymes. This is the first drug reported to reduce the spontaneous enzyme efflux from isolated skeletal muscle. It remains to be established that a similar effect accounts for the reduction in serum enzyme levels when DES is administered to persons with DMD.     

Enzymatic adaptation to physical training under beta-blockade in the rat. Evidence of a beta 2-adrenergic mechanism in skeletal muscle.

Nonselective and beta 1-selective adrenergic antagonists were tested for their effects on enzymatic adaptation to exercise training in rats as follows: trained + placebo (TC); trained + propranolol (TP); trained + atenolol (TA); and corresponding sedentary groups, SC and SP. Trained rats ran 1 h/d at 26.8 m/min, 15% grade, 5 d/wk, 10 wk. Both beta-antagonists were given at doses that decreased exercise heart rates by 25%. Training increased skeletal muscle citrate synthase, cytochrome c oxidase (Cyt-Ox), carnitine palmitoyltransferase (CPT), beta-hydroxyacyl coenzyme A dehydrogenase, mitochondrial malate dehydrogenase (MDH), and alanine aminotransferase (ALT) activities significantly in the TC group, but not in TP. These enzyme activities, except Cyt-Ox and CPT, were also significantly increased in TA. Hepatic phosphoenolpyruvate carboxykinase activity did not alter with training or beta-blockade. Fructose 1,6-bisphosphatase activity was lower in TC than in SC, but unchanged in TP or TA. Hepatic mitochondrial MDH and ALT activities increased with training only in TC. It is concluded that beta 2-adrenergic mechanisms play an essential role in the training-induced enzymatic adaptation in skeletal muscle.     

Hemostatic alterations with exercise conditioning in NIDDM

Various parameters of coagulation and fibrinolysis were measured in 13 men (aged 54 +/- 3 yr) with non-insulin-dependent diabetes mellitus (NIDDM) before and after 12-14 wk of exercise training. Subjects exercised for 30 min 3 times/wk at 70% of maximum O2 consumption (VO2max). Training increased VO2max by 12.5% but did not alter body weight, relative body fat, blood pressure, cholesterol, triglycerides, or high-density lipoprotein cholesterol. Slight downward trends were apparent for fasting glucose and insulin, but glycosylated hemoglobin was unchanged. There were no changes in coagulation parameters of plasminogen, hematocrit, or alpha 2-antiplasmin. Plasma fibrinogen (303 +/- 24.2 vs. 256 +/- 12.3 mg/dl) and fibronectin (380 +/- 41.9 vs. 301 +/- 22.2 micrograms/ml) were significantly reduced (P less than 0.02) by exercise conditioning. Three assays of fibrinolytic activity (tissue plasminogen activator, euglobulin lysis time, and an isotopic measure of fibrinolysis) confirmed that neither basal fibrinolysis nor the fibrinolytic responses to venous occlusion and maximal exercise were significantly altered. Exercise conditioning may have antithrombotic effects in NIDDM by reducing plasma fibrinogen and fibronectin. Although the significance of the fall in fibronectin awaits further studies, the reduction in plasma fibrinogen gives a rationale for the use of exercise training in men with NIDDM.     

Altered fiber distribution and fiber-specific glycolytic and oxidative enzyme activity in skeletal muscle of patients with type 2 diabetes

OBJECTIVE: We investigated whether alterations of glycolytic and oxidative enzyme capacity in skeletal muscle of patients with type 2 diabetes pertain to specific muscle fibers and are associated with changes in muscle fiber composition. RESEARCH DESIGN AND METHODS: Vastus lateralis muscle was obtained by percutaneous biopsy from 10 patients with type 2 diabetes and 15 age- and BMI-matched healthy volunteers. Using cytophotometry, muscle fiber composition and fiber type-specific glycolytic and oxidative enzyme activities were measured in slow oxidative, fast oxidative glycolytic, and fast glycolytic fibers. RESULTS: In the whole muscle, oxidative activity was decreased in patients with type 2 diabetes. The slow oxidative fiber fraction was reduced by 16%, whereas the fast glycolytic fiber fraction was increased by 49% in skeletal muscle from the diabetic patients. Both oxidative and glycolytic enzyme activities were significantly increased in fast glycolytic and fast oxidative glycolytic fibers of type 2 diabetic patients. However, the fiber-specific ratio of glycolytic enzyme activity relative to oxidative activity was not different between type 2 diabetic patients and the control subjects. The myofibrillic ATP activity was significantly lower in all fiber types of patients with type 2 diabetes and correlates with glucose infusion rate during the steady state of a euglycemic-hyperinsulinemic clamp and maximal aerobic capacity and negatively with HbA(1c) values. CONCLUSIONS: Reduced oxidative enzyme activity in muscle of type 2 diabetic patients is most likely due to a reduction in slow oxidative fibers. Increased glycolytic and oxidative enzyme activities in individual muscle fibers are closely related to measures of long-term glycemic control and whole-body insulin sensitivity and could therefore represent a compensatory mechanism of the muscle in function of the altered glucose metabolism.     

Increased hepatic mitochondrial capacity in rats with hydroxy-cobalamin[c-lactam]-induced methylmalonic aciduria.

Treatment of rats with the vitamin B12 analogue hydroxy-cobalamin[c-lactam] (HCCL) impairs methylmalonyl-CoA mutase function and leads to methylmalonic aciduria due to intracellular accumulation of propionyl and methylmalonyl-CoA. Since accumulation of these acyl-CoAs disrupts normal cellular regulation, the present investigation characterized metabolism in hepatocytes and liver mitochondria from rats treated subcutaneously with HCCL or saline (control) by osmotic minipump. Consistent with decreased methylmalonyl-CoA mutase activity, 14CO2 production from 1-14C-propionate (1 mM) was decreased by 76% and 82% after 2-3 wk and 5-6 wk of HCCL treatment, respectively. In contrast, after 5-6 wk of HCCL treatment, 14CO2 production from 1-14C-pyruvate (10 mM) and 1-14C-palmitate (0.8 mM) were increased by 45% and 49%, respectively. In isolated liver mitochondria, state 3 oxidation rates were unchanged or decreased, and activities of the mitochondrial enzymes, citrate synthetase, succinate dehydrogenase, carnitine palmitoyltransferase, and glutamate dehydrogenase (expressed per milligram mitochondrial protein) were unaffected by HCCL treatment. In contrast, activities of the same enzymes were significantly increased in both liver homogenate (expressed per gram liver) and isolated hepatocytes (expressed per 10(6) cells) from HCCL-treated rats. The mitochondrial protein per gram liver, calculated on the basis of the recovery of the mitochondrial enzymes, increased by 39% in 5-6 wk HCCL-treated rats. Activities of lactate dehydrogenase, catalase, cyanide-insensitive palmitoyl-CoA oxidation, and arylsulfatase A in liver were not affected by HCCL treatment. Hepatic levels of mitochondrial mRNAs were elevated up to 10-fold in HCCL-treated animals as assessed by Northern blot analysis. Thus, HCCL treatment is associated with enhanced mitochondrial oxidative capacity and an increased mitochondrial protein content per gram liver. Increased mitochondrial oxidative capacity may be a compensatory mechanism in response to the metabolic insult induced by HCCL administration.     

Effect of exercise intensity on oxygen consumption kinetics in non-exercising muscle during exercise

This study examined the effect of exercise intensity on the kinetics of muscle oxygen consumption in non-exercising forearm flexor muscles (VO(2mf)) during exercise. Seven healthy male subjects performed cycling exercise for 60 min at 30% of maximal oxygen consumption (%VO(2max)) and 30 min at 50% VO(2max) on separate days. The VO(2mf) values at rest and during exercise were measured by near-infrared spectroscopy. The VO(2mf) at 30% VO(2max) significantly increased to 1·2 ± 0·1-fold over resting value at 20 min after the beginning of exercise (P<0·05) and remained constant within 1·2- to 1·3-fold over resting value until 60 min during exercise. The VO(2mf) at 50% VO(2max) significantly increased to 1·2 ± 0·1-fold over resting value at 15 min after the beginning of exercise (P<0·05). Subsequently, the VO(2mf) at 50% VO(2max) increased with time to 1·3 ± 0·1-fold over resting value at 20 min after the beginning of exercise and to 1·5 ± 0·2-fold over resting value at 30 min. The VO(2mf) 15-30 min of exercise at 50% VO(2max) was significantly higher than that at 30% VO(2max) (P<0·05). These data suggest that the increase in VO(2mf) has a time lag from the beginning of exercise, and the kinetics of VO(2mf) during exercise differs with exercise intensity. Therefore, we conclude that the kinetics of VO(2mf) during exercise is dependent on exercise intensity.     

Isokinetic strength training protocols: do they induce skeletal muscle fiber hypertrophy?

Sedentary subjects were submitted to repeated concentric isokinetic strength training protocols separated by a 50-day detraining period. Peak torque output of the quadriceps muscle group increased by 54% after the first ten-week training protocol. No significant changes in mean skeletal muscle fiber area were observed while a significant increase in percent fiber type and percent fiber area was noticed for type IIa fibers. The activities of the enzymes hexokinase, malate dehydrogenase, 3-hydroxyacyl CoA dehydrogenase, and oxoglutarate dehydrogenase were also increased significantly. Fifty days without training induced a significant decline in peak torque output. All the enzymes that responded to the first training protocol maintained their elevated activities over the detraining period except for the enzyme oxoglutarate dehydrogenase. A second training protocol administered to the same subjects following the 50-day inactivity period did not result in any significant increase in maximum torque output and fiber area. It is concluded that the isokinetic strength training protocol used can increase the functional capacity of skeletal muscle, but this effect does not appear to be related to skeletal muscle fiber hypertrophy.     

Hyperglycemia after intense exercise in IDDM subjects during continuous subcutaneous insulin infusion

Exercise is conventionally considered a modality for improvement of glycemia in diabetes. We have found that a short period of intense exercise (80% VO2max) in normal lean subjects produces sustained postexercise hyperglycemia 20% above basal with a corresponding 100% increase in plasma insulin. In people with insulin-dependent diabetes mellitus (IDDM) incapable of this insulin response, it was predicted that postexercise hyperglycemia would be of greater magnitude and/or duration. To investigate this possibility, the effects of the same intense exercise (80% VO2max) were studied in 8 IDDM subjects (2 on 2 occasions) in the postabsorptive state with continuous subcutaneous (abdominal) insulin infusion (CSII). When the preexercise plasma glucose was normal (n = 6, 86 +/- 4 mg/dl), there ensued a postexercise hyperglycemia to 127 +/- 7 mg/dl (P less than .001) sustained for 2 h postexhaustion. Plasma free immunoreactive insulin (IRI) was 1.43 +/- 0.12 ng/ml before exercise and did not change postexercise. When mean preexercise plasma glucose was 149 +/- 9 mg/dl (n = 4), it rose progressively throughout the 2 h of recovery to 229 +/- 28 mg/dl (P less than .025). A small but statistically significant decrease in free IRI occurred during the last 80 min of recovery. Hyperglycemia in the diabetic subjects was not explained by abnormal or differing responses of glucagon or catecholamines. Thus, with intense exercise, diabetic control deteriorates rather than improves. Therefore, different therapeutic strategies may be required for intense compared with moderate exercise in IDDM patients.