Exercise training fails to prevent glucocorticoid-induced muscle alterations in young growing rats.

The aim of this study was to determine the impact of chronic treatment for 8 weeks with hydrocortisone acetate (5 mg kg-1 day-1) on skeletal muscles, and to evaluate whether sprint training can prevent glucocorticoid-induced muscle atrophy better than endurance training. Biochemical, histological and contractile properties were employed to determine the influence of this steroid on skeletal musculature, and the results were compared to pair-weight animals to take into account the influence of corticoids on growth rate. It was found that hydrocortisone acetate treatment results in a stunted growth, adrenal atrophy and depressed plasma corticosterone levels. Mild corticoid-induced losses of muscle mass and protein content (9%-13%) were observed in fast-twitch skeletal muscles. It appeared that the impact of corticoids is strictly directed toward type IIb fibres, which displayed a 12%-18% reduction in cross-sectional areas. No alterations occurred in plantaris contractile speed or tensions properties. Neither endurance training (30 m/min; 90 min/day; 5 days/week) nor sprint training (60 m/min; 15 min/day; 5 days/week) for 8 weeks was able to counteract the effects of corticoids. These data suggest that increased contractile activity, as induced by treadmill running, is not sufficient to counteract the muscular effects of glucocorticoids when administered at a dose of 5 mg kg-1 day-1.

Soleus muscle alterations in spontaneously hypertensive rats are not dependent on activation of beta 2-adrenergic receptors.

The effects of selective beta 2-adrenergic blockade with ICI 118,551 on the histochemical, biochemical, and contractile properties of slow-twitch soleus muscle from spontaneously hypertensive (SHR) and normotensive (WKY) rats were examined from birth to 8-10 weeks of age. Chronic treatment of normotensive rats with ICI 118,551 caused an impairment in the differentiation of slow type fibers during development but failed to alter the fiber type distribution of hypertensive rats. beta 2-Adrenoreceptor blockade was ineffective in reducing the enhanced glycolytic and oxidative capacities of soleus in hypertensive rats. The suggestion can be made that beta 2-adrenoreceptor activation is not responsible, at least directly, for the histochemical and biochemical alterations of slow muscle from hypertensive rats.

Additive effects of training and high-fat diet on energy metabolism during exercise.

This study was conducted to obtain additional information about the adaptations after 12 wk of high-fat diet (HFD) per se or HFD combined with endurance training in the rat using a two [diet: carbohydrate (CHO) or HFD] by two (training: sedentary or trained) by two (condition at death: rested or exercised) factorial design. Adaptation to prolonged HFD increases maximal O2 uptake (VO2max; 13%, P less than 0.05) and submaximal running endurance (+64%, P less than 0.05). This enhancement in exercise capacity could be attributed to 1) an increase in skeletal muscle aerobic enzyme activities (3-hydroxyacyl-CoA dehydrogenase and citrate synthase in soleus and red quadriceps) or 2) a decrease in liver glycogen breakdown in response to 1 h exercise at 80% VO2max. When training is superimposed to HFD, the most prominent finding provided by this study is that the diet-induced effects are cumulative with the well-known training effect on VO2max, exercise endurance, oxidative capacity of red muscle, and metabolic responses to exercise, with a further reduction in liver glycogen breakdown.

Exercise endurance and fuel utilization: a reevaluation of the effects of fasting.

The effect of fasting on energy utilization during running or swimming was studied in adult male Wistar rats. Compared with fed rats, fasted animals displayed a decreased contribution of carbohydrates in energy supply, with decreased liver and muscle glycogen contents and decreased rate of glycogen breakdown. This was compensated by an enhanced rate of beta-oxidation. In addition, fasting induced an exaggerated sympathoadrenal response during exercise, reflected by a greater epinephrine plasma level and a higher norepinephrine turnover rate in both liver and soleus. Nevertheless, endurance capacity was similar in fasted and fed animals. These results contrast with the impairment of endurance observed in fasting humans but also with the improvement of endurance in rats previously reported by Dohm et al. (J. Appl. Physiol. 55: 830-833, 1983). These data suggest that the metabolic responses to exercise subsequent to food deprivation depend not only on the considered species but also, in the same species (rat), on the age of the animals and the duration of the fast. These factors probably determine the hormonal secretion and substrate utilization during prolonged exercise in fasting conditions.

Effect of almitrine administration on pulmonary arterial pressure in resting and exercising dogs.

In addition to its well-known ventilatory effect, a small rise in pulmonary arterial pressure or pulmonary vascular resistance is occasionally observed with chronic administration of almitrine. In order to test the hypothesis of enhancement of exercise pulmonary vasoconstriction by almitrine, mongrel dogs were studied at rest and during submaximal exercise before and after 4 weeks of chronic ingestion of almitrine (10 mg/kg). It was shown that resting pulmonary arterial pressure (PAP) remained unchanged by almitrine treatment. However, when exercise was superimposed on almitrine medication, PAP was significantly increased throughout the exercise bout. Thus, the rise in PAP during the 20th min of exercise averaged 8.7 +/- 3.4 mm Hg after almitrine treatment while PAP increased by only 1.3 +/- 1.7 mm Hg before medication. The exaggerated exercise-induced PAP response in conjunction with the enhanced secretion of norepinephrine that we observed during almitrine treatment suggests that catecholamine could be involved in the pulmonary haemodynamic adjustments. Furthermore, mixed-venous PO2 (PvO2) both during rest and exercise declined with the prolongation of almitrine ingestion, suggesting that PvO2 might possibly be implicated in the pulmonary haemodynamic response to almitrine, in the same way as it is involved in the hypoxia-induced pulmonary vasoconstriction. These findings demonstrate that almitrine medication, even at a high dose, does not have any deleterious effect on pulmonary vasculature in resting conditions, but prolonged submaximal exercise should be proscribed in patients on a long-term therapy.

Evidence of a slow-to-fast fiber type transition in skeletal muscle from spontaneously hypertensive rats.

The histochemical, biochemical, and electrophysiological properties of selected muscles were evaluated in spontaneously hypertensive rats (SHR) and compared with their normotensive Wistar-Kyoto (WKY) counterparts. As early as 4 wk of age, slow muscles (soleus) of SHR displayed a significant alteration in fiber type distribution with a decrease of slow-twitch fibers (from 64 to 53%) and a simultaneous increase of type IIA-fibers (from 19 to 39%). In addition, soleus from young SHR had a significant enhancement of both oxidative (citrate synthase, 3-hydroxyacyl-CoA dehydrogenase) and glycolytic [lactate dehydrogenase (LDH)] capacities, which could be partly related to a capillary rarefaction. During development (from the 4th to the 12-14th wk), in the soleus muscle the histochemical differences between SHR and WKY were amplified, whereas most of the enzymatic differences between strains were abolished, except for a significantly higher LDH activity. These histochemical changes had only marginal repercussions on soleus electrophysiological properties. SHR animals had a significantly higher basal metabolic rate, which could not be accounted for by elevation of thyroid hormones. The origin of the slow-to-fast fiber type transition in slow muscle remains unclear but could be related to the increased level of plasma catecholamines in SHR. Indeed, chronic treatment of rats with a beta 2-receptor agonist has been reported to cause slow-to-fast muscle fiber transition [R. J. Zeman, R. Ludemann, T. G. Easton, and J. D. Etlinger. Am. J. Physiol. 254 (Endocrinol. Metab. 17): E726-E732, 1988].

Large variations in skeletal muscle carnitine level fail to modify energy metabolism in exercising rats.

1. The importance of carnitine status in energy metabolism during exercise was studied in experimentally carnitine-depleted or supplemented rats. 2. Muscle carnitine concentration can be decreased by 40% with D-carnitine and increased by 40% with L-carnitine supplementation. 3. In spite of large variation of carnitine content, neither the exercising capacity nor the rate of muscle or liver glycogenolysis were modified during submaximal exercise. 4. The increased lipid metabolism induced by exercise can be adequately supported by endogenous levels of tissue carnitine. 5. Before any impairment in energy metabolism during exercise can be demonstrated, carnitine concentration has to be reduced to a level close to that measured with primary carnitine deficiency, i.e. less than 20 mumol/l of plasma.

Skeletal muscle adaptation to physical training and beta-adrenergic blockade in spontaneously hypertensive rats.

The effects of training alone or in combination with long-term, non-selective, beta-adrenergic blockade on histochemical and biochemical properties of fast-twitch [extensor digitorum longus muscle (EDL)] and slow-twitch [soleus muscle (Sol)] muscle were analyzed in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto strain rats (WKY). Fiber type distribution of Sol was drastically modified in SHR with fewer type I fibers and more type IIA fibers. No such histochemical alterations were observed in EDL. While prolonged swimming training remained ineffective in inducing both histochemical and biochemical improvement in WKY, SHR displayed a significant enhancement of capillarization and oxidative capacity in both Sol and EDL. However, in long-term beta-blocks rats training failed to improve significantly the oxidative capacity of SHR muscles, suggesting that beta-adrenoreceptor stimulation is necessary for a fully efficient adaptation of muscular metabolism to physical training.

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.

Metabolic and structural adaptations to exercise in chronic intermittent fasted rats.

The effect of repetitive alternance of 3 days fasting and 3 days refeeding on morphological and biochemical ability to perform exercise was investigated in adult male rats. At the end of 10 wk of chronic intermittent fasting, the rats had consumed 20% less food but were able to maintain their initial body weight. Intermittent fasted rats (IF) had significantly lower carcass fat but had maintained the percent contribution of proteins to total carcass weight. The relative mass of liver, heart, kidney, and muscles was not affected by such dietary manipulation. Both glycolytic and oxidative enzyme capacities were reduced in IF rat muscles. In response to exercise (2 h of swimming), control rats displayed hypoglycemia, whereas IF rats were able to maintain plasma glucose level in spite of a reduced energy supply from liver (low glycogen stores) and adipose tissue (low plasma free fatty acid levels). This had been obtained by accumulating glycogen and triglycerides in muscles and by deriving energy for muscular contraction from the in situ breakdown of these energetic substrates. In addition, although IF rats displayed a markedly reduced liver protein content, the liver exercise-induced protein breakdown was abolished in these animals.

Effects of gluconeogenic precursor flux alterations on glycogen resynthesis after prolonged exercise.

The importance of gluconeogenic substrates (i.e., lactate, glycerol, and alanine) in the glycogen resynthesis observed in fasting rats after exhausting submaximal exercise [R.D. Fell et al. Am. J. Physiol. 238 (Regulatory Integrative Comp. Physiol. 7): R328-R332, 1980] was examined in muscles and liver in response to pharmacological alterations of gluconeogenic precursor flux. The minor role of lactate for glycogen resynthesis after prolonged submaximal exercise was confirmed by the insignificant accumulation of lactate neither in muscles nor in plasma. When the rate of lipolysis is reduced either by beta-blockade or by nicotinic acid injection, the replenishment of muscle glycogen persisted, suggesting that glycerol released by triglycerides hydrolysis did not play an important role in glycogen resynthesis. On the other hand, when pyruvate oxidation is enhanced by dichloroacetate (DCA), thus reducing plasma levels of lactate and alanine, glycogen resynthesis was completely blocked in liver and partly in some but not all muscles. This failure in total inhibition of glycogen resynthesis associated with the significant reduction of the plasma alanine level could be attributed to the possible stimulation of gluconeogenesis from alanine by DCA (R.A. Harris and D.W. Crabb. Arch. Biochem. Biophys. 189: 364-371, 1978). The results could point out alanine as the major gluconeogenic substrate during recovery from exhaustive exercise in fasting conditions.

Energy metabolism in contracting rat skeletal muscle: adaptation to exercise training.

Rats were trained by means of a program of treadmill running. Hindlimb muscles were stimulated to contract in anesthetized rats. Measurements were made on the plantaris and the deep, predominantly fast-twitch red portion of the gastrocnemius. The concentration of ATP plus phosphocreatine (approximately P) decreased less and stabilized at a higher level, whereas inorganic phosphate (Pi) and AMP concentrations increased less and attained lower steady-state levels in trained than in untrained muscles at the same work rate. Similarly, when muscles were stimulated to contract in the perfused rat hindquarter preparation, phosphocreatine (PC) concentration decreased less in trained plantaris muscle during contractile activity that resulted in the same rate of oxygen uptake by trained and untrained muscles. In both preparations, glycogen concentration decreased less and lactate increased less in the trained muscle. From the changes that occurred in the PC-to-creatine ratio during contractile activity and from ATP concentration, it could be estimated that free ADP concentration increased less than one-half as much in trained as in untrained muscles. We conclude that, as a consequence of the adaptive increase in muscle mitochondria, approximately P concentration is higher and Pi, ADP, and AMP concentrations are lower in muscles of exercise-trained compared with untrained rats during the same contractile activity.

Bradykinin does not mediate activation of glucose transport by muscle contraction.

The purpose of this study was to evaluate the report that bradykinin is the "muscle activity hypoglycemia factor" responsible for the activation of glucose transport that occurs in response to muscle contractile activity. Stimulation of rat epitrochlearis muscles to contract resulted in approximately a fourfold increase in the rate of intracellular accumulation of the nonmetabolizable glucose analog 3-O-methylglucose. Incubation of the muscles with high concentrations of aprotinin (Trasylol), a polypeptide inhibitor of kallikrein which blocks formation of kinins, did not inhibit the activation of sugar transport by contractile activity. Furthermore incubation of muscles with bradykinin did not have a stimulatory effect on the uptake of 3-methylglucose either at a physiological concentration or at high concentrations. These results provide no support for the claims that aprotinin prevents the activation of sugar transport in muscle by contractile activity or that bradykinin is the muscle activity hypoglycemia factor.

Endurance exercise training reduces lactate production.

In situ muscle stimulation in trained and untrained rats was used to reevaluate whether adaptations induced by endurance exercise training result in decreased lactate production by contracting muscles. The gastrocnemius-plantaris-soleus muscle group was stimulated to perform isotonic contractions. After 3 min of stimulation with 100-ms trains at 50 Hz at 60/min, the increases in lactate concentration in the plantaris, soleus, and fast-twitch red muscle (deep portion of lateral head of gastrocnemius) were only approximately 50% as great in trained as in sedentary rats. In the predominantly fast-twitch white superficial portion of the medial head of the gastrocnemius the increase in lactate concentration was 28% less in the trained than in the sedentary group. The decreases in muscle glycogen concentration seen after 3 min of stimulation at 60 trains/min were smaller in the trained than in the untrained group. The reduction in lactate accumulation that occurred in the different muscles in response to training was roughly proportional to the degree of glycogen sparing. These results show that endurance training induces adaptations that result in a slower production of lactate by muscle during contractile activity.

Exercise and glycogen depletion: effects on ability to activate muscle phosphorylase.

Phosphorylase activation reverses during prolonged contractile activity. Our first experiment was designed to determine whether this loss of ability to activate phosphorylase by stimulation of muscle contraction persists following exercise. Phosphorylase activation by stimulation of muscle contraction was markedly inhibited in rats 25 min after exhausting exercise. To evaluate the role of glycogen depletion, we accelerated glycogen utilization by nicotinic acid administration. A large difference in muscle glycogen depletion during exercise of the same duration did not influence the blunting of phosphorylase activation. Phosphorylase activation by stimulation of contraction was more severely inhibited following prolonged exercise than after a shorter bout of exercise under conditions that resulted in the same degree of glycogen depletion. A large difference in muscle glycogen repletion during 90 min of recovery was not associated with a significant difference in the ability of muscle stimulation to activate phosphorylase, which was still significantly blunted. Phosphorylase activation by epinephrine was also markedly inhibited in muscle 25 min after strenuous exercise but had recovered completely in glycogen-repleted muscle 90 min after exercise. These results provide evidence that an effect of exercise other than glycogen depletion is involved in causing the inhibition of phosphorylase activation; however, they do not rule out the possibility that glycogen depletion also plays a role in this process.

Effects of hypoxia on catecholamine and cardiorespiratory responses in exercising dogs.

The sympathoadrenal contribution to cardiorespiratory response elicited by hypoxia and/or exercise was assessed in the dog. The increased plasma norepinephrine (NE) and dopamine (DA) levels which follow hypoxia (fraction of inspired O2 equals 0.12) while epinephrine (E) remained unchanged ruled out the possibility of a primacy of the adrenal medulla in the response to hypoxia. In contrast to the lack of effect of hypoxic exposure, the adrenal medulla was substantially stimulated during exercise. The exercise-induced sympathoadrenal response remained unchanged during hypoxia as compared to normoxia when expressed as function of relative work intensity. Nevertheless at a given oxygen uptake, all plasma catecholamines were increased by hypoxia. These modifications in hormonal milieu failed, however, to alter the cardiac responses to exercise but were associated with a change in breathing pattern.