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Metabolic adaptations to training

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					Metabolic adaptations to training
The improvements in exercise performance which result from training are the result of adaptations in a variety of the body’s systems (cardiovascular, neural, metabolic etc.). The metabolic adaptations that occur in response to exercise training have been of considerable interest to exercise biochemists for the last 30 years, but as yet are not completely described nor particularly well understood. There are marked changes in the activities of the enzymes in the aerobic metabolic pathways in response to endurance (aerobic) training. Individuals who have adapted to endurance exercise exhibit higher maximal oxygen uptakes and lower blood and muscle lactate concentrations at a given submaximal work load. In addition, endurance trained individuals derive more of their energy from fat and less from carbohydrate than untrained individuals during submaximal exercise. This serves to delay the onset of fatigue by depleting muscle and glycogen levels less. All of these adaptations contribute to improved maximal and submaximal exercise performances. There are also changes in the activities of enzymes in the anaerobic metabolic pathways in response to stregth/speed training which allow for increased accumulation of ATP and an ability to tolerate higher lactic acid loads.

ADAPTATION TO ENDURANCE TRAINING
The ability to maintain prolonged exercise is dependent on the ability to match the rate of ATP supply to the rate of ATP utilisation. If this cannot be achieved then the rate of ATP use must fall and power output will decline. The adaptations to training which contribute to an increased rate of synthesis of ATP are both central and peripheral. It is the peripheral adaptations which are of interest here.

Intramuscular fuel stores
Training increases the availability of carbohydrate and lipid as substrate to meet cellular needs for ATP resynthesis.

Training can increase muscle glycogen content by up to 2.5 times. The increased muscle glycogen accumulation may be due to:  increase in GLUT 4 transporter protein content in trained muscle (up to 25% higher)  increase in glycogen synthase activity

 increase in hexokinase activity. Hexokinase activity increases in response to single bouts of prolonged exercise, or a few brief bouts of exercise. The significance of an increase in hexokinase activity in terms of endurance performance is that it will facilitate the entry of a greater proportion of glucose taken up from the blood into the glycolytic pathway which could contribute to a greater rate of pyruvate formation for entry into the Krebs cycle at maximal or near maximal exercise intensities, as well as assisting in the sparing and replenishment of muscle glycogen stores. In terms of the lower blood and muscle lactate concentrations observed following training, the role of an increase in hexokinase activity is presently unclear. However, patients with McArdles disease who lack the enzyme glycogen phosphorylase are incapable of increasing blood lactate levels during exercise despite the presence of hexokinase in their muscles. This suggests that carbohydrate entering the glycolytic pathway via hexokinase might be preferentially metabolised in the Krebs cycle, and does not contribute to lactate formation. Thus, an increase in hexokinase activity may increase glycolytic flux and pyruvate production with no subsequent increase in lactate production. However, there is no direct experimental evidence to support this theory. Training also leads to a higher intramuscular triacylglycerol content.

GLYCOLYTIC CAPACITY
The content of glycolytic enzymes in the muscles of successful endurance athletes is usually low, but this can be accounted for by the usually higher proportion of Type I fibres in these individuals. Most studies have reported either no change or a slight decrease in the activity of glycolytic enzymes following endurance training in both rats and humans.

LDH
The principal adaptation that occurs in enzymes of the glycolytic pathway is that endurance training elicits a decrease in total lactate dehydrogenase (LDH) activity, with an increase in the proportion of the heart-specific isozyme (LDH-H) and a decrease in the skeletal muscle-specific isozyme (LDH-M). LDH-H has a lower Km for lactate than it does for pyruvate and so favours the oxidation of lactate to pyruvate. LDH-M on the other hand, has a lower Km for pyruvate than for lactate and so favours the reduction of pyruvate to lactate. The overall effect of the adaptations in LDH would be to decrease the reduction of pyruvate to lactate when pyruvate and NADH concentrations are elevated in the cytosol of muscle cells.

Lactate transporters
High intensity training leads to an increase in both the number and activity of lactate transporters in skeletal muscle membranes. This would assist in a more rapid removal of lactate from the cytosol into the blood, thereby lessening fatigue induced by lactate accumulation within the muscle. High intensity (ie. anaerobic) training also increases the buffer capacity of skeletal muscle. This too would help to lessen the fatiguing effects of decreases in muscle pH. These adaptations are important for anaerobic athletes, but are also of importance for endurance athletes in terms of the ability to ‘kick’ or ‘push’ during the final stages of a race.

Adaptations in mitochondrial enzymes
John Holloszy showed in 1967 that endurance training induces an increase in the mitochondrial content of skeletal muscle, and Morgan et al. in a subsequent study in 1971, showed that this increase is due to gains in both the size and number of mitochondria, although increases in size are not as great as increases in number. Increases in mitochondrial content occur in both Type I and Type II fibres. An increase in mitochondrial content enhances the muscles oxidative capacity due to increases in the levels of the enzymes of the ß-oxidation pathway, the Krebs cycle and components of the respiratory chain. Endurance training also leads to an increase in lipoprotein lipase activity (located in capillary endothelium), as well as in levels of the enzymes responsible for the activation of fatty acids and their transport into the mitochondria. The combined effect of these changes is an increase in the capacity to oxidise carbohydrate and FFA and an increased capacity to generate ATP in the presence of oxygen.

Mitochondrial shuttles
The inner mitochondrial membrane is impermeable to NAD and NADH. NADH formed in the cytosol from glycolysis is transported into the mitochondria and NAD is transported the other way by either the dihydroxyacetone phosphate shuttle or the malate aspartate shuttle.

In contrast to the enzymes in the dihydroxyacetone phosphate shuttle, which do not increase, the enzymes of the malate aspartate shuttle increase in response to training. Increases in the levels of these enzymes enables NADH produced in the cytosol to be removed to the electron transport chain more rapidly.

Other significant adaptations
Myoglobin
Evidence from studies on animals suggests that endurance training can increase the myoglobin content of skeletal muscle fibres by up to 80%. An increased myoglobin content would facilitate the maintenance of a low PO2 in the sarcoplasm of the muscle fibre, thereby increasing the gradient for oxygen diffusion from the blood. Despite the evidence of an increase in skeletal muscle myoglobin content in animals, there does not appear to be an increase, and may even be a decrease, in myoglobin content in human muscle with training.

Alanine aminotransferase (previously known as alanine transaminase)
Alanine aminotransferase activity is increased with endurance training. Alanine aminotransferase converts pyruvate to alanine in a transamination reaction. An increase in the activity of alanine aminotransferase would mean that this enzyme would provide more competition with lactate dehydrogenase and pyruvate dehydrogenase for the pyruvate formed in glycolysis. This could lead to a reduced availability of pyruvate for the lactate dehydrogenase reaction, with a concommitant reduction in lactate formation.

Mitochondrial bound creatine kinase (MBCK)
The levels of MBCK are increased through training.

MBCK facilitates the rephosphorylation of creatine to creatine phosphate in the mitochondria. The ATP produced in the mitochondria is used to rephosphorylate the creatine in the creatine kinase reaction. The creatine phosphate is then used to rephosphorylate ADP to ATP at the contraction site via the creatine phosphate shuttle. An increase in the level of activity of this enzyme would facilitate a more rapid removal of ADP from the cytosol and assist in maintaining a higher cytosolic ATP concentration during exercise. Both a reduced cytosolic ADP concentration and an increased ATP concentration, would lead to a reduction in PFK activity, with a possible reduction in lactate production.

Pyruvate dehydrogenase
Pyruvate dehydrogenase activity is increased with training. This would increase the competition with lactate dehydrogenase for the pyruvate formed in glycolysis.

Physiological consequences of endurance training induced metabolic adaptations
Training effects on VO2max
Maximal oxygen uptake (VO2max) can be increased as a result of endurance exercise training. The metabolic adaptations to endurance training that facilitate this increase in VO2max are numerous. It has been suggested that there is an excess of glycolytic capacity in untrained subjects. This suggestion has arisen due to the observation that the glycolytic pathway in untrained subjects is able to generate levels of NADH and pyruvate in excess of those which can be adequately processed by the Krebs cycle and respiratory chain, leading to relatively high levels of lactate production. With training, although there appears to be no significant change in glycolytic capacity, the increase in PDH activity leads to a greater conversion of pyruvate to acetyl CoA.

In addition, the increased capacity for fatty acid metabolism resulting from increases in the ability to hydrolyze triglycerides, activate fatty acids, transport them into the mitochondria and then break them down in the -oxidation pathway results in an increased production of acetyl CoA from fat metabolism. The increased formation of acetyl CoA from both the PDH reaction and from oxidation provides more substrate for the Krebs cycle. The increase in the availability of acetyl CoA to the Krebs cycle, along with the increases in the enzymes in the Krebs cycle which increase the capacity of this cycel to process the acetyl CoA leads to a greater rate of formation of NADH. The adaptive increases in the enzymes of the respiratory chain lead to an increase in the capacity of the respiratory chain to process NADH, with a resultant increase in oxygen uptake since the respiratory chain is where the oxygen extracted from the blood is used as the final electron acceptor. All of these metabolic adaptations, combined with the adaptations in other physiological systems serve to increase oxygen delivery to the active muscles and increase maximal oxygen uptake.

Training effects on muscle and blood lactate concentrations
Blood and muscle lactate concentrations at a given relative or absolute workload are decreased following endurance training. The extent to which this decrease can be attributed to either a decreased rate of lactate production or an increased rate of clearance is presently the subject of some controversy.

Decreased lactate production
The factors which can contribute to a reduced rate of lactate production following endurance training are numerous and only the metabolic adaptations are discussed here. It was long believed that lactate production during exercise reflected muscle hypoxia, and that the lower rate of lactate production seen in trained individuals during submaximal exercise was the result of cardiovascular adaptations which increase oxygen delivery to the muscle, reducing the hypoxic state of the muscle during exercise. However, in light of the substantial body of evidence refuting muscle hypoxia as being the cause of lactate production (see lactate tutorial), adaptations which occur within the muscles themselves may better explain the lower lactate levels and increased endurance capacity following training. Indeed, there is considerable experimental evidence supporting the proposition that changes within the active skeletal muscles could

be more important than any cardiovascular adaptations in mediating the lower posttraining blood lactate response to submaximal exercise. A possible mechanism by which increases in mitochondrial content and respiratory enzyme levels may attenuate lactate production during submaximal exercise is via tighter control of cytosolic adenine nucleotide concentrations (ATP and ADP). SInce the VO2 for a given absolute submaximal workload is the same in the trained and untrained states, and because there is an increased number of mitochondria following endurance training, the rate of electron transport and oxygen consumption per mitochondria must be less in order to achieve a given VO2 in the trained state. Since the oxygen consumption per mitochondrion must be less in the trained state the respiratory stimulus per mitochondrion, in terms of changes in the cytosolic phosphorylation potential, must also be less. Experimental evidence supporting this reasoning comes from the finding that following endurance training muscle ATP decreases less at the same absolute submaximal workload and VO2. Tighter control over cytosolic adenine nucleotide levels would also result from adaptations in mitochondrial blund creatine kinase (MBCK) activity. Endurance training has been reported to increase the relative amount of MBCK, which forms an integral part of the phosphorylcreatine shuttle. An increase in its activity would facilitate the translocation of ADP from the myofibrillar ATP-ase site into the mitochondria and the transfer of ATP in the opposite direction. An increased rate of translocation of these nucleotides would assist in minimizing cytosolic ADP concentrations whilst maintaining high cytosolic ATP levels. This would decrease stimulation of PFK, reducing glycolytic flux and presumably lactate production.

Malate-aspartate shuttle and alanine aminotransferase
Endurance training may also attenuate lactate production via the combined actions of the increases in the enzymes of the malate-aspartate shuttle and alanine aminotransferase activity. The inner mitochondrial membrane is impermeable to NAD and NADH and the translocation of these substances is mediated by the transfer of reducing equivalents via shuttle systems, of which the malate-aspartate shuttle is considered to be, quantitatively, the most important in skeletal muscle. An increase in the enzymes of the malate-aspartate shuttle through endurance training would increase the capacity for removal of NADH from the cytosol. Alanine aminotransferase catalyzes the transamination of pyruvate to alanine. Increases in alanine aminotransferase activity combined with the increased ability of the malate-aspartate shuttle to remove NADH from the cytosol would increase competition with LDH for pyruvate and NADH which, combined with the decrease

in total LDH activity and the shift in isoenzyme pattern towards the LDH-H form, would contribute to the post-training decrease in lactate production.

Fat metabolism
Perhaps the most important adaptation to endurance training however, in terms of moderating the blood lactate response to submaximal exercise is the increased capacity to oxidize fats for energy. An increased capacity for fat oxidation enables a greater proportion of the energy required during submaximal exercise to be derived from fats with a proportional reduction in carbohydrate utilization. This carbohydrate sparing is the result of a complex interaction between carbohydrate and fat metabolism. The increased mitochondrial content of trained muscle provides a greater surface area for the uptake of fatty acids which, combined with an increased concentration of ß-oxidation enzymes would result in an increased production of acetyl-CoA from FFA. This increased production of acetyl-CoA from FFA, coupled with a training induced increase in citrate synthase activity, would raise the intramitochondrial concentration of citrate, which would in turn inhibit PFK activity. Inhibition of PFK in such a manner would increase the glucose-6phosphate concentration in the cytosol which would in turn allosterically inhibit hexokinase. At the same time, the increased production of acetyl units from fatty acids would increase the acetyl-CoA/CoA ratio, further inhibiting PFK, and also inhibiting pyruvate dehydrogenase (PDH) activity. As PFK, hexokinase and PDH are all rate limiting enzymes (all catalyze essentially non-reversible reactions) their inhibition due to an increase in FFA oxidation would decrease glycolytic flux, thereby reducing carbohydrate utilization. This regulatory pathway could account for the decreased lactate production and greater glycogen sparing associated with endurance trained individuals.

Increased lactate clearance
Lactate that is produced by active muscle fibres within a muscle during exercise can be removed by other fibres within the same muscle before it ever reaches the circulation. Once taken up by other fibres the lactate can be converted to pyruvate by the action of LDH. LDH-H levels which are increased with training would facilitate this process. Once converted to pyruvate it can be removed either by conversion to acetyl CoA or transamination to alanine, although most evidence suggests that it is converted to acetyl CoA and oxidized in the Krebs cycle for energy.

TIME COURSE OF ENDURANCE TRAINING ADAPTATIONS Peak adaptation in mitochondrial content seem to occur with shorter duration – higher intensity training. The benefit of prolonged training sessions in improving endurance performance may be more related to adaptations in cardiovascular function, blood volume and fluid balance rather than to muscle-specific adaptations in oxidative capacity. The time course of alterations in substrate utilisation during exercise parallel the increases in mitochondrial enzyme activities. However, during the first 5-7 days of training changes in substrate utilisation appear to be due to factors other than changes in mitochondrial enzymes since RER and muscle glycogen usage have been shown to decline without being able to detect an increase in mitochondrial enzymes. This initial change in substrate utilisation could be due to an early alteration in the hormonal response to exercise since the catecholamine response to exercise has been shown to attenuate after only a few training bouts. About 50% of the increased mitochondrial content of muscle can be lost within 1 month of detraining.

HORMONAL ADAPTATIONS TO ENDURANCE TRAINING Neuroendocrine adaptations also play an important role in the modified substrate metabolism that occurs in response to training. In general, the hormonal responses to a given exercise intensity are attenuated after training eg. there is a smaller increase in epinephrine concentration at the same absolute and relative work loads following training. ACTH, cortisol, glucagon and hGH also increase less during submaximal exercise. Insulin concentration usually falls during exercise and in trained subjects this decrease is less and therefore, plasma insulin concentrations tend to be higher in trained subjects during exercise. However, during exercise about 85% of glucose uptake by skeletal muscle is via non-insulin dependant mechanisms so the increase in insulin is probably more significant in terms of inhibiting lipolysis and liver glucose production.

ADAPTATIONS TO SPRINT & STRENGTH TRAINING

Training for strength, power or speed has little if any effect on aerobic capacity and results in relatively little cardiovascular adaptation. Muscle biopsies taken before and after resistance training which increased muscular strength by 28% indicated that resting intramuscular concentrations of ATP, PCr and glycogen were increased by 5%, 10% and 10-30% respectively. Sprint and weight training also increases glycolytic capacity via an increase in glycolytic enzymes eg. LDH activity is increased in both Type I and II muscle fibres and PFK activity is also increased. However, there is a reduction in relative aerobic capacity of muscle fibres due to a relative reduction in activity of oxidative enzymes through mitochondrial dilution. After anaerobic training, higher concentrations of lactate in the blood can be achieved during maximal exercise. This may be due to the higher levels of intramuscular glycogen and glycolytic enzymes which are present after training, but improvements in the capacity of muscle to buffer the protons associated with lactate accumulation might also be important. Type II muscle fibres have a high buffering capacity and , therefore, the growth of these fibres relative to Type I fibres could account for the increased buffering capacity observed following anaerobic training.

MECHANISMS OF MUSCULAR ADAPTATIONS TO TRAINING
Most evidence suggests that the myosin gene family holds the key to muscle plasticity. There are at least 7 different versions available which allows for a great deal of flexibility in muscle composition. In theory a muscle fibres contractile properties can be modified by using a different type of myosin heavy chain. Most genes are switched on and off by the indirect actions of signalling molecules such as hormones or growth factors. Adaptations in muscle in response to training are specific to the muscles used in the activity. It would seem therefore, that muscle genes are regulated largely by mechanical and/or metabolic stimuli. Stretching muscle fibres during exercise is one potent stimulus to adaptation. Passive stretch increases hypertrophy even in the absence of innervation, hormones and adequate nutrition. The transduction of mechanical forces to the nuclei and ribosomes may occur either directly via the cytoskeleton, or indirectly via stretch activated ion channels or other molecules (e.g stretch activated adenyate cyclase) in the membrane. Exercise induced muscle damage might also provide a stimulus for muscle hypertrophy. High concentrations of muscle specific growth factors are released following muscle damage and contact inhibition between satellite cells and muscle fibres is lost leading to satellite cell proliferation and fusion resulting in hypertrophy.

Either increased cAMP levels or the rate of metabolic flux is hypothesised to be the signal for increased mitochondrial development resulting from endurance training.


				
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