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    Brooks 1986

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    or9s9131/8/1800-casot0209 MEDICINE AND SCENCE N SPORTS AND EXERCSE Copight ©1985 by te AmorcanCoogo of Sperts Medina a. 18, 0.3 Pinta USA. The lactate shuttle during exercise and recovery GEORGE A. BROOKS Exercise Physiology Laboratory, Department of Physical Education, University of California, Berkeley, CA 94720 ADSTRACT BROOKS, G. A. The laciate shuttle during exercise and recovery ‘Med, Sci. Sports Exerc, Vol. 18, No. 3, pp, 360-368, 1986, Most (158+) of the lactate formed during sustained, seady-rate exercise is removed by otidation during exercie, and only a minor fraction (~20%) is converted to glucose, Significant lactate extraction occurs, during net lactate release from active skeletal muscle; the total lactate extraction approximates half the net chemical release. Othe lactate which appears in blood, most ofthis wil be removed and combusted by oxidative (musck) fibers in the active bed and the heart. The “shuttling” of exidizable substrate inthe form of lactate from areas, ofhigh lycogenolytie ate o areas of high cellular respiration through the interstitium and vasculature appears to represent an important means by which substrate is distributed, metabolic “waste” is re moved, and the functions of various tissues are coordinated during, During recovery from sustained exhausting exercise, most of the lactate accumulated during exercise will continue to be removed by direct oxidation, However, as the muscle respiratory rate detines in recovery, lactate becomes the prefered substrate for hepatic gluco- neogenesis. Practically all of the newiy formed liver glucose ill be released into the circulation to serve as a precursor for cardiae and skeletal muscle glycogen repletion. Liver glycogen depots will not be resiored, and muscle glycogen will not be completely restored until, refeeding. Thisis because the diversion of lactate carbon to oxidation during exercise and recovery represen an irreversible loss of ghuco~ neogenic precursor and because the processes of protein proteolysis, and gluconeogenesis from amino acids are insufficient to achieve complet glycogen restitution after exkausting exercise. An exception, is cardiac muscle glycogen, which preferentially receives glucose during recovery and supercompensates its glycogen reserves despite fasting in recovery. , ‘The “Lactale Shuttle” during exercise and recovery is reviewed ‘within the context ofthe new “Glucose to Liver Glycogen Pathway.’ GLUCONEOGENESIS, GLYCOLYSIS, LIVER GLYCOGEN, MUSCLE GLYCOGEN, EXERTION, PROTEOLYSIS, CARBOHYDRATE METABOLISM. By means of the emerging hypotheses of a new “Lac- tate Shuttle” (6) and a new “Glucose to Liver Glycogen Pathway” (“Glucose Paradox” (37)], our views of the interrelationships among hepatic glycogen synthesis, muscle glycogenolysis and glycolysis, and hepatic glu- coneogenesis are changing dramatically. The distribu- tion of dietary substrates and their mobilization, utili- zation, and recycling during times of physiological Sibaied or pabltion Aven, 985 ‘ceed for pulesion Otc, 198, 360 stress may be explainable by one integrated and rela- tively simple model. It may be that the phenomena which have been described separately as the glucose paradox, the Cori Cycle, the ghucose-alanine cycle, and the lactate shuttle represent different aspects of the same integrated control system. The classic concept of lactate metabolism during exercise suggests that a deficit in O, uptake and delivery results in muscle anaerobiosis. In turn this stimulates muscle glycogenolysis and glycolysis and the produc- tion of lactic acid (29). However, this view is changing rapidly because of the findings of tracer kinetic experi- ments (8, II, 13, 16-19, 22, 23, 34, 35, 53). Lactate production is an ongoing process which takes place in the resting individual (38, 41, 50); moreover, during exercise lactate production is highly correlated to met- abolic rate (11, 13, 17, 35). Moreover, not only is lactate production the inevitable result of muscle glycogeno- lysis and glycolysis but lactate production during exer- cise appears 10 serve at least two purposes (6): the maintenance of blood glucose through gluconeogenesis, and, mOre importantly, the shuttling of oxidizable sub- strate, in the form of lactate, from areas of glycogeno- lysis (production) to areas of high cellular respiration (removal). The generally accepted view of postprandial glucose metabolism is that glucose from dietary carbohydrate is taken up by the liver from the portal circulation, stored fora while as hepatic glycogen, and then released, depending on need, into the systemic circulation (9). ‘This view is undergoing revision. Rather, during refeed- ing after fasting, a substantial amount of dietary glucose appears to bypass the liver, circulate to the skeletal muscle, and be converted to C-3 compounds (mainly lactate), which then recirculate to the liver and undergo slycogenesis (37). Given the emerging concept of mus- cle as playing a profoundly important role in the car- bohydrate metabolism of resting individuals, and given the tremendous metabolic adjustments in muscle re- sulting from exercise, the study of glycolytic carbon flow before, during, and immediately after exercise LACTATE SHUTTLE DURING EXERCISE AND RECOVERY represents a powerful tool to understand metabolic regulation. In the following narrative the studies leading to a revision in the glucose to liver glycogen pathway will be described. Subsequently, the effects of exercise on this pathway will be described. The remarks to follow should be prefaced with the acknowledgment that the ideas and experimental work described result from the contributions of several indi- viduals, In particular Casey Donovan, Glenn Gaesser, Bob Mazzeo, and Bill Stanley have played central roles in the University of California at Berkeley Exercise Physiology Laboratory. Additionally, recent collabora- tive efforts with Ed Gertz and colleagues at the Univer- sity of California at San Francisco Cardiovascular Re- search Institute and the Department of Cardiology, at the San Francisco Veterans Administration Hospital are acknowledged. Besides the experimental reports from several groups which are referenced, recent papers by Brooks (6), Katz and McGarry (37), and Foster (21) should be consulted, as the following introductory comments represent syn- ‘opses of these perspectives. THE GLUCOSE TO LIVER GLYCOGEN PATHWAY IN RESTING, REFED RATS ‘Much of our current thinking on the glucose paradox results from research performed by McGarry and as- sociates. With an experiment on rats in vivo, Boyd et al, (4) showed that refeeding fasted rats significantly raised plasma glucose and lactate levels as well as re- sulted in a significant deposition of liver glycogen. However, when hepatocytes isolated from fasted rats were studied in vitro, even very high (20 m Mf) concen- trations of exogenous glucose did not stimulate glyco- gen deposition. On the other hand, fructose, or lactate plus pyruvate and glutamine resulted in significant glycogen deposition. In subsequent experiments on rats in vivo, Newgard et al, (45) observed that intravenously infused lactate was a more potent stimulator of hepatic glycogen dep- sition than as orally administered glucose. These re- sults supported but could not be taken as proof of the hypothesis that glucose is converted to lactate and that lactate then is the precursor to glycogen. In the same paper, Newgard et al. (45) reported results of experiments in which rats were given [3/H}-glucose and [U-'‘C]glucose intragastrically. The investigators then compared the specific activities of hepatic glycogen and blood glucose. If glucose was converted to glycogen directly, then the specific activi- ties of the precursor and product should have been the same. If, on the other hand, glucose traversed the glycolytic pathway prior to synthesis into glycogen, then the “H-label would be lost. Additionally, the “C-label 361 would be diluted due to trichloroacetic acid cycle car- bon crossover and dilution of tracer glucose by unla- beled carbon during gluconeogenesis, Results of Newgard et al, indicate that the tracer specific activities of newly synthesized glycogen were only 12% (for 5H) and 33% (for '*C) of those of blood glucose. Therefore, only a smiill fraction of the glycogen carbon could have been directly derived from glucose. Very recently, Katz and McGarry (37) have reported additional results obtained using tracer techniques to support the view that glucose passes through the pe- ripheral lactate pool prior to synthesis into glycogen in the liver. In these experiments, either [1-'C]glucose or [6-"Clglucose was infused continuously into the sys- temiccirculation of rats. After several hours of infusion, analysis of liver glycogen revealed 27% of the label at the opposite end of the glucosyl subunits in hepatic glycogen. This randomization of label in hepatic gly- cogen, when at the same time randomization is only approximately 10% in circulating glucose, strongly sup- ports the conclusion that glucose is cleaved to a C-3 compound and passes through a pool (e.g., oxaloacetic acid) which dilutes the specific activity prior to incor- poration into liver glycogen. These results also indicate that little liver glycogen is formed by the direct pathway (ie, portal glucose — liver G-6-P — G-1-P > UDP-G. — glycogen), Rather, the indirect, paradoxical pathway [glucose —> peripheral (muscle) lactate —> hepatic gly- cogen] was operative. A systemic view of the “New Glucose to Liver Gly- cogen Pathway” is presented in Figure 1. In an earlier report by McGarry and associates (42- 45), the hormonal regulation of liver function was studied. Results indicate that anabolic liver functions (cg. fatty acid synthesis) are directly related to the levels of malonyl-coenzyme A (CoA). When isolated hepatocytes from fasted rats were incubated with lactate plus pyruvate, glutamine, and glucose, large effects were observed on ‘the stimulation of lipogenesis and the diminution of fatty acid oxidation. In contrast, glucose alone or glutamine alone had no effect on malonyl- CoA level or the rate of lipogenesis. Moreover, insulin plus glucose had no effect on lipogenesis. In contrast, glucagon had the effect of depressing malonyl-CoA levels and the rates of anabolic processes. The catabolic effects of glucagon, however, were blocked by insulin, On the basis of these results McGarry and associates suggested that insulin is not required for the stimulation of glycogen or fatty acid synthesis by hepatocytes in vitro (45). Rather, it was concluded that the role of insulin is to antagonize the catabolic effects of glucagon. In this way, the insulin/glucagon ratio determines the balance of anabolic and catabolic processes in liver. So far as the substrate effects were concerned, it appears that glucose or glucose plus insulin is insuffi- cient to stimulate the synthetic processesafter refeeding. 362 VENA CAVA — Laeuee 4 GG: Pee SKELETAL MUSCLE igure |—Scheniaic representation of the proposed new “Glucose to Hepatic Glycogen Pathway” as it operates after breaking a fast, Glucose from dietary carbohydrate enters the portal circulation but largely bypasses the liver. Rather, glucase reaches the peripheral musculature, where it is metbolized via diverse pathways, These include glycogen synthesis, glycolysis, and oxidation. According to the MeGarry and associates(37, 44-46) much of the glucose undergo- ing glycolysis in muscle is converted to lactate and other 3-C com- pounds, These are released from muscle and recireulate to the liver to provide gluconeogenic and slyeogenie precursors. By comparison, fructose or a collection of gluconeo- genic precursors (lactate, pyruvate, glutamine) stimu- lates the process (46). In the presence of the gluconeo- genic substances, glucose stimulates hepatocyte glyco- gen and fatty acid synthesis. Thus, glucose appears to serve a catalytic role. In a subsequent paper, Katz and McGarry (37) explained the fructose effect by the action of fructokinase, which in the liver catalyzes the conver- sion of fructose to fructose I-P, which subsequently is split into the gluconeogenic precursors dihydroxyace- tone phosphate and glyceraldehyde, THE GLUCOSE TO GLYCOGEN PATHWAY IN RATS RECOVERING FROM EXERCISE Several reports on glycogen restitution following ex- hausting exercise support the hypothesis that the indi- rect glycose to glycogen pathway operates during recov- ery from exercise. In rals following prolonged exercise and a sprint to exhaustion, Brooks et al. (7) observed glycogen depletion and lactacidema. However, during, recovery lactate wasremoved (Fig, 2), but little glycogen was repleted in muscle, and none was restored in liver because animals were not refed (Fig. 3). Interestingly, MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LACTATE CONCENTRATIONS. BEFORE ANO AFTER EXERCISE 6 G 8 MMOLES/q WET WEIGHT wo REST RECOVERY MINUTES Figure 2—Tissue lactate concentrations (mean + SE) as a function of time after prolonged exercise and a sprint to exhaustion in fasted rats (closed symbols). The dotted line is to visually connect pre-and ise values. Open symbols at rest and recovery are non- exercised controls and 36-h fasted, nonexercised controls respectively; N = 6 or more aninals at each point. Reprinted from Ref. 7 with permission of the American Physiological Sneiety. (24 HRD GLYCOGEN CONCENTRATIONS BEFORE AND APTER EXERCISE. Fo 5650 F578 709} g 8 600} $ “{ mq/I00g WET WEIGHT t 1 { i ' { 1 t 1 1 i uver " W wuscue = a 60440 nest RECOVERY MINUTES (24 HRD ure 3—Liver and muscle glycogen concentrations (mean + SE) 36 4 function of time after prolonged exercise folloned by a sprint to exhaustion, Same rats and symbols as in Figure 2. The severe lactacidemia from exercise (Fig. 2) is removed without significant liver glycogen restitution and only minor muscle glycogen resttut Reprinted from Ref. 7 with permbsion of the American Physiolog Society. 200} LACTATE SHUTTLE DURING EXERCISE AND RECOVERY during recovery from the severe exercise, blood glucose was restored close to control level while blood lactate was cleared (Fig. 4). The primary fate of injected [*C]lactate was oxidation (7). In subsequent experiments on rats exhausted by either prolonged continuous or intermittent exercise, Brooks and Gaesser (10) and Gaesser and Brooks (25) again observed very slow rates of liver glycogen resti- tution until animals were refed. The very slow (insig- nificant) hepatic glycogen repletion occurred despite the fact that blood glucose was significantly increased toward pre-exercise levels during recovery and despite the fact that significant (though incomplete) muscle glycogen restitution occurred. Amazingly, within 4 h after exhausting exercise, cardiac glycogen was repleted to levels significantly greater than pre-exercise values without refeeding. Again, the predominant fate of in- jected ['*C]lactate was oxidation, with only a minor proportion (<20%) reconverted to glycogen (Fig. 5). In the experiments of Brooks and Gaesser (10, 25) two lines of evidence suggest that the source of restored carbohydrates was gluconeogenic even though the liver repleted little glycogen, First, the mass of the post- exercise lactate pool was less than 5% of the muscle (skeletal plus cardiac) glycogen repleted. Second, ['Clglucose injected at the point of fatigue resulted in the formation of much higher specific activity muscle glycogen than did injection of [‘C}lactate. In this case, the lactate tracer was probably diluted by the entry of carbon from C-3 and C-4 amino acid derivatives into the glucogeogenic stream so the specific activity of the resulting glucose was greatly depressed in comparison sob | To 10 20 35 4080 ~60_laa0 Rest RECOVERY (MINUTES) (24 HOUR, Figure 4—Blood glucose concentration before and after prolonged ‘exerciseand a sprit to exhaustion by rats, Same symbols asin Figure 2. Lactate (Fig, 2) is removed and blood glucose is returned toward control levels during the immediate post-exercise period. There is, however, insignificant glycogen restitution (Fig. 3). Reprinted from Ref.7 wich permission of the American Physiological Society. 363 FATE OF LACTATE. AFTER EXHAUSTING EXERCISE Oridotion (1Lactote + 30, —* 300, + 34,0) 55-70% Figure 5—Endpoints of lactate metabolism following prolonged ex- ercise to exhaustion in rats. Data represent 4h postexercise per~ ‘centage of recoveries of C injected as [U-'Cllactate at the time of ‘exhaustion. Data from Ref. 10; figure reprinted from Ref. 24 with permission of the American College of Sports Medicine. to that of the presursor (lactate) pool. Therefore, it appears that the precursor to hepatic gluconeogenesis can vary depending on substrate availability in vivo. After exercise, lactate will be favored (in comparison to other compounds) as a glycogenic precursor in liver, but the mass of lactate, though elevated, is insufficient to restore glycogen to “normal” pre-exercise levels. This is because most of the lactate carbon is disposed of as CO; during both exercise and recovery. For this reason, other gluconeogenic and glycogenic precursors must be utilized after exhausting exercise. Aspects of the results of Brooks et al. (10) were corroborated by Fell et al. (20), who exercised rats to exhaustion and studied liver and muscle glycogen res- titution. Subsequently, the same group (53) attempted ‘to demonstrate that glycerol was the precursor for gly- cogen restitution after exhausting exercise. Those re- sults were unsuccessful and indicate that glycerol is not an effective glucogeogenic or glycogenic precursor. We conclude that after exhaustion rat amino acids provide most of the substrate for gluconeogenesis and alycogenesis in fasted animals during recovery. LIVER GLYCOGEN IN HUMANS DURING REST AND RECOVERY ‘Though sparse, the data available on humans are supportive of the more extensive results on animals. 364 Radziuk (49) calculated that % of the hepatic glycogen, synthesized in fasted subjects given an oral glucose load was of gluconeogenic origin. Additionally, Nilsson and Hultman (47) demonstrated that humans deposit more than twice as much liver glycogen when given fructose as compared to glucose. This result was obtained despite the result that glucose infusion raised blood glucose to approximately three times the level of fructose infusion, (310 vs 110 mg.

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