J Clin Pathol: first published as 10.1136/jcp.42.11.1121 on 1 November 1989. Downloaded from

J Clin Pathol 1989;42:1121-1 125

Occasional article

Chemistry of running

A C AMES From the Department ofChemical Pathology, Neath General Hospital, Neath, West Glamorgan

Introduction performance to be reached. Intensive training increases the maximal cardiac output and blood The upsurge of interest in the beneficial effects of volume of skeletal muscles, and by conditioning, exercise and participation in endurance events like increases the mitochondrial density, oxidative marathon running, which started in the early 1980's, enzymes, and myoglobin in muscle cells. These adap- has been maintained, and the 22000 competitors who tations combine to raise the maximal total body completed the 1989 London Marathon bear witness to oxygen consumption (V02 max), thus enabling greater the continuing involvement of a mass ofordinary men workloads to be tolerated with a consequent and women. Most who train and compete regularly improvement in endurance.2 undergo adaptive physiological changes, with During aerobic metabolism, intracellular muscle improved physical fitness and benefits to long term and triglyceride with extracellular health. For a few, rigorous exercise is not without its and free fatty acids (FFA) are oxidised to provide copyright. hazards to health. energy. As glycogen stores become depleted during This review briefly and selectively outlines the prolonged exercise the relative contribution from FFA normal physiological responses, together with adverse increases, and this ability to oxidise FFA at any pathological effects and their clinical consequences intensity of exercise is an important adaptation of where appropriate. training. If tissue oxygenation becomes inadequate, anaerobic occurs with the production of General metabolism lactate. During a marathon race, muscle glycogen stores http://jcp.bmj.com/ The ability of a person to become a high performance, become depleted at around 20 miles, fatigue occurs, endurance athlete is inherited and is due primarily to and poorly prepared runners experience a state of the predominance of slow twitch fibres in skeletal exhaustion referred to as "hitting the wall". Whether muscle-unlike sprinters and jumpers who have a this state is experienced depends on the degree of higher proportion of fast twitch fibres. fitness, the intensity of exertion, the degree of hydra- Slow twitch fibres have a low contractile speed, tion and the initial level of muscle glycogen. FFA

producing minimal but highly efficient force with low become the major energy source and performance on September 29, 2021 by guest. Protected fatiguability. This is largely due to their low myosin progressively deteriorates. adenosine triphosphatase content and the poor affin- Many factors may contribute to exhaustion and ity of troponin for calcium. They have more fatigue. The untrained athlete is more likely to suffer capillaries, more mitochondria and greater oxidative from ketosis after exercise, and the increased produc- capacity, more myoglobin and less glycogen than fast tion of pyruvate, acetoacetate, and 3-hydroxy- twitch fibres. Slow fibres, therefore, have a greater butyrate can exert an antilipolytic and hypoglycaemic capacity to produce energy for long periods using effect in high concentrations. The concentration of aerobic metabolism, being less efficient under serum lactate is higher in this group in contrast to the anaerobic conditions.' conditioned athlete who shows a minimal increase. Regular aerobic exercise, which involves a proges- This is probably due to enhanced metabolism of sive increase in cardiorespiratory and muscle activity, lactate, either by muscle oxidation or hepatic gluco- induces physiological changes which enable peak neogenesis.3 Hypoglycaemia can occur in endurance events lasting more than four hours and the untrained Accepted for publication 7 June 1989 person is more susceptible,4 but its presence does not 1121 J Clin Pathol: first published as 10.1136/jcp.42.11.1121 on 1 November 1989. Downloaded from

1122 Ames necessarily limit endurance if FFA are readily avail- increase in HDL-C through exercise conditioning able. would help to delay the development of ischaemic To prevent or delay collapse from exhaustion the heart disease and premature coronary thrombosis. amount ofstored muscle glycogen can be increased by Although various studies in several species of dietary manipulation before the race. This is referred animals indicate that the development of athero- to as " loading". It involves depletion of sclerosis is reduced by regular exercise, it remains muscle glycogen before the race by a combination of speculative whether it is beneficial in man in the exercise and a diet high in protein and fat, but low in primary prevention of ischaemic heart disease.' carbohydrate for three days. This is followed by a diet Epidemiological studies have failed to provide con- high in complex , forming 80% of the clusive proof that regular aerobic exercise offers total calorie consumption for a similar period before protection from the morbidity and mortality the event. Glycogenesis is stimulated and glycogen in associated with ischaemic heart disease because ofthe the leg muscles can be doubled compared with that difficulty of long term projects in controlling the obtained on a mixed conventional diet. This man- multiple risk factors involved. Nevertheless, there are oeuvre significantly increases the time exercise can be several reports" covering a variety of sports where a maintained, improving endurance, and delaying the reduced incidence of ischaemic heart disease has been onset of fatigue.5 Carbohydrate loading, which in an observed with improved longevity in athletes who average man involves the storage of700 g ofglycogen, regularly participate. Life expectancy may be requires 2 litres ofwater for intracellular storage which increased by up to three years, but to achieve this it has may, incidentally, delay the effects of dehydration. been estimated that a comparable time would have to Caffeine taken as strong coffee before a race, by be dedicated to exercise! This would involve running stimulating lipolysis and release of FFA, has a orjogging 20 miles a week with an energy expenditure glycogen sparing action and contributes to better of 2000 kilocals on a regular basis, indefinitely. endurance. Sudden death and myocardial infarction Lipoproteins, atherosclerosis, and ischaemic heart disease Sudden death during or while recovering from stren-copyright. uous exercise is rare. Participation during the incuba- Investigations to assess the effect of endurance exer- tion period of a viral illness can aggravate and cause cise on serum lipoproteins have shown variable and death from myocarditis. Most reported cases are due inconsistent results. The weight of evidence indicates to cardiac arrhythmias secondary to underlying that serum triglyceride (TGL), total and low density coronary artery disease. Myocardial ischaemia in the lipoprotein cholesterol (LDL-C) are reduced and that face of an increased oxygen demand predisposes to high density lipoprotein cholesterol (HDL-C) is ventricular fibrillation. The only practical screening

increased. Many studies have been inconclusive due to procedure to detect ischaemic heart disease before http://jcp.bmj.com/ the difficulty ofdetermining whether these changes are regular high level exercise is undertaken is electro- directly attributable to exercise, rather than a change cardiography, but the high incidence of abnormal in lifestyle which incorporates healthy eating with a tracings in 10% of well trained but otherwise normal reduced fat intake, reduction in obesity, and abstin- athletes makes interpretation very difficult. ence from tobacco and alcohol.2 Bundle branch block, pseudo-ischaemic T waves, an When compared with sedentary people, endurance increase in ST-segment and postero-inferior ischaemic runners, skiers, and cyclists are able to maintain patterns are not unusual,'0 but the development of significantly lower LDL-C and TGL and higher HDL- coronary thrombosis, which depends on the presence on September 29, 2021 by guest. Protected C serum concentrations. It is also evident that those at ofpre-existing atherosclerosis, is unpredictable. It also risk from premature ischaemic heart disease who have requires the presence of a hypercoagulable state, high TGL, LDL-C and low HDL-C concentrations which may be stimulated by physical stress or exercis- benefit favourably from regular exercise, thereby ing in conditions of extreme heat and humidity. reducing the risk.6 The diagnosis ofmyocardial infarction in a "collap- The mechanisms for the change in serum lipid sed" runner with an abnormal ECG can cause diag- profile remain undetermined. Attention has focused nostic problems. The increased activity in serum on the induction of higher activities of lipolytic "cardiac enzymes" may be difficult to interpret as enzymes such as lipoprotein lipase in muscle and severe exercise results in significant increases of adipose tissue after exercise, but similar changes occur creatine kinase (CK), lactate dehydrogenase, aspar- with weight loss alone, which is also associated with an tate, and alanine aminotransferase activities which are increase in HDL-C. It might be anticipated that a released from ." Increased muscle cell sustained reduction in LDL-C associated with an membrane permeability can be induced by hypoxia, J Clin Pathol: first published as 10.1136/jcp.42.11.1121 on 1 November 1989. Downloaded from

Chemistry ofmarathon running 1123 dehydration, hyperpyrexia, ionic and pH changes. "Heat stroke" which is invariably accompanied by After a marathon, serum total CK activity, which is collapse has a high mortality." It is characterised by a predominantly due to release of the MM isoenzyme rectal temperature greater than 41°C (106°F), from muscle, and its normally undetectable "heart anhidrosis, delirium and coma. In fatal cases his- specific" isoenzyme CK-MB, are increased, becoming topathological findings include myocardial fragmen- maximal 24 hours later. The percentage of CK-MB to tation, subendocardial haemorrhages, acute tubular total CK activity has been observed to vary between necrosis, cerebral oedema with congestion, petechial 1%-18%. Values greater than 6% are usually haemorrhages and generalised parenchymal changes associated with myocardial infarction, but after stren- in the central nervous system, fatty infiltration of the uous exercise the measurement of CK-MB can be liver with hepatocellular degeneration and rhab- misleading."2 Although long regarded as a sensitive domyolysis. and specific indicator of myocardial damage, small Biochemical changes reflect the multisystem amounts of CK-MB have been found in skeletal involvement.'8 Myocardial, skeletal muscle, and liver muscle. A biopsy specimen of thigh muscle from damage result in large increases in the serum activity of trained runners has nearly three times the CK-MB creatine kinase, the aminotransferases, and lactate activity of muscle from untrained people and approa- dehydrogenase. Jaundice may occur a few days after ches the concentration found in heart muscle.'3 Inter- collapse. If acute oliguric renal failure supervenes the pretation of the results of CK enzyme assays in these associated hyperkalaemia may be exacerbated by the circumstances should be made with caution. Myocar- extensive muscle damage which releases potassium, dial scintigraphy with technetium-99 m pyrophos- and hypocalcaemia may be precipitated by calcium phate, a specific diagnostic technique for myocardial becoming sequestered in devitalised muscle. Survival infarction, can be used in difficult cases. into the second week may be accompanied by hyper- calcaemia, consistent with compensatory secondary Heat exhaustion and heat "stroke" hyperparathyroidism.'5 Circulatory shock with poor muscle and liver Hyperthermia is a hazard when exercise is performed perfusion contribute to hyperlactaemia and eventually in hot and humid conditions, especially by unacclimat- to severe lactic acidosis. In fatal heat stroke dissemin- copyright. ised persons.'4 Prolonged exposure to heat from ated intravascular coagulation is common and the radiation and convection with inefficient dissipation generalised tissue destruction may well be secondary combined with heat generated from metabolic activity to the occlusion of the microcirculation. There is also predisposes to heat exhaustion which may culminate evidence that hyperpyrexia can cause thermal cell in "heat stroke". Although heat exhaustion can be due damage. to either dehydration or salt depletion, they may be Training in hot and humid conditions can reduce difficult to distinguish.'5 the risk of developing heat exhaustion. The body

Heat exhaustion due to predominant water deple- adapts by increasing the sweat volume and rate, http://jcp.bmj.com/ tion which follows excessive sweating causes intense enhancing heat loss. Sweat sodium concentration is thirst, fatigue, weakness, incoordination and mental reduced and the plasma volume expands, probably in impairment. The severe dehydration is associated with response to the increased production of antidiuretic hypernatraemia and a hyperosmolar state. If, hormone and aldosterone. Together with an increase however, fluid losses due to sweating are replaced by in stroke volume of the heart, more efficient heat loss adequate water but no salt, heat exhaustion due to salt from the skin can occur and improved oxygen transfer depletion can occur with hyponatraemia. Signs of to muscles and other organs can be better maintained. on September 29, 2021 by guest. Protected dehydration and thirst are usually absent, but fatigue, weakness, headache, giddiness, muscle cramp, diarr- Endocrine effects hoea and vomiting occur with hypotension and tachycardia. In contrast to heat exhaustion due to Endogenous opioid peptides, f,-endorphin, and its water depletion, body temperature usually remains precursor lipotrophin are released from the anterior normal. pituitary in response to exercise, together with met- Profound hyphohosphataemia has been observed in enkephalin originating from the adrenal medulla, runners who have collapsed on completion of severe sympathetic nervous system, and the gut.'9 They are exercise, and is associated with muscle weakness, part of the adaptive changes that contribute to the dyspnoea, confusion, convulsions and coma.'6 This is "runner's high" which is a period of temporary believed to be due to the intracellular shift of phos- euphoria with dulling ofthe senses to pain and fatigue. phate induced by stress and catecholamine release, They also depress gonadotrophin release at the symptoms developing with a serum phosphate concen- hypothalamic level in women in whom regular stren- tration below 03 mmol/l. uous exercise can be associated with menstrual distur- J Clin Pathol: first published as 10.1136/jcp.42.11.1121 on 1 November 1989. Downloaded from

1124 Ames bances in about 20% of female athletes. These include and myoglobinuria, followed by acute oliguric renal delay of the menarche and secondary oligo/amenorr- failure.22 hoea which are a result of anovulation or deficient During exercise there is an activation ofthe coagula- luteal activity, with low activities of progesterone.2 tion mechanism, with a shortened kaolin-activated The situation is reversible by reducing the amount of partial thromboplastin time, increased factor VIII, exercise. and a raised platelet count.23 This is balanced by an Attention has been focused on the similarity be- increased fibrinolytic activity and reduced platelet tween the build and personality of dedicated female aggregation, which may contribute to the preventive runners and women with anorexia nervosa.20 As effect of exercise on ischaemic heart disease, as they reduction in body fat is often accompanied by oligo/ persist at rest after exercise.24 amenorrhoea, and because adipose tissue produces and fixes oestrogen, its reduction may contribute to Effects on the immune system irregular menstrual function. As the amounts of oestrogen produced by fat are small in relation to that There is evidence that moderate exercise in animals of ovarian origin this seems an unlikely explanation, and man actually stimulates the immune system and but it is thought that women require an optimal recreational runners seem to be less susceptible to amount of body fat to preserve menstrual function. respiratory infections. In contrast, high performance Although modest exercise maintains the mineral athletes in a variety ofsports under intense training are density of bone, in some women there is a risk of more susceptible to glandular fever, toxoplasmosis, developing osteoporosis as a consequence of reduced infective hepatitis, viral and other opportunistic infec- quantities ofcirculating oestrogens. tions that may progress to the debilitating post viral fatigue syndrome.25 Haematological effects Exercising to exhaustion temporarily suppresses cell mediated immunity with reduced in vitro response to Regular and prolonged exertion is associated with a T and B cell mitogens, reduction in lymphocyte CD4: variable reduction in haematocrit and haemoglobin CD8 ratio (helper:suppressor cells), reduced natural concentration. This is usually due to an increase in killer cell activity and lymphocyte function. Thesecopyright. plasma volume following enhanced sodium retention effects persist throughout the resting phase and is a physiological "pseudo-anaemia".2' Some immediately after exercise. Humoral immunity is also athletes develop an actual increase in haemoglobin compromised and reductions in serum immuno- mass, which, together with an increase in red cell 2, 3 globins, salivary IgA secretion, and total lymphocyte diphosphoglycerate, might be regarded as a compen- counts have also been observed, effects which become satory mechanism to improve oxygen uptake by the cumulative with regular training. Changes in neutro- tissues. No "shift to the right", however, ofthe oxygen phil function indicate that non-specific immunity is dissociation curve which might be expected has been also depressed. http://jcp.bmj.com/ observed. The benefits to performance from the The physical and psychological stress of competi- compensatory polycythaemia obtained by high tion and repeated exhaustion stimulating release of altitude training and "blood doping" using corticosteroids and catecholamines, which are both autologous blood transfusion indicate that the oxygen immunosuppressive, may contribute to the process of carrying capacity is suboptimal for peak performance. increased susceptibility. On the other hand, interferon anaemia may be caused by occult a and interleukin I both increase during exercise, Pathological enhancing the immune process.26 Further investiga- gastrointestinal bleeding. Minor reductions in serum on September 29, 2021 by guest. Protected iron and ferritin concentrations are found in trained tions are required to determine the optimal amount of runners, but may reflect iron translocation from exercise which is beneficial to a person and the factors storage sites to red cells. It has been suggested that contributing to immune deficiency in professional increases in circulating C-reactive protein and athletes. interleukin- 1, part of the acute phase inflammatory References response following severe exercise, may depress erythropoiesis. I Lamb DR. Physiology ofexercise-responses andadaptations. 2nd ed. London: Macmillan Publishing Co, 1984. In susceptible subjects running on hard surfaces can 2 Anonymous. Medical aspects of exercise. Med Clin North Am cause mechanical destruction of red cells (march 1985;69:1. haemoglobinuria), a rare cause of anaemia, with 3 Johnson RH, Walton JL, Krebs HA, Williamson DH. Metabolic haemolysis, reduced serum haptoglobins, fuels during and after severe exercise in athletes and non athletes. Lancet 1969;ii:452-5. haemoglobinuria and hyperbilirubinaemia. Pro- 4 Felig P, CherifA, Minagawa A, Wahren J. Hypoglycaemia during longed exertion severe enough to cause muscle damage prolonged exercise in normal men. N Engi J Med 1982;306: may provoke rhabdomyolysis with myoglobinaemia 895-900. J Clin Pathol: first published as 10.1136/jcp.42.11.1121 on 1 November 1989. Downloaded from

Chemistry ofmarathon running 1125 5 Bergstr6m J, Hermansen L, Hultman E, Saltin B. Diet, muscle hypophosphataemia in patients collapsing after a "fun run". Br glycogen and physical performance. Acta Physiol Scand Med J 1986;292:447-8. 1967;71:140-50. 17 Whitworth JAG, Wolfman MJ. Fatal heat stroke in a long 6 Bonanno JA, Lies JE. Effects ofphysical training on coronary risk distance runner. Br MedJ 1983;287:948. factors. Am J Cardiol 1974;33:760-4. 18 Nicholson MR, Somerville KW. Heat strokein a "run forfun". Br 7 Anonymous. Marathon runners and ischaemic heart disease. MedJ 1978;1:1525-6. [Editorial.] Lancet 1978;ii:718-9. 19 Howlett TA, Tomlin S, Ngahfoong L, et al. Release of B- 8 Morris JN, Everitt MG, Pollard R, Chave SPW. Vigorous exercise endorphin and met-enkephalin during exercise in normal in leisure time: protection against coronary heart disease. women: response to training. Br Med J 1984;288:1950-2. Lancet 1980;ii:1207-10. 20 Yates A, Leehey K, Shisslak CM. Running-an analogue of 9 Blackburn H, Jacobs DR. Physical activity and the risk of anorexia. N Engl J Med 1983;308:251-5. coronary heart disese. N Engl J Med 1988;319:1217-9. 21 Anonymous. "Anaemia" in athletes. Lancet 1985;1:1490-1. 10 Oliver LR, De Waal A, Retief FJ, et al. Electrocardiographic and 22 Schiff HB, MacSearraigh ETM, Kallmeyer JC. Myoglobinuria, biochemical studies on marathon runners. S Afr Med J rhabdomyolysis and marathon running. Q J Med 1978; 1978;53:783-7. NS47:463-72. 11 Ohman EM, Teo KK, Johnson AH, et al. Abnormal cardiac 23 Mandalaki T, Dessypris A, Louizou C, Panayotopoulou C, enzyme responses after strenuous exercise: alternative diagnos- Dimitriadou C. Marathon Run III: effects on coagulation, tic aids. Br MedJ 1982;285:1523-6. fibrinolysis, platelet aggregation and serum cortisol levels. 12 Stansbie D, Aston JP, Dallimore NS, Williams HMS, Willis L. Thromb Haemostas 1980;43:49-52. Effect ofexercise on plasma pyruvate kinase and creatine kinase 24 Watts EJ, Weir PJ. Coagulation changes in long distance runners. activity. Clin Chim Acta 1983;132:127-32. Br J Haematol 1988;69:142. 13 Apple SF, Rogers MA, Sherman WM, Costill DL, Hagerman FC, 25 Fitzgerald L. Exercise and the immune system. Immunol Ivy JL. Profile ofcreatine kinase isoenzymes in skeletal muscles Todayl988;9:337-9. ofmarathon runners. Clin Chem 1984;30:413-6. 26 Simon HB. The immunology ofexercise. JAMA 1984;252:2735-8. 14 Pugh LGCE, Corbett JL, Johnson RH. Rectal temperatures, weight losses and sweat rates in marathon running. J Appl Physiol 1967;23:347-52. for to: Dr A C Ames, Consultant Chemical 15 Knochel JP. Environmental heat illness: an eclectic review. Arch Requests reprints Int Med 1974;133:841-64. Pathologist, Neath General Hospital, Neath, West Glamor- 16 Dale G, Fleetwood JA, Inkster JS, Sainsbury JRC. Profound gan SA 1I 2LQ, Wales. copyright. http://jcp.bmj.com/ on September 29, 2021 by guest. Protected