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BIOC2201 / SPSC2201 Lectures 2010: Dr. J.A. Illingworth

Hormonal regulation during exercise

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The Biochemical Basis of Sports Performance (Maughan & Gleeson)

– Anabolic hormones (page 45)
– Steroid hormones (page 61)
– Energy metabolism (page 137)
– Immune function (page 212)

Human Physiology (Lauralee Sherwood) 7th edn. 2010

– An excellent general physiology text with an emphasis on sport. Good chapters on immunology and endocrinology, but specific details are scattered throughout the book. More information than you need.

exercise intensity & duration

Exercise intensity and duration are very important both for the choice of fuel and the effects on the muscles.

High level endurance training damages muscles, causing inflammation, but also has an immunosuppressive effect which increases the risk of infection.

Over-training damages the hypothalamus–pituitary–testis axis, leading to reduced testosterone, LH and FSH levels, lower sperm counts and a decline in reproductive function. High-intensity training has adverse effects on the female reproductive system, may cause secondary amenorrhea.

Deleterious effects are less at lower training intensities. Moderate exercise has generally beneficial effects.

alternative energy stores

Fat is a much more compact source of energy than either carbohydrates or proteins. Dietary carbohydrates can be easily converted into fats, and most of our food is processed in this way. The reverse process is not possible for animals, and only the 6% glycerol content in fat can be used to make glucose. Any shortfall can be supplied from proteins, but only at the cost of muscle mass. Animals must conserve their limited carbohydrate stores.

Liver glycogen is used to buffer blood glucose. Glycogen is broken down when blood glucose is too low, or synthesised when blood glucose is too high. Muscle glycogen can also be used to store surplus carbohydrate (when insulin is present - see below) but muscle glycogen cannot contribute to the blood glucose pool because there is no export route for glucose from the interior of muscle cells.

It is important to remember the biochemical as well as the physiological specialisation between tissues. During vigorous exercise type IIx muscle may be metabolising glucose anaerobically to lactic acid, while the liver is carrying out the reverse reactions of gluconeogenesis, converting lactate from the muscles back into blood glucose. The overall process is known as the Cori cycle, after the husband and wife team who discovered it in the 1920s. Other non-carbohydrate precursor molecules, such as glycerol and amino acids may also be used by the liver to maintain blood glucose supplies.

The Krebs cycle serves as a clearing house between the different branches of metabolism, as well as providing the bulk of the cellular ATP.

energy stores for a 70kg male

5mM blood glucose is only sufficient for a few minutes normal activity, 12MJ is enough for a marathon

choice of fuels

Fat is a much more compact source of energy than either carbohydrates or proteins, and on a wet weight basis packs in 10 times as much energy per gram. Nevertheless, fats can ONLY be metabolised aerobically and it seems to be difficult to oxidise fats quickly enough to support the highest rates of physical activity. Animals therefore prefer fats to power gentle “routine” physical activity, with a gradual shift towards aerobic oxidation of the more expensive carbohydrates as the work output increases. Anaerobic glycolysis is used at the highest work rates, but these can only be sustained for very short times.

The switch in fuels broadly parallels the increasing recruitment of type IIa and type IIx muscle fibres as the workload increases. Low output postural activity mainly uses the economical, aerobic, type I muscle fibres, which show a strong preference for fats as a source of energy.

hormonal control of metabolism

effects on
hormones and cytokines
insulin glucagon / adrenalin growth hormone cortisol TNF-α
























TNF-α (tumour necrosis factor alpha) is the best known member from a group of pro-inflammatory cytokines which also includes interleukin-1 (IL-1) and interleukin-6 (IL-6) which are collectively responsible for the fever and inflammation associated with infections and serious disease.


Insulin is a peptide hormone secreted by the beta cells in the Islets of Langerhans, primarily in response to raised arterial blood glucose, although there are many other secretagogues, incretins and modulators.

Insulin binds to a plasmalemma receptor in most tissues and activates a complex network of protein kinases. It stimulates blood glucose uptake via GLUT4 porters in most tissues except for liver, red blood cells and brain.

Insulin stimulates glycogen, fat and protein synthesis in all target tissues (including liver) and modifies gene expression, but the effects vary between tissues. Exercising muscles can take up glucose from the blood in the absence of insulin.

normal blood glucose regulation

Liver glycogen is the short-term glucose buffer. Long term surplus glucose is converted into fats via lipogenesis. Long term shortages are made good via hepatic gluconeogenesis from non-carbohydrate precursors. Only the liver can perform significant gluconeogenesis, because the required enzymes are missing from most other tissues.

short term
long term


glucose too high
secrete insulin

make glycogen, allow
glucose into most cells

make triglyceride (lipogenesis)


OK - no action
is required

limited amounts of
"futile cycling"

limited amounts of
"futile cycling"


glucose too low
secrete glucagon
adrenalin & cortisol

split glycogen, exclude
glucose from most cells

make glucose (gluconeogenesis)
from muscle proteins and other
non-carbohydrate precursors

Glucose can enter exercising muscle cells whether or not insulin is present.

Liver both takes up and secretes glucose, depending on the circumstances. Internal hepatic glucose concentrations are similar to those in the blood. In contrast to this, most other tissues have a major barrier to glucose entry at the plasmalemma. Glucose is only allowed into these cells during intense metabolic activity, or when the hormone insulin is circulating in the blood. Liver, enterocytes and kidney tubule cells can all export glucose to the blood, but most other tissues cannot do this, so their glycogen reserves are strictly for internal use.

glucose transporters

portermechanismglucose Kmlocationtissuescharacteristics



20 mM


brain, red cells, endothelium, β cells

constitutive porter



42 mM


kidney, ileum, liver, pancreatic β cells

low-affinity porter



10 mM


neurones, placenta (trophoectoderm)

high-affinity porter



2 - 10 mM


skeletal muscle, heart, adipocytes






widely distributed

fructose transport


Na+ dependent

high affinity


small intestine, kidney tubules

high affinity uptake


Na+ dependent

low affinity


kidney proximal tubule

high capacity uptake

glucagon & adrenalin

Glucagon is a peptide hormone produced by the alpha cells in the Islets of Langerhans, mainly in response to low blood glucose. It signals via cyclic AMP. It generally has anti-insulin effects, and promotes glycogenolysis, gluconeogenesis and the mobilisation of stored fat.

Adrenalin is a catecholamine secreted by the adrenal medulla, in response to sympathetic nervous stimulation controlled ultimately by the hypothalamus. Low blood glucose, exercise and fear promote adrenalin release. Its actions are similar to glucagon. It signals via several receptors: α1 (calcium release from internal stores), α2 (less cyclic AMP), β1 and β2 (both more cyclic AMP).

Both glucagon and adrenalin have dramatic effects on cardiac metabolism and cardiac contractilty. Their effects on voluntary skeletal muscle are much smaller. On reflection this should be expected, because skeletal muscles execute detailed programs specified and coordinated by the central nervous system. Large changes in contractile performance would play havoc with this delicate regulation, and would be extremely disadvantageous.


Liver cytosolic PEPCK is an important control point, where non-carbohydrate precursors from the Krebs cycle are committed to the gluconeogenesis pathway. Gene expression is regulated by cyclic AMP, cortisol and IL-6 (see below).

Pyruvate dehydrogenase (PDH) is a mitochondrial matrix enzyme that is also closely regulated, but for different reasons. It is the irreversible step whereby glycolytic intermediates finally leave the carbohydrate domain and enter the world of lipids and acetyl CoA. There is no way back in animals.

regulation of lipolysis

Lipid mobilisation from adipocytes is regulated by a complex network of protein kinases. Adrenalin and glucagon raise cyclic AMP activating protein kinase A, which phosphorylates and activates hormone-sensitive lipase and the lipid droplet protein perilipin. This increases lipolysis.

Insulin activates protein kinase B which then activates phosphodiesterase 3B which lowers cyclic AMP and reduces lipolysis.

Atrial natriuretic peptide (ANP) is released by stretched cardiac atria. It rises about 3-fold during exercise, and activates lipolysis by a completely independent pathway involving cyclic GMP and protein kinase G.

growth hormone

Growth hormone (somatotropin) is a polypeptide secreted by specific cells in the anterior pituitary, in response to chemical signals from the hypothalamus. It causes target tissues to produce “insulin-like growth factors” (IGFs) which mediate most of the effects. Children produce more growth hormone than adults and there is a peak in secretion shortly after falling asleep.

Physical activity stimulates growth hormone production.

Growth hormone stimulates gluconeogenesis, glycogen synthesis, protein synthesis and muscle growth, fuelled by the mobilisation and breakdown of fats. Growth hormone also stimulates bone growth, producing taller children, and (in adults) acromegaly.

growth hormone feedback loops

The negative feedback helps to ensure a pulsatile pattern of hormone release.


There is an optimal amount of muscle tissue: too much is a biological disadvantage. Myostatin is a cytokine produced by muscle which autoregulates the total muscle mass by inhibiting mesenchymal stem cell proliferation and differentiation. Occasionally the myostatin gene is defective, both in animals and humans. Myostatin-null animals have increased bone density and double the normal muscle mass, heterozygotes may show enhanced athletic performance.

Some breeds of beef cattle (e.g. Belgian blues) and racing dogs (whippets) have been selectively bred for defective myostatin regulation.


Cortisol is a steroid hormone produced by the adrenal cortex (this means “rind” not “core”) when stimulated by the polypeptide ACTH from the anterior pituitary. It is produced in response to stressful situations: worry, physical exposure, injury, infection, lack of food… It acts mainly on the nucleus of target cells, and slowly alters the pattern of gene expression, normally taking 24-48 hours for a full effect. There is a pronounced diurnal variation in the basal secretion rate, with an early morning peak.

It maintains blood glucose through gluconeogenesis by promoting muscle protein degradation. It also has powerful osteoporotic and immunosuppressive effects.

corticosteroid feedback loops

The key points here are (1) regulation of cortisol production by pituitary corticotropin (=ACTH), (2) regulation of blood glucose concentration and regulation of the immune system activity are inextricably muddled up together, and (3) the sluggish operation of the various negative feedback loops effectively guarantees a pulsatile pattern of hormone release.

anabolic steroids

Steroid hormones such as testosterone (and, allegedly, its precursor androstenedione) increase muscle mass in response to training against a resistive load. They may also increase aggression and the "will to win".

Testosterone forms part of a negative feedback loop which regulates the secretion of pituitary gonadotropins such as FSH and LH. These peptide hormones from the anterior pituitary are important for normal sexual function in both men and women. One side-effect of anabolic steroid abuse is a marked reduction in FSH and LH, which paradoxically reduces testicular volume and sperm counts.

pro-inflammatory cytokines

A group of cytokines produced by macrophages (and by various lymphocytes, and by many other damaged cells) which attract additional defenders to sites of infection and also indicate the overall level of immune system activity to the hypothalamus. Key members are IL-1, TNF-α and IL-6 (but see later)

Important stimuli are infections, burns, crush injuries, and many other potentially life-threatening conditions.

Important systemic effects include fever and secretion of ACTH (and therefore cortisol, which has an immuno-suppressive action that normally brings the immune system back into overall balance).

Bloated fat cells (adipocytes) also secrete cytokines, leading to persistent low-level inflammation among obese subjects. Such disregulation contributes to many serious, often terminal diseases, including atherosclerosis and hypertension.


This is a Greek word, meaning "poor condition", that describes patients suffering from life-threatening diseases, such as cancer, severe burns, trauma, major surgery, AIDS, tuberculosis, heart failure and the like.

Cachexia is a hypermetabolic state, dominated by the pro-inflammatory cytokines, where all the degradative pathways are operating at high rates. Apparently recognising the futility of long-term planning, the body throws all available resources into the fight. Much medical effort has been expended on preventing or minimising cachexia, especially in surgical patients, but "in the wild" it could be making the best of a bad job.


This hormone was previously considered to be one of the pro-inflammatory cytokines, like IL-1 and TNF-α.

IL-6 is particularly associated with the acute phase response, which is an early, stereotypical activation of the innate immune system, that puts the body on a “war footing” to deal with serious and unexpected threats. IL-6 causes the liver to secrete a number of acute phase proteins such as C-reactive protein (CRP), which are often measured as inflammatory markers.

It is now recognised that the situation is more complex than this, because IL-6 is also secreted by exercising muscles, and seems to play a major role in substrate mobilisation and other beneficial effects. In particular, recent work shows that IL-6 strongly activates PEPCK gene transcription in a dose-dependent manner, and probably contributes to the maintenance of blood glucose during prolonged and vigorous exercise.

pulsatile or steady state?

In the “old days” hormone secretion was often regarded as a pseudo-steady-state response that allowed the body to compensate for an abnormal situation. For example, the higher the blood glucose concentration, the more insulin is needed to bring it under control.

Nowadays this is seen to be an over-simplification because hormone release is often pulsatile, like neuro-transmitters, and there is useful information coded into the pulses. For example, continuously high levels of parathyroid hormone lead to bone dissolution, but the normal pulsatile release leads to increased bone density.

self-assesment test

Select the options from the list of hormones which best fit the descriptions provided below. Each option may be used once, more than once, or not all. This is an extended-matching question (EMQ) with adjustable feedback levels.



1. Marathon running: a muscle product that helps to maintain blood glucose.

2. Mountaineering: a hormone that controls blood glucose after meals.

3. Long jump: a protein hormone that maintains skeletal muscle mass.

4. Rugby football: a steroid hormone that increases skeletal muscle mass.

5. Sports medicine: a polypeptide causing sarcopenia and bone fractures.


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