Draft:Pacing and Homeostasis

Homeostasis and physiological optimal functioning

One of the most important general principles underpinning pacing is that of homeostasis. Homeostasis is defined scientifically as the tendency towards a relatively stable equilibrium between inter-dependent elements. Put simply, homeostasis is the property of a system whereby it attempts to maintain itself in a stable, constant condition, and resist any changes or actions on the system which may change or destabilise this stable state. Any system operating using homeostatic principles has setpoint levels for whatever substance or process is being regulated in the system, and boundary conditions for the substance or process which are rigidly maintained and cannot be exceeded without a response occurring which would attempt to bring the activity or changes to the substance or process back to the pre-determined setpoint levels or within the allowed boundary conditions for them. The reason for having these set boundary conditions are protective, in that if they were exceeded, the expectation would be that the system would be damaged if the substance or process being regulated was used up to quickly or worked too hard, or was allowed to build up to a level or work not enough to produce life-supporting end products, which would endanger the life or continued activity of the system being monitored.

In order for a system to maintain the substance or process within these homeostatic related acceptable limits, three regulatory factors are required to be components of the system, or to act on the system from an external source. The first is the presence of a sensory apparatus that can detect either changes in whatever substance or process being monitored, or changes in the internal environment or others systems which interact with or impact on the substance or process being monitored. The second would be a control structure or process which would be sent the information from the sensory apparatus, and would make a decision regarding whether to respond to the information or to ignore it as not relevant. The third would be an effector mechanism or process which would make the changes to the system decided upon by the control structure.

An example of the action of homeostatic regulation is evident in the regulation of glucose concentrations in the blood. Blood glucose is the essential fuel required to create energy which is used by all the body and brain structures to function normally. Blood glucose concentrations are maintained in a narrow range of between approximately 4 and 6 mmol/L. If blood glucose levels drop too low, a condition defined as hypoglycaemia results, which is potentially fatal, and is associated with a variety of physical symptoms including tiredness, sweating, shaking, muscle weakness and pale skin colour, and mental symptoms including irritability, impaired cognitive function, aggressive behaviour and eventually loss of consciousness and brain death. Paradoxically, if the blood glucose levels become too high, this can also damage the body, and a condition known as hyperglycaemia results. There are not likely to be any short term life-threatening consequences of hyperglycaemia, unless the individual is diabetic, but if the blood sugar concentrations remain above the upper homeostatic set limits for too long, damage to the heart, kidney, nerves and eye can occur that eventually impairs their function.

Therefore, there are relatively fast acting regulatory mechanisms which maintain the concentrations of blood glucose concentrations within these optimal upper and lower levels. The two main organs in the body which directly regulate blood glucose concentrations are the pancreas and liver. The pancreas produces and secretes the two principle hormones which regulate blood glucose concentration, namely insulin and glucagon. Blood glucose receptors in the pancreas continually assess the concentration of glucose in the blood, and if they increase above the acceptable limit described above, control processes in the pancreas stimulate the release of insulin. Insulin is a hormone which is transported from the pancreas to its target sites in the liver, where it stimulates the liver to change blood glucose into glycogen, which is the stored energy version of glucose. Insulin also induces the storage of glycogen in more distant sites such as the peripheral skeletal muscle. This change of blood glucose to glycogen will therefore reduce the concentration of glucose in the blood, until it is within acceptable limits, and when it is so, the concentrations of insulin will therefore fall, as is no longer required. In contrast, if the blood glucose concentration decreases below acceptable levels, the control processes in the pancreas stimulate the release of glucagon. Glucagon has the opposite effect to insulin in the liver, and induces the change of liver glycogen into glucose, which is released into the bloodstream and increases the blood glucose concentrations to acceptable levels. Similar to the integrated response of insulin and glucose, as the blood glucose concentrations rise, the quantity of glucagon released by the pancreas falls, as it is no longer required. The relationship between blood glucose, insulin and glucagon is therefore synergistic (Figure 1), with changes in the concentration of each resulting in changes in the concentration of the other, in a manner which would maintain the values of each within set boundaries, according to homeostatic principles.

The regulation of blood glucose concentration, as described above, would appear to be a tightly controlled self-contained closed system that would operate sufficiently on its own to protect and maintain blood glucose concentrations within the acceptable set limits. However, as with all things in life, the regulation of blood glucose is more complex than the isolated regulatory system described above. First, during emergencies when the integrity of the individual is threatened, as part of a ‘fight or flight’ response, adrenaline is released, mainly from the adrenal gland in the kidney. Adrenaline, or epinephrine as it is also known, apart from increasing heart and breathing rate, also causes the breakdown of liver and muscle glycogen to glucose, which is released into the bloodstream, and would therefore impinge on, and alter, the pancreatic regulated homeostatic system described above. Second, changes in blood glucose concentrations, particularly if the blood glucose concentration is reduced, initiate several long loop and behavioural changes that are designed to return the concentration of blood glucose to its optimal level. Blood glucose sensors, particularly in the hypothalamic region of the brain, become aware of an increase or decrease in blood glucose and, initiate behavioural changes. If the blood glucose concentration goes down, symptoms of hunger are produced, and the individual will look for and ingest food, which ultimately leads to an increase in blood glucose concentration after a period of time. Third, if one ingests either a carbohydrate drink or food, blood glucose concentrations are increased from this exogenous source. Fourth, exercise increases the utilization of blood glucose, and causes an increase in the breakdown of muscle and liver glycogen to glucose. Therefore, a number of factors other than the pancreatic regulatory system affect blood glucose concentration, and make its overall regulation complex and challenging. Indeed, it is almost miraculous that blood glucose concentrations are kept within homeostatically acceptable limits on a continuous basis in healthy individuals.

A further important example of homeostatic control is that of temperature regulation. Physiological systems in most species of animals are particularly sensitive to changes in temperature and operate best in a relatively narrow temperature range, although in some species a wider range of temperatures is tolerated. There are two broad mechanisms used by different organisms to control their internal temperature, namely ectothermic and endothermic regulation. Ectothermic temperature regulators, such as the frog, do not use many internal body processes to maintain temperature in the range which is acceptable for their survival, but rather utilize external, environmental heat sources to regulate their temperature. Therefore if the temperature is colder, they will use the sun to heat themselves up, and if warm, will look for shadier conditions. Ectotherms therefore have energy efficient mechanisms of maintaining temperature homeostasis, but are more susceptible to vagaries in environmental conditions than endoderms. In contrast, endotherms, into which classification humans would fall, use internal body functions to either generate heat in cold environments or reduce heat in warm conditions. In endotherms, if the external environment is too cold, and if this cold environment impacts on body temperature, temperature receptors measuring either surface skin temperature or core body temperature will send afferent signals to the brain, which subsequently initiates a shiver response in the muscles, which increases metabolic rate and provides greater body warmth as a by-product of fuel breakdown and use. If environmental temperature is too warm, or if skin or core temperature is too high, afferent receptors will send afferent signals to different brain areas, which initiates a chain of events involving different efferent neural and humoral outputs which result in increased blood flow to the skin by vasodilatation, which increase blood cooling capacity, and will also increase sweat rate of the skin, thereby producing cooling by water evaporation. All these endotherm associated heating and cooling processes utilize a large amount of energy, so from an energy perspective are not as efficient as that of ectotherms, but they do allow a great independence from environmental fluctuations in temperature. It must be noted that endotherms also use similar behavioural techniques to ectotherms, such as moving into shady or cool environments if excessively hot, but as described above, can tolerate a greater range of environmental temperatures and conditions. Furthermore, humans are capable of further higher level behavioural changes such as putting on or taking off clothes or moving to indoor environments which are more temperature to those outdoors as required.

Similar to the examples described above for blood glucose concentration and temperature regulation, all fuel substrates, organ function and physiological processes in the human body need to be maintained within homeostatic limits in order function effectively, and all use similar negative feedback mechanisms involving receptor sensing, afferent signalling, information processing and decision making in the brain, and efferent outputs that induce physiological or behavioural changes which attenuate whichever system or processes activity is challenged from a homeostatic perspective. Given the number of different physiological processes, body organs and fuel substrates which are required to be maintained within homeostatic limits of activity or quantity all at the same time in a continuous manner, there is a requirement for a hierarchy of homeostatic regulation, with the processes more important for the maintenance of life at a second by second or minute by minute basis being most tightly defended at the expense of those whose homeostatic requirements are necessary over a longer period of time or cycle of change. For example, oxygen is essential to life, and if the oxygen concentration is reduced for more than a few seconds, life-threatening tissue damage may occur, so obviously this would be the most tightly defended variable from a homeostatic perspective, and heart rate, breathing rate and vascular function are all rapidly altered in the presence of changes in oxygen levels, as are behavioural responses which will hasten the attenuation of the changes in oxygen concentration once they are detected.

Glucose would be another variable whose absence for longer than several minutes can also cause life threatening tissue impairment, and therefore it is also defended more tightly than other variables. Indeed, in a closed system experimental environment, where only glucose, insulin and glucagon concentration are observed and no external changes impact on them, the concentrations of gluose are more tightly defended and maintained within relatively small limits of acceptability compared to that of either insulin or glucagon, whose concentrations fluctuate to a far greater degree in order to maintain the concentrations of glucose within these smaller acceptable concentration limits. Therefore in effect, insulin and glucagon are ‘slaves’ to blood glucose, and work to defend blood glucose from fluctuation at their own homeostatic expense, although it appears that these greater fluctuations in insulin and glucagon concentrations are tolerated by the body, while major fluctuations in blood glucose concentrations are not. The level of fluctuation (also described as an oscillation) of a physiological variable or system is called its ‘gain’, and the time taken for the entire system to return to a state of zero fluctuation, although ‘zero’ fluctuation is essentially a theoretical concept as any variable in a living system fluctuates continuously, even if at a very low amplitude, is called the time constant of the gain of the system. Obviously as the different variables of physiological system interact with each other and affect the function of all the other variables in the system, the gain of a particular system or variable is a function and result of all the other variables or systems and how they affect the particular variable being assessed. Interestingly, systems or variables with the lowest gain have high levels of complexity and multiple interactions with other variables and systems, and are in general a sign of a system being in good health, both from an engineering and clinical perspective. In contrast, more simple systems with few variables interacting together generally have the potential for larger system gain and therefore greater capacity for fluctuation, and are usually a sign of a system that is in poor health. These concepts are particularly important in the understanding of the effect of exercise as a potential threat to exercise, and the role of pacing in attenuating this threat, will be examined in detail later in this chapter.

It must be noted that certain metabolic values are more tightly regulated than others. For example, in an isolated compartment experiment examining the interactions between blood glucose, insulin and glucagon concentrations described above, blood glucose concentrations were found to oscillate with significantly lower amplitudes away from its baseline levels compared to the amplitude of oscillations of blood insulin and glucagon concentrations. This would indicate that blood glucose concentrations are more tightly ‘defended’ than those of insulin and glucagon, or possibly the increased amplitude of the oscillations of insulin and glucagon are perceived by whatever sets the regulatory parameter to be acceptable as they are necessary to maintain blood glucose concentration within more narrow homeostatic limits. The reason for this is likely to be that glucose is an essential fuel for creating ATP, which is the basic energetic requirement of all metabolic function, while in contrast the function of insulin and glucagon are to maintain the level of glucose concentrations necessary for survival, and therefore are ‘slaves’ to the more highly ‘prized’ glucose concentration maintenance requirement. Furthermore, as both insulin and glucagon can both regulate blood glucose concentrations, there is a degree of redundancy to their function, and blood glucose concentrations can be maintained, albeit with reduced efficiency, if the function of either insulin or glucagon is individually compromised. Therefore the concentrations of physiological variables which are to a degree redundant are less likely to be tightly regulated from a homeostatic perspective as compared to those such as blood glucose whose function is essential and without which death would occur. As can be imagined, this hierarchy of importance of physiological variable adds another layer of complexity to the requirements of the regulatory algorithm which sets the homeostatic setpoint levels for each physiological variable, whatever this is, though it also may paradoxically reduce the complexity of decision making requirements when multiple changes to different physiological systems occur in response to an external perturbation which impinges on the physiological systems within which the different variable are regulated.

The requirement of system setpoints for maintenance of homeostasis

As described above, the human body is an extremely complex system to manage from a control perspective, because of the huge number of physiological processes continuously active and interacting with each other, all of which requires regulation. Given the large number of different physiological processes active at any one time point, one would expect large variability in the concentrations of metabolites, substrates or activity of physiological processes between different people. One would also expect this potential variability between different people to also fluctuate with time. However, somewhat surprisingly, the actual values and range for any physiological variable, metabolic activity or fuel concentration is very similar in different individuals. For example, the blood glucose concentrations are usually maintained between 4-6 mmol/l in health subjects, and only go out of these limits if the blood glucose regulatory mechanisms are impaired, as in the case of an individual suffering from Diabetes Mellitus. Therefore similar physiological system, metabolic activity and fuel concentration setpoints appear to be present in all individuals. Furthermore, whatever the gain of a physiological system’s activity or body organ’s function, what is crucial to the maintenance of homeostasis in any system is the baseline activity levels for each variable in the system, which become the frame of reference to which the system works towards when attempting to attenuate changes in the gain of the system which occur in response to external perturbations. A register of the setpoint of every variable is therefore an absolute requirement to allow homeostatic responses by regulatory processes in the body to perform their task of returning the system to these baseline levels, and to act as a frame of reference in order for metabolic and physiological calculations to be made by the regulatory processes in order to maintain physiological activity within acceptable limits across a range of activities of different durations and intensities.

How these setpoint registers are set and maintained is currently not well known. Several different mechanisms have been proposed for their regulation and control. A potential mechanism is that the metabolic setpoints are stored in, or are part of a regulatory system of, the central nervous system. The hypothalamus, and in particular the suprachiasmatic nucleus are important areas of the brain where metabolic regulation occurs, and the metabolic stepoint registers may reside in these brain areas, although a number of other brain areas may be involved. In this potential mechanism, information regarding these metabolic setpoints for each peripheral system variable would be used to regulate the corresponding activity levels or concentrations in the related peripheral system using the hypothalamic-pituitary-adrenal or other neural or humoral efferent neural command mechanism. If the levels of activity in the peripheral system changed in response to any external perturbation or change in the status of the internal physiological milieu, afferent information generated by receptors monitoring the peripheral physiological systems would be sent to the central nervous system, and compared to the baseline level of activity for the variable being monitored which is stored in the brain circuitry as part of the setpoint register. If there was a difference between the detected and setpoint levels of activity or concentration, the brain would initiate behavioural, efferent neural command or hormonal changes in order to restore the altered peripheral variable’s activity back to the original setpoint value.

While the concept of metabolic registers being maintained in certain brain regions is an attractive one, and to a degree must be an absolute requirement, given that the brain initiates responses to perturbations of any system away from these metabolic registers, and therefore intuitively it would make sense that the comparator against which the changes are made are close to the sites where changes are effected, there are other potential mechanism which may also be involved with setting and maintaining the setpoint registers. External agents or energy forces, which act equally on all individuals, and which individuals have to constantly act against, may also be involved in maintaining the metabolic setpoint registers. As each individual would need to respond in a similar manner to this external agent, this similar response would set similar internal physiological activity levels in all individuals.

A potential external energy force which could operate in this manner is gravity. Gravity occurs over the entire surface of the earth, and humans are continuously required to work against the effect of gravity on the body. Merely standing upright requires constant force output to resist the force of gravity, and therefore muscle activity and the associated level of metabolic activity required to maintain the muscle actively contracting would also be maintained at a constant level. Experiments performed in conditions of zero gravity show that physiological and metabolic activity is markedly altered by lack of gravitational force, and eventually become dysfunctional. This finding would indicate that just having a setpoint register of baseline metabolic activity in the brain is not enough to maintain control of the different physiological systems adequately, and there is an absolute requirement for individuals to resist external forces, such as gravity described above, or other continuous electromagnetic forces which occur on the earth, such as the coriolus force, in a continuous manner, otherwise the control systems deteriorate.

Another potential external controller of levels of activity in different physiological systems may be ‘zeitgebers’, which are cyclical regulatory factors which create and entrain an individual’s physiological and metabolic activity in an ongoing rhythmic but stable manner. An example of a strong potential zeitgeber is the day to night light cycle created by the earth’s rotation which is generally responsible for setting the alternating sleep and wake period of a human being’s daily existence in repeating 24 hour periods known as the circadian rhythm. It is perhaps obvious that activity levels in all physiological and metabolic systems in the body would be different during wake and sleep cycles, and therefore that the circadian rhythm and associated day and night periods set low frequency oscillatory activity of physiological systems in a repetitive and continuous manner, and may therefore be described as dynamic physiological system controller. Further examples of zeitgebers include daily feeding cycles, such as eating three regular meals per day. These habitual eating patterns similarly induce oscillatory, cyclical changes in physiological systems which absorb, use up or store the ingested food. The scheduled eating habits of individuals would also create anticipatory social and physical activity in order to procure or produce food, and reduction of activity during and after mealtimes, which would also entrain the physiological systems which would need to respond to these changes in levels of physical activity and adjust the activity of the physiological systems in order to allow the particular level of physical activity to occur. These zeitgebers would be an example of external factors which regulate activity in a periodic and continuous manner, and would be potentially responsible for maintaining the homeostatic setpoints in different physiological systems in an indirect but continuous and oscillatory / rhythmical manner. As they would exert similar influences on all individuals, they would set similar metabolic setpoints in all individuals, and as this indeed is the case, with individuals having remarkably similar levels of most physiological and biochemical function, there is a strong possibility that these external ‘forces’ are indeed the ultimate long-term regulator of baseline human physiological and metabolic function, or at least are important components of homeostatic regulation of physiological function.

However physiological system setpoint levels are regulated, it is perhaps obvious to say that the level of activity in any physiological system or body organ, and its absolute maximal and minimal functional capacity, is also dependent on anatomical structures and mechanical or biochemical flux capacity constraints in the body. For example, developing the example described earlier in this chapter of regulatory principles of blood glucose homeostasis, maintenance of specific levels of blood glucose in peripheral skeletal muscle is dependent also the anatomical structure and connections of blood vessels and capillaries between the liver and the peripheral skeletal muscle, as well as the rate of transfer capacity of blood glucose across the cell membrane of the individual muscle fibres, as well as it’s rate of utilization in the different muscle fibre organelles, pathways and processes. Similarly, the quantity of organelles responsible for the utilization of glucose in the peripheral skeletal muscles, such as the number of mitochondria in muscle fibres which are responsible for the oxidation of glucose-derived pyruvate into the energy required for contractile function of the muscle, and the concentration of enzymes in the mitochondria themselves, may also be factors regulating glucose concentration and utilization in the peripheral skeletal muscle, and therefore are also important factors either impacting on, or are components which would be take account of by, homeostatic regulatory processes.

Exercise as a challenge to homeostasis

In the section above, we have described a number of exquisite mechanisms and processes which are active in the body which act to maintain the activity of all physiological systems within homeostatically acceptable limits, which are set around baseline setpoint levels of activity. We have also suggested that any change of activity of any variable in any physiological system away from the baseline levels as a result of a perturbation of the system, initiates a chain of events which are designed to return the variable to the baseline level, which occur according to the regulatory principle of the negative feedback loop. All these homeostatic regulatory processes and setpoint register therefore serve the purpose of ‘defending’ the physiological systems of the human body potential catastrophic failure which would result from the system being active to levels either too high to be sustainable or too low to sustain life. Therefore, any activity that altered the activity of a peripheral physiological variable away from its homeostatic setpoint value would be regarded as a threat to the physiological system’s integrity by the regulatory mechanisms which maintain homeostasis.

From this perspective, initiating and continuing an exercise bout is an anti-homeostatic action, and would be counter-intuitive from a homeostatic perspective. The exercise bout would result in potentially harmful changes in physiological systems, with many metabolic or physiological variables increasing, and fuel stores reducing as the exercise bout continues, to levels further way from their setpoint values compared to their resting state, or even performing activities of daily living. Anyone who has performed exercise will be aware that almost immediately exercise has been initiated, and to an increasing degree as the exercise bout continues, corrective behaviour is induced which is designed to attenuate or halt the performance of the exercise bout and return the physiological activity levels to their baseline setpoint state. These changes would include the conscious symptoms of fatigue which would reduce the desire of the individual to continue exercising, reductions in efferent neural command to the peripheral skeletal muscles to reduce the exercise intensity and thus the metabolic rate, often despite the conscious desire of the athlete to continue exercising, and also changes in the regulatory systems of biochemical pathways in peripheral physiological systems which would attenuate the capacity of the peripheral systems to continue working at a rate which would induce a metabolic induced catastrophe.

Given that performing an exercise bout is anti-homeostatic, there must be a belief of the individual performing the exercise bout that the benefits of performing the exercise bout outweigh the potential negative consequences which could be the result of the threat to homeostasis which the exercise bout may induce. There are documented long term benefits of performing regular exercise, including reducing the morbidity of both acute and chronic diseases, particularly lifestyle-associated disorders such as obesity, high blood pressure and diabetes. Indeed, after a bout of exercise, and to a greater degree with long-term regular exercise activity, resting heart rate is reduced, blood lipid and cholesterol profiles are reduced, and muscle enzymatic and mitochondrial function are altered to a more efficient state. Therefore, with chronic activity it would appear that the physiological setpoint values are altered for the period of perfuming the exercise training in a manner that is potentially beneficial for the individual. Exercise itself often feels ‘good’ both during the exercise bout itself and even more so after the bout is completed, and there are material and social rewards from performing exercise, such an enhanced social and financial status from being physically fit and being successful in athletic competitions, which would serve as stimuli to induce the individual to perform athletic activity.

However, there are also a number of potential negative consequences of performing the exercise bout, which need to be given valence by the individual when intending to initiate an exercise bout or to continue the exercise bout in the presence of symptoms of fatigue and reduced capacity to produce power output as described above. There are a number of documented collapse and deaths of individuals performing exercise, either during or immediately after the exercise bout. High volumes of high intensity or long duration exercise activity have been shown to be harmful to some individuals, with evidence of individuals who train regularly showing increased incidence of permanent muscle damage, acquitted training intolerance or even chronic fatigue syndrome. Furthermore, as many as 70% of runners, for example, at some point in their athletic endeavour developing musculoskeletal injuries, often chronic, which are clearly not beneficial to the individual performing acute or long term exercise activity. It must also be noted that the changes in physiological activity described in the paragraph above that result from performing exercise are not permanent effects, and are maintained only as long as the exercise bouts continue. Once the exercise bouts are halted, and the stimulus for change thereby removed, the metabolic values in the different physiological systems which have been up-regulated or down-regulated by the exercise return fairly quickly to their original setpoint values associated with the original untrained state of the individual. These ‘detraining’ effects occur at a faster rate than the ‘training’ effects, individuating that it is easier to return physiological system values to their untrained values than it is to alter the setpoint values away from the untrained baseline values, and therefore that the trained state is not the ‘normal’ routine human state.

Therefore, there is a ‘competition’ associated with any exercise bout between whatever drives the athlete to perform the exercise bout, and both the awareness of the potential negative consequences of performing the exercise bout and the homeostatic regulatory factors which are designed to reduce any activity which increases the activity of physiological systems away from their baseline levels, and this competition will impact on both the frequency of performing exercise activity and the power output levels chosen to perform a particular exercise bout, which will also likely change during the exercise bout according to how the individual valences the choice between positive and negative consequences of performing the exercise bout at any point in time during the exercise bout (Figure 2). In a nutshell, therefore, how an athlete paces themselves will be both the result of the competition of drives to compete a particular event, for whatever reason, and the homeostatic regulatory mechanisms described above, and pacing is itself a regulatory mechanism which allows homeostasis to be maintained, both concepts which will be examined further in the following chapters.

Summary

In summary therefore, underlying the mechanisms involved in regulating pacing, are a number of principles such as homeostasis and negative feedback, and there is also the requirement for a register of the setpoint values of all metabolic variables which the homeostatic regulatory processes, which are intrinsically associated with pacing as both a mechanism of enabling physiological variables to be maintained with acceptable limits during exercise and as an outcome of the attempts by homeostatic regulatory mechanism to return to perceived ‘safe’ limits’ when pace is reduced. Changes of pace are the mechanism by which homeostatic regulation is enacted during exercise bout, and therefore pacing is both a component of homeostasis and a regulatory factor associated with the maintenance of homeostasis.