Energetics of Muscular Exercise and Cardiorespiratory Responses to Exercise

NIH-2018, OSLO

CARLO CAPELLI, MD

CHAPTER 1

Energetics of muscular exercise

Carlo Capelli, M.D.Norwegian School of Sport SciencesNIH - 2018

PREMISES

Skeletal muscle transforms into mechanical work the chemical energy made available by the hydrolysis of adenosine triphosphate (ATP) during cross bridge cycling.

The muscular concentration of ATP remains constant even during very high intensity exercise. This implies that ATP during exercise must be synthesized at the same speed at which it is hydrolyzed, otherwise the ATP stores will be rapidly depleted.

This chapter describes the metabolic processes responsible for the synthesis of ATP and that provide the energy for muscular contraction. We propose an approach that makes their study possible in vivo in humans. Namely, the total metabolic energy produced by the muscles will be considered equal to the sum of the energies provided by each of the three bioenergetic pathways involved in the synthesis of ATP: the oxidative, the anaerobic lactic and the anaerobic alactic pathways.

The in vivo study of the ATP resynthesis processes aims to quantify the maximum metabolic power and the maximum amount of energy (capacity) obtained by using the energetic metabolic pathways.

SYLLABUS 1

Energetics of muscular exercise

1.1 Energy sources of contraction

The muscle can not transform the heat into work as a thermic engine and it can perform mechanical work during the contraction only by con-

verting into work part of the free energy ( ) released by the ATP hydrolysis reaction to ADP and inorganic phosphate (Pi) (Figure 1):

𝐴𝑇𝑃 + 𝐻2𝑂 → 𝐴𝐷𝑃 + 𝑃i + 𝑓𝑟𝑒𝑒 𝑒𝑛𝑒𝑟𝑔𝑦 1.

In the most favorable conditions, about 40% of the energy released during this reaction (roughly 50 kJ per mole) can be transformed into mechanical work.

Figure 1: Schematic representation of muscular energy. Adenosine triphosphate hydrolysis (ATP) releases free energy (Δ𝐺) that contractile proteins use for contraction. ATP is resynthesized by the indicated metabolic pathways. CO2, carbon dioxide; Cr, creatine; H2O, water; O2, oxygen; PCr, pho-sphocreatine; Pi, inorganic phosphate; W, mechanical work; H, heat produced by the muscle (redesi-gned by di Prampero, 1981).

The concentration of ATP (about 5 mmol per kg of fresh muscle) is suf-ficient only for a limited number of contractions and a prolonged con-tractile activity can be maintained only if the ATP is continuously resynthesized at the same speed with which it is used. Therefore, the

splitting rate of the ATP ( ) must be the same as the rate of resynt-

hesis ( ). The resynthesis of ATP is ensured by the biochemical pro-cesses listed in Table 1.

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These processes, however, intervene more slowly than the impo-sed by the contractile events that determine the energy demands of the muscle.

This delay is filled by the hydrolysis of the muscular phosphocreatine

(PCr) whose splitting rate can keep the pace of the rate of at the beginning of the exercise. PCr cedes its phosphate to ADP, which was formed during the ATP splitting, turning it back into ATP:

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where H+ is the proton, Cr the free creatine and K1 and K2 the velocity constants of the reaction.

This process, known as Lohmann's reaction because it was first described in 1929 by Karl Lohmann (1898-1978), is catalyzed by the enzyme creatine phosphoki-nase (CPK) and it is very effective in maintaining ATP concentration stable du-ring muscle contraction because the activity of CPK in vivo is sufficient to main-

tain Lohmann's reaction near to equilibrium. Therefore, the concentration of ATP changes very little as the stores of PCr are progressively used.

The muscle contains a finite amount of PCr (20-30 mmol of PCr per kg of fresh muscle) and it is therefore able to support ATP resynthesis via this anaerobic alactacid pathway for a limited number of contrac-tions. However, it allows the resynthesis of ATP until the other bioche-mical processes have not reached a speed sufficient to guarantee a

identical to .

During maximal and supra-maximal exercises, however, these processes are not sufficient for the resynthesis of all the ATP necessary to perform work. In these cases, the hydrolysis of PCr continues until PCr concentration reaches a mini-mum value. In these conditions, also the concentration of ATP decreases and it becomes impossible to perform further work.

The concepts illustrated and table 1 indicate that the sources of ATP resynthesis. They include a substances schematically divided into:

• group 1: substances that can be used directly for muscle contrac-tion (anaerobic alactacid pathway);

• group 2: substances that can only be used indirectly, through substances of group 1 (anaerobic lactic acid pathway);

• group 3: substances that, in addition to being used only indi-rectly, need the presence of oxygen (oxidative pathway).

The maximum metabolic power, i.e. the maximal amount of energy produced in the unit of time, decreases from group 1 to group 3, while the capacity, i.e. the maximum amount of energy that can be used, in-creases from group 1 to group 3.

The study of muscular bioenergetics in vivo is easier if we assume that the total metabolic power produced by the muscle is proportional to the sum of the ATP resynthesis rates of the three pathways mentioned before.

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First, we can assumed that total metabolic power ( ) is proportional to

the rate of splitting of ATP ( ), which in turn is equal to its rate of

resynthesis ( ) since the concentration of ATP ([ATP]) remains con-

stant. In turn, is nothing else that the sum of the ATP resynthesis rates of the three pathays:

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where, , and indicate the rates of PCr splitting, the oxygen consumption and the moles of lactate (La-) produced in the muscle in the unit of time, and c and b represent the moles of ATP resynthesized per mole of oxygen consumed and lactate produced.

As we will see in detail, the relative contribution of each energetic pathway to the total resynthesis of ATP depends on the intensity of the exercise and differs in the different phases of exercise.

2. The oxidative processes

Oxidation processes are mostly used in daily activities and they are the only ones that allow us to perform muscular work for prolonged pe-riods of time.

2.1 The steady state

At the beginning of a moderate intensity exercise, the oxygen uptake (

) increases until it reaches, within about 3-4 minutes, a stable le-vel, called steady state ( ), which can be maintained for long pe-riods.

Under these conditions, called aerobic, quantifies the intensity of the exercise since all the ATP used by the muscles is resynthesized through the oxidative pathway and the rate of PCr splitting and the mo-les of La- produced in the unit of time are equal to zero. As a consequen-

ce, the metabolic power can be described as:

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where c, the number of moles of ATP resynthesized per mole of O2 con-sumed, varies between 5.6 and 6.2 depending on the oxidized substra-tes (Table 1).

Since during exercise we mainly oxidize carbohydrates and lipids for the resynthe-sis of ATP and the RQ (ratio between the produced CO2 to the consumed O2) de-pends on their relative utilization rates, one can express c as a function of RQ:

C = 4.15 + 2.05 × QR 5.

This shows that the amount of ATP produced per mole of O2 consumed is about 9% lower when only free fatty acids are oxidized compared to the case where only carbohydrates are used. This entails that, for the same O2 consumption, we will obtain a lower production of moles of ATP in the unit of time, i.e. a lower metabo-lic power.

2.2 Energy substrates during muscular work

The energy substrates used for the oxidative resynthesis of ATP depend on the intensity and duration of the exercise. The main energetic sub-strates of muscle are lipids and carbohydrates.

2.2.1 Lipids

During exercises whose power does not exceed 50% of maximum con-

sumption of oxygen ( ), the oxidation of lipids is the main source of resynthesis of ATP. The energetic contribution of lipids increases

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with the time of exercise, especially in the case of light-to-moderate in-tensity exercises, in parallel with the decrease of the muscular and he-patic glycogen stores.

2.2.2 Carbohydrates

For exercise intensities above 50% of , the carbohydrate oxida-tion rate is a linear function of and the amount of energy coming

form carbohydrate oxidation increases; for intensities close to about 90% of the total energy comes from carbohydrates utilization.

For intensities between 60 and 80% of , the main fate of gluco-se is oxidation. At higher exercise intensities, anaerobic glycolysis - the lactacid anaerobic pathway - becomes progressively more important and it is responsible for the synthesis of progressively higher amounts of ATP.

The stores of carbohydrates available for the ATP resynthesis are much lower than the lipidic ones: they amount to about 2% of the energy that can be obtained from the oxidation of lipids. During low-intensity daily activities, hepatic glycogen (150 g) and plasma glucose (5 g) are predo-minantly used, whereas muscle glycogen (350-400 g) is rarely utilised. In total, the body's carbohydrate reserves amount to about 9-10 MJ.

As exercise intensity increases, muscle glycogen is progressively more

utilized for ATP resynthesis: at an intensity of 45% of , hepatic glucose provides only about 25% of the total metabolic energy; at 70%

of , the percentage decays to about 10%. The stores of muscle glycogen, with the prolongation of the exercise, can run out. In this ca-se, the mobilization of the hepatic glycogen contributes significantly to the production of energy by oxidation, a fact that can lead to the deple-tion of the stores in the liver and to hypoglycemia.

2.2.3 Proteins

Proteins are poorly used for energy-oxidative purposes: their contribu-tion amounts to about 12% of total energy production at rest and decli-nes to about 2-4% during exercise. However, during prolonged exerci-se, and the consequent depletion of muscle and liver glucose stores, this percentage may increase up to about 10%.

2.3 The time of exhaustion

The availability of carbohydrates and lipid substrates for ATP oxidative resynthesis is one of the factors that influence the percentage of maxi-

mum consumption of O2 (% ) that can be maintained at a con-

stant level during exercise. % is a decreasing function of the in-tensity of aerobic exercise and the time during which a constant %

can be maintained is defined as exhaustion time (tlim). tlim is shorter the greater the intensity of the exercise. Once this limit is excee-ded, the subject is forced to decrease the power and the intensity of the

exercise. Both % and tlim are characterized by considerable in-ter-individual variability.

In the course of muscular exercise of high intensity (over 80% of

), there is a progressive decline in muscle glycogen that can de-crease, in 45 min, by 85% compared to pre-exercise values (Figure 2).

tlim coincides with the point at which the depletion of the stores of muscle glycogen is attained. It is therefore possible to demonstrate a linear relationship between tlim and the concentration of muscle glyco-gen at the beginning of exercise (Figure 3). Therefore, tlim can be mani-pulated through nutritional interventions able to increase the stores of muscle glycogen.

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Figure 2 : Average decrease of glycogen content in the quadriceps femoris muscle of ten subjects in during muscular exercise at the cycle ergometer performed at a power equivalent to 80% of the ma-ximum oxygen consumption (redesigned by Hultman, 1992).

Figure 3: Relationship between the concentration of glycogen in the quadriceps muscle before exer-cise and the time of exhaustion during exercise at the cycle ergometer performed at a metabolic power equivalent to 75% of the maximum oxygen consumption. Each subject has been studied on three occasions over ten days: the first time after three days of mixed diet (full triangles), after three days of hypoglucidic diet (empty circles), after three days of hyperglucidic diet (full circles). tlim increases from about one hour to more than two hours when one passes from a glycogen concentra-tion in the quadriceps muscle of 35 mmol per kg of muscle to one of 120-130 mmol per kg of muscle (redesigned by Hultman, 1992).

2.4 Transient phases and oxygen deficiency

The deficit of oxygen (defO2) contracted at the beginning of the exerci-se quantifies the energy obtained from energy pathways other than the oxidative one before reaching .

2.4.1 Exercise onset and transient

At the onset of muscular activity, the ATP splitting rate increases in-stantaneously to a level proportional to the power imposed by the exer-cise. However, following the step increase of power, the muscular O2 uptake increases gradually following a mono-exponential kinetics and attains in about 3-4 min (Figure 4).

Figure 4: Muscle oxygen consumption (V’O2) as a function of time at the start of a square-wave exer-cise. The energy request for the resynthesis of adenosine triphosphate in terms of O2 is indicated by the dotted line. At the beginning of exercise, the contribution from oxidation O2 is lower than the demand: a deficit of O2 is contracted (darker area at the beginning of the year). At the end of exerci-se, it is higher: the O2 debt is paid (darker area after the end of the year). In the steady state phase, the request and contribution of O2 coincide (redesigned by di Prampero, 1981).

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At the beginning of the exercise, the kinetics of the O2 measured from the respira-tory exchanges measured at the lungs is partly distorted by the cardiovascular responses that evolve at the onset of the exercise so that the kinetics of O2 at the lungs is characterized by two phases: an early component, rapid and of low am-plitude, due to the increase of the cardiac output and of the blood flow in the net-work of the pulmonary capillaries, followed, after about 15 seconds from the be-ginning of the exercise, by a mono-exponential, slower phase whose amplitude is proportional to the energy demand. The first phase - mainly of cardiovascular origin - is called cardiodynamic phase; the second, principal or metabolic phase, is considred to describe accurately the kinetics of muscular O2.

Since in the initial phases of the exercise the has not reached the steady state yet, the O2 consumed is not sufficient to ensure the comple-te oxidative resynthesis of all the split ATP. However, since ATP con-centration ([ATP]) remains constant also in this early phase - called transient -, the re-synthesis and splitting rates of ATP must be identi-cal. It follows that the split ATP must be partly re-synthesized via ener-gy pathways other than the oxidative one.

defO2 is defined as the difference between the volume of O2 consumed at steady state and the volume of O2 actually consumed during an iden-tical equal time in the transient. It is therefore a measure in ml or in l of O2 of the metabolic energy that, even in the case of moderate inten-sity exercise, is obtained from energy sources other than the oxidative ones before reaches .

2.4.2 Energy sources of oxygen deficiency

The main energy sources of defO2 are the hydrolysis of phosphocreati-ne (PCr), the transient production of early lactate (eLa-) and, in the ca-se is measured at the pulmonary and not at the muscle level, the depletion of O2 stores of the body (resO2).

At the beginning of exercise, the concentration of the PCr of the active muscles decreases to reach a constant level in about 3-4 min following a kinetic that mirrors that of the . The steady state concentration of

PCr is a linear decreasing function of (Figure 5). The amount of PCr disappeared during the transient is used to re-synthesize part of the ATP split during this phase.

Figure 5: Concentration of highly energetic phosphates in the gastrocnemius dog muscle during steady-state aerobic work (ADP, ATP, PCr). The ATP and the ADP remain unchanged, while the PCr decreases proportionally to the consumption of O2 to the steady state (V’O2ss) (redesigned by di Prampero, 1981).

If the exercise exceeds a given intensity, there may be also a transient production of ATP via the lactic anaerobic pathway with accumulation of La-. At the end of the transient, the blood concentration of La- may be therefore greater than the one present at rest, but it will then remain stable as the exercise continues. The amount of La- accumulated du-ring the transient - early lactate, eLa- – depends on the relative inten-sity of the exercise, on the individual characteristics and on the trai-ning level.

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If defO2 is measured starting from the measurement of the consumption of pulmo-nary O2, i.e. in a site upstream and far away from the place of muscular utiliza-tion of O2, it is necessary to consider a third component. At the beginning of the exercise, also the volume of O2 present in the resO2 - consisting in the O2 bound to the haemoglobyn of the mixed venous blood and the one bound to muscle myoglo-bin -, is used by the oxidative muscular metabolism. Obviously, the decrease in the volume of O2 present in the resO2 at the onset of the exercise does not appear in the measurements carried out at the lung, since this volume of O2 is already pre-sent inside the body: the O2 measured by gas exchanges quantifies only the flow of O2 from the external environment into the body.

It follows that defO2 can be described, in its most general form, as the sum of three terms:

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where VO2PCr, VO2eLa and ∆VO2resO2 are the volumes of O2 corre-sponding to the splitting of PCr, to eLa- and to the decrease of resO2.

During aerobic work, the VO2PCr is a linear increasing function of :

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where τ represents the time constant of the mono-exponential function that describes the increase of at the beginning of the exercise. This equation expresses the linear relationship between the decrease in PCr concentration that occurs during the transient, expressed in O2 equivalents, and the intensity of the exercise expressed as .

The time constant τ in seconds describes in a quantitative manner the speed with which a mono-exponential function of the form y = A · (1 - e- (t / τ)), such as the kinetics of O2 uptake and PCr concentration at the beginning of the exercise, rea-ches, starting from the basal level, the amplitude A at steady state. In practice, τ is the time that the mono-exponential process takes to attain 63% of the final va-lue A. For practical purposes, it is stated that the process reaches the value A in a period equal to 5 time constants.

The contribution of the resO2, in total corresponding to about 0.4 - 0.5 L of O2 at rest, is in proportion greater at low intensities of exercise than at the higher ones.

This is due to the marked non-linearity of the haemoglobyn dissociation curve for O2 and to the position on this curve of the point corresponding to the mixed ve-nous blood at rest: a slight decrease in the partial pressure of O2 of the mixed ve-nous blood, induced by the increased peripheral muscle extraction of O2 is able to cause a large decrease of the concentration of O2 of the mixed venous blood and leads to a substantial reduction of resO2 even during exercise of moderate inten-sity.

The relative contribution of VO2eLa and ∆VO2resO2 depends, for the same exercise intensity, on several factors: training, muscle groups in-volved, posture of the subject during the exercise, filling status of the resO2 before exercise...

2.5 End of the exercise and recovery

At the end of exercise - during recovery -, the diminishes accor-ding a complex decaying function composed by several phases that, in turn, depend on the intensity and duration of the exercise. The volume of O2 taken up during the recovery in excess of the consumption of O2 at rest has been called O2 debt (debO2) or, in more recent times, EPOC (Excess Postexercise Oxygen Consumption).

debO2 quantifies the total volume of O2 consumed during the recovery minus the volume of O2 that would have been consumed in the same period of time by the metabolism at rest. For example, if during 10 minute of recovery the total volume of O2 consumed is 5 L and the consumption of O2 at rest before exercise was 0.2 L · min-1, debO2 will be equal to: 5 - 0.2 L · min · 10 min = 3 L O2. In this case, it is necessary to assume that the resting metabolism during recovery remains identi-cal to the one prevailing before exercise.

2.5.1 Moderate intensity exercise

During the recovery after exercise of moderate intensity, decrea-ses rapidly following a mono-exponential kinetics characterized by a

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time constant of about 20 - 25 s (Figure 4). The excess of O2 consumed in this interval represents the so-called rapid phase of debO2 and it in-cludes VO2RecPCr, the volume of O2 utilised to resynthesize PCr via the oxidative phosphorylation, and ΔVO2resO2, the volume of O2 used to reconstitute resO2:

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2.5.2 High intensity and prolonged exercise

After high intensity exercise with accumulation of La- and of protons (H+), the kinetics of during the recovery is more complex due to the existance of additional slow components of the repayment of de-bO2. Depending on the intensity and duration of the exercise, the slow component may vanish after several hours.

The full explanation of the causes of deb O2 remains elusive and the historical view of the repayment of deb O2 has recently changed. As already specified, there is a general consensus that the rapid component corresponds to PCr resynthesis. For this reason, this part is also called the alactacid debt of O2 or obligatory com-ponent of deb O2.

If the intensity of the exercise increases, we notice an increase in lactate produc-tion, an index of the activation of anaerobic glycolysis. This entails a creation of a greater defO2: the accumulated lactate represents the use of glycogen for energy purposes. The O2 debt resulting from the contraction of this part of defO2 is sub-stantially devoted to oxidize La- via the pyruvate-citric acid pathway during reco-very. The produced ATP is then used for the reconstitution, starting from the lac-tate, of the glycogen used during the exercise. This fraction of the excess of O2 ta-ken up during the recovery is defined as the lactacid O2 debt and it contribution gradually disappears with a half-time of about 15 min.

In more recent times it has been shown that the volume of O2 consumed during recovery after an exercise of moderate intensity, therefore without substantial production of lactate, is larger the longer the time of exercise. The excess of O2 con-sumed during this prolonged recovery phase is not linked to lactate production.

At the end of prolonged muscular exercise, further phenomena intervene as cau-ses of EPOC. There is a general increase in the resting metabolism due to the in-crease in body temperature and cardiac and ventilatory work, to the thermogenic action of some hormones produced during exercise (adrenaline, noradrenaline, thyroid hormone), etc. etc.

2.6 Maximum oxygen consumption and maximum aerobic power

If we exceed a given intensity of exercise, the increase in workload is no longer accompanied by a proportional increase of O2 (Figure 6). The value corresponding to this limit - or plateau - is defined as maximum

oxygen consumption ( ).

Figure 6: Consumption of oxygen (V’O2ss) at steady state as a function of the mechanical power in a healthy and well-trained subject. The maximum consumption of oxygen (V’O2max) is reached at a power of 350 W and is equal to 4.05 l min-1. Above this level, the exercise requires the intervention of anaerobic energy mechanisms (darker area).

it is a measure of the maximum aerobic power ( ) becau-se it is proportional to the number of moles of ATP that the oxidative pathway is able to synthesize at maximal rate:

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is also an indication of the maximum exercise intensity that a subject can tolerate for long periods of time. It is obvious, therefore, that athletes specialized in endurance activities have very high values of max,aer.

The main factor limiting the maximal O2 uptake in normoxic conditions (at sea level) is the maximum transport of O2 (Q’aO2max) by the cardiovascular system to the active muscles. Q’aO2max) is in turn equal to the product of the maximum car-diac output (Q’max) times the O2 concentration of the arterial blood (CaO2).

Usually, we can maintain an exercise intensity corresponding to

for about 7 ± 1 minutes; this time being characterized by a rat-her wide range (3.8 - 8.4 min) that depends mainly on the level of trai-ning and of the individual fitness.

2.6.1 Inter-individual variations and genetic determinants

The maximum aerobic power is characterized by remarkable inter-indi-vidual variations and it is partly genetically determined.

Studies conducted on family and mono-zygotic twins suggest that the hereditary factor justifies about 25% of the phenotypic variability once it has been corrected for age and sex and that the habits of life shared by all the members of the family are even more important factors. Most of the studies carried out on sedentary subjects show that inheritance would contribute marginally to the phenotypic variability of the para-meters related to long-term performance. The response to physical trai-ning, on the other hand, seems to be much more linked to hereditary factors. For example, it was possible to demonstrate that the inter-geno-type variability of the training response is about six times greater than the intra-genotype variability.

Recent advances in genomics have expanded the horizons of the search for correlations between gene markers and phenotypes related to physi-cal performance. Until 2005, 165 autosomal genes were identified, 5 on the X chromosome and 17 mitochondrial genes - of maternal origin – that influence phenotypes clearly associated with physical performan-ce. It has been understood that there are at least 37 loci able to influen-ce endurance performance and, therefore, maximum aerobic power

and the ability to exploit high fractions of for prolonged time. For example, we now know that subjects homozygous for the D / D alle-le of the ACE gene, located on chromosome 17 in position q23 (17q23), appear to be predisposed for resistance competions.

2.6.2 Differences between sexes and age groups.

Maximum aerobic power is different in men and women and depends

on age. Figure 7 shows the average values of in sedentary Cau-casian men and women as a function of age. The difference varies from about 30%, when it is expressed in absolute value (Figure 7a), to about 15% when it is normalized per kg of body weight (Figure 7b). The diffe-rences between the two sexes can not be attributed only to the different percentage of body fat between men and women, since they remain even after normalization by unit of lean body mass (Figure 7 c): they are essentially due to the lower haemoglobyn mass in women.

increases during puberty to reach a maximum around twenty years of age in sedentary subjects.

After its complete maturation, it has been suggested that the maximal O2 uptake decreases by about 10% every 10 years regardless of the state of training and life-style. The analyzes carried out on élite Masters athletes, however, have not clari-fied yet whether in very active subjects the maximal O2 uptake begins to decrease from the second or third decade of age or around 40 - 45 years of age. The decay of maximal O2 uptake is related to central cardiovascular (decrease in maximum heart rate) and peripheral (alterations of mitochondrial function, altered metabo-lic vasodilation of the vascular bed of muscles) factors.

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Figure 7: Maximum consumption of oxygen (V’O2max) as a function of age in sedentary men and women. a, O2max in absolute values. b, V’O2max normalized per unit of body mass. c, V’O2max norma-lized by unit of lean body mass (redesigned by Cerretelli, 2001).

3. Lactacid mechanisms

Lactic acid (HLa) has a dissociation constant (pK) of about 3.8. Thus, at normal muscle and plasma pH (6.4 to 7.4), the ratio of the sum of the lactate (La-) and proton (H+) concentrations to the concentration of HLa is about 1,000 to 1 in muscle and 4,000 to 1 in plasma.

When muscular exercise intensity increases, the concentration of La- in the blood increases compared to that detected at rest (1-1.5 mM). If the

exercise is performed at intensities higher than , the concentra-tion of La- increases continuously and can reach values between 10 and 20 mM, leading to exhaustion of the subject in a few tens of seconds.

Even in the course of muscular exercises performed at lower intensiti-es, however, the concentration of La- can attain values higher than the ones present at rest, but it may remain constant over time or continue to increase, leading the subject to interrupt the exercise within a few minutes.

In the light of what it has just been stated, it is clear that in the study of the lactic mechanisms of production of metabolic energy one has to di-stinguish different situations. In the first, which corresponds to a su-

pra-maximal exercise (intensity higher than ), the resynthesis of ATP via the oxidative pathway is insufficient to satisfy the require-ment of ATP; typical examples are very intense exercise or exercise per-formed by small muscle groups or in conditions where the availability of O2 to the muscles becomes insufficient to support oxidative phospho-rylation (e.g. hypoxia).

In the second situation, corresponding to exercises performed for a few

minutes at intensity lower than , but characterized by the pre-sence of blood La- concentrations higher than the ones prevailing at rest, glycolysis would guarantee the availability of substrates (pyruvate and lactate) for mitochondrial oxidative phosphorylation.

By analyzing these conditions, we will illustrate how we can calculate the maximum metabolic power that the muscles can produce during supramaximal exercise when exploiting anaerobic glycolysis at maxi-mal rate. Secondly, it will be shown how it is possible to perform high intensity sub maximal exercise for prolonged time maintaining at the same time stable blood La- concentrations.

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3.1 Supra-maximal exercise and energetic equivalent of lacta-te

If the metabolic power required by the exercise exceeds that correspon-

ding to , can be described by a modified version of equation 3:

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In this case, the speed of resynthesis of ATP ( ), proportional to ,

can be expressed as the sum of the product times the number of moles of ATP synthesized per mole of O2 consumed (c) plus the pro-

duct between the rate of production of muscle lactate ( ) and the number of moles of ATP synthesized per mole of La- (b).

Equation 10 is difficult to apply if we aim to quantify the amount of energy obtained from the lactic anaerobic pathway, as is the rate of mu-scular production of lactate, an entity that is difficult to determine ea-sily in vivo unless we apply invasive approaches taking samples of mu-scular tissue.

It would be obviously easier to utilize the concentrations of La- de-tected in the venous or capillary blood. In this way, it is possible to de-termine the numerical value of an empirical constant b', valid for the organism in toto, applying the methods and concepts described in Box 1. The value of b' in vivo takes the name of energetic equivalent of lac-tate and would allow us to calculate the amount of energy produced by the glycolytic anaerobic pathway measuring the net increase of La- con-centration in the peripheral blood occurring during the exercise. The energetic equivalent of lactate in vivo has the value of about 3 ml O2 per kg of body weight per mmol of lactate accumulated in one liter of blood. This is tantamount to say that, whenever we have a net increase of 1 mmol of La- in a liter of blood during exercise, we have produced

an amount of metabolic energy equal to 3 ml of O2 per kg of body weight via the lactic anaerobic pathway.

The maximal lactic anaerobic power is about one and a half times the maximal aerobic metabolic power (Table 4); the maximal lactic capa-city is around 35 - 50 ml O2 per kg of body mass in high-level athletes.

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Box 1 - The energy equivalent of lactate in vivo

The knowledge of the energetic equivalent of lactate in vivo allows cal-culating the amount of metabolic energy produced during the exercise by exploiting anaerobic glycolysis by sampling lactate from venous or capillary blood.

Strictly speaking, the only correct way to quantify the amount of energy produced by muscular anaerobic glycolysis during exercise would con-sist in taking, immediately after the effort, a small piece of muscular tissue and measure the concentration of muscular La-. Since we know that, according to the stoichiometry of the anaerobic glycolysis, for each mole of lactate produced 1.5 mole of ATP are obtained via substra-te phosphorylation, we are able to quantify the amount of energy produ-ced by this energetic pathway. This procedure has been applied in seve-ral circumstances for scientific aims and the results allowed us quan-tifying the maximal rate of muscular La- production – 1.4 mmole La- s-1 kg-1 of muscle - and the maximal concentration of muscular La- at the end of supra-maximal exercise – 60-75 mole La- kg-1 of muscle. Of cour-se, this invasive approach cannot routinely applied if we aim to quan-tify the amount of energy produced by exploiting the anaerobic lactic energetic pathway during supramaximal exercise. Therefore we should try to utilize a more convenient and less invasive way to quantify La- production and estimate anyway the energy obtained from the anaero-bic lactacid pathway.

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Equation 10 in the main text illustrates that during supramaximal exer-cise the rate of production of muscular La- is a linear function of meta-bolic power.

Indeed, if the right and left arms of Equation 10 are divided by the num-ber of moles of ATP reconstituted per mole of consumed O2 (c), we ob-tain:

B1

where the left arm of the equation expresses the metabolic energy re-quired by the exercise in terms of O2 uptake. We have underlined that

the total amount of lactate produced by muscle in the unit of time ( ) is difficult to determine; it is however possible to assume that the peak

of lactate concentration measured in the blood ( ) during recovery at the end of the exercise of duration t is somehow proportional to the total amount of La- produced by the muscles. Therefore, Equation B1 becomes:

B2

The term b has been replaced by the empirical constant b', which has a different numerical value since it now represents the amount of ATP that has been resynthesized anaerobically when the lactate production of body is able to increase [La]b of 1 mmol per liter of blood . Concep-tually, therefore, b and b 'maintain a similar meaning. In turn, the rate of lactate accumulation in the peripheral blood is calculated by divi-

ding the accumulated lactate concentration peak in the blood ( ) by the time of exercise, t.

We know the energy demand ( ) of many forms of exercise (running, walking, cycling, swimming, etc.). In track cycling, for examp-

le, the metabolic power necessary to advance ( = in mlO2 s-1 kg-1) can be calculated knowing the speed of progression, the anthropo-metric characteristics of the subject, the frame used and the environ-mental and path conditions etc. etc. by multiplying the so-called ener-gy cost of cycling (Cc, mlO2 m-1 kg-1) times the speed in m min-1). The

ratio ( ), in this case, can be determined under the condition of

knowing the individual and of measuring in the venous blood

the differences between and blood La- concentration prevailing before exercise. Finally, the time t taken to perform the test allows cal-culating the maximum speed of La- accumulation in the peripheral blood.

In order to normalize the data obtained from different subjects who ha-ve covered various distances (in different times), the two arms of Equa-

tion B2 can be divided by the individual (ml O2 s-1 kg-1) and ob-tain:

B3.

Equation B3 shows that, for supramaximal exercises (intensity larger

than ), the relationship between the energy requirement or power and the speed of accumulation of La- can be described by a straight line, whose intercept is equal to one.

In humans, this has been verified in cycling (Figure B1) and in other forms of exercise. The value close to 1 of the y intercept in the figure suggests that the lactate begins to accumulate before the subjects attain

13

. The slope of the line is the amount of energy (in equivalents of O2 per kg of body mass) that is obtained when the concentration of lac-tate in the blood increases by 1 mmol and is therefore defined as an energetic equivalent of the lactate in vivo. In this case it is equal to 3.0 ml O2 mmol-1 per kg of body mass.

This empirical constant has considerable practical importance, as it al-lows determining experimentally the energy expenditure in all those conditions in which, alongside the oxidative contribution, there is a si-gnificant production of La-.

Figure B1.: Energy expenditure per unit of time in track cycling (vertical axis) as a function of the rate of accumulation of blood lactate (horizontal axis) normalized by the individual values of maximum oxygen consumption. The linear regression is equal to: y = 3.0 × x + 0.88. The slope of the line corresponds to the energy equiva-lent of lactate in ml O2 mM-1 kg-1 of body mass.

In the following example, the calculations are used to obtain the overall energy balance of a supramaximal exercise. Let’s ask an athlete (

= 4.2 l O2 min-1 = 70 ml O2 s -1, body mass BM = 75 kg) to run the distance of 1 km at his/her highest possible speed. At the end of the test, completed in a time t of 150 s, a venous blood sampling carried out at the fifth minute of recovery allows measuring a peak of net lacta-

te concentration in the blood ( ) of 15 mM. The total metabolic power expressed by the subject in O2 equivalents in the unit of time (, ml O2 s-1) will be given by:

B4

B5,

where BM is in kg, is mM and b’ is equal to 3.0 ml O2 per mM per kg of BM. In this case, expressed during the test is equal to 130%

of .

The maximum lactacid anaerobic power can be calculated in each indi-vidual by multiplying b’ and the maximum blood lactate accumulation rate measured during supramaximal exercises leading to exhaustion in

about of 40-50 s. Finally, by multiplying net and b’ it is possible to estimate also the maximum amount of energy obtainable by an anae-robic glycolytic pathway, i.e. the maximal lactacid capacity.

------------------------------------------------------------------------------------

14

3.2 Sub-maximal exercise

During an exercise in which the load is gradually increased, the La- con-centration increases, at first not much, then more and more markedly

as the exercise intensity approaches the of the subject. In order to illustrate this concept, it is useful to imagine an experiment during which the cycling workload is increased every 3-5 minutes until exhau-stion. During the last minute of each phase, a blood sample is taken form the subject to determine the concentration of La-. By plotting the concentrations of La- as a function of the corresponding workloads, a graph similar to that shown in Figure 8 is obtained.

Figure 8: Lactate concentration in the peripheral blood as a function of the mechanical power du-ring exercise at the cycle ergometer. The subject cycles for 5 minutes at each load and the lactate is sampled at the end of each phase. Then, the workload is increased by 50 W.

This type of curve led to define anaerobic threshold the exercise inten-sity at which there is an abrupt increase of La- concentration, implying a causal link between the insufficiency of O2 delivery to the muscle and the increase in the concentration of muscular La-. As a matter of fact, the traditional hypothesis, which links the increase in the concentra-tion of La- to the appearance of areas hypo-anoxia in the muscles is not acceptable, so that we now prefer to speak of lactic threshold rather than anaerobic threshold. Strictly speaking, the highest exercise inten-sity corresponding to a concentration of La- higher than one mmol per liter of blood compared to the concentration at rest defines and corre-sponds the so-called lactic threshold.

The conclusion regarding the partial condition of anaerobiosis as the main cause of the aforementioned threshold must be considered criti-cally because the determination of the concentration of La- is not time-independent. In fact, let’s imagine now that we ask the same subject to perform cycling exercises in different days maintaining a constant power for several minutes. From day to day, the power is increased and the concentration of La- is evaluated at regular intervals during the test. It is observed that, for a certain intensity range, the concentration of La-, after a transient increase at the beginning of the exercise, re-mains constant during the entire test. Once a given intensity has been

exceeded, in the case of Figure 9 about 85% of , the concentra-tion of La- continues to increase with time. Even more significant is the observation that the intensity of exercise at which the so-called anaero-bic-lactic threshold was established corresponds, in the case of the con-stant load test, to a situation of constant La- concentration.

15

Figure 9: Blood lactate concentration as a function of time during exercise at the cycle ergometer performed at intensities equivalent to the indicated percentages of maximum oxygen consumption.

The maximum metabolic power still compatible with a long-term stab-le concentration of La- during prolonged exercise has been defined Ma-ximal Lactate Steady State (MLSS) or, sometimes, Onset of Blood Lac-tate Accumulation (OBLA) and it also coincides with the so-called Criti-cal Power (CP). This power level constitutes the upper limit of the "heavy" intensity exercise domain. Below MLSS, we are still able to per-form prolonged muscle exercise in spite of the fact that the blood con-centration of La- is higher than the one at rest. The lower limit of this exercise domain is the metabolic power corresponding to the lactacid threshold. Muscular exercise performed below the lactacid threshold is defined as “moderate intensity” exercise: it is performed under fully aerobic conditions, is characterized by concentrations of La- that devia-te very little from the ones at rest and defines an intensity of exercise that can be maintained for a long time without causing considerable disturbance of the muscular milieu and without leading to fatigue. Me-tabolic powers higher than MLSS correspond to the so-called "very heavy" intensity exercise. In this case, the equilibrium between accu-mulation and disposal rates of La- disappears and La- concentration

increases over time. Secondly, does not stabilize, but continues to

"drift" until it reaches . This happens in parallel with the radical perturbation of the muscular milieu with a progressive accumulation of H+ and a gradual and slow decrease of PCr concentration. All these phe-nomena herald the early onset of fatigue and exhaustion. It is therefore not unexpected that MLSS and CP are well correlated in endurance athletes with competitive performance and time limit.

The determination of lactic threshold, MLSS, CP allows to define, for each individual - patient, healthy subject, athlete - different domains of exercise intensity that can be selected with the necessary expertise in rehabilitation and training protocols.

3.4 Imbalance between production and elimination of lactate

At this point, it is obvious that there is some legitimate doubt about the definition of anaerobic threshold: the concept of threshold implies that, once this limit has been exceeded, anaerobiosis at the muscle le-vel would inevitably induce a continuous increase of blood in the cour-se of a protracted exercise, a hypothesis completely in contrast with the experimental evidence.

Actually, with increasing exercise intensity, both production and lacta-te elimination rates increase (Figure 10).

16

Figure 10: Schematic representation of the relationship between disappearance rate (d) and appea-rance (s) of blood lactate and the subsequent concentration of blood lactate during incremental exer-cise (redesigned by Brooks, 1985).

As long as the two speeds remain the same, it is possible to maintain a stable concentration of La- over time. Once a given intensity of exercise has been attained, which is different from individual to individual and can be influenced by training, the production of La- exceeds disposal and there is a progressive accumulation of La- in the blood. The absolu-te value of the concentration of La- that is established at equilibrium is higher than the one at rest because the glycolytic pathway is more acti-vated. Moreover, a high concentration gradient of La- concentration between muscles and blood-interstitium promotes the functioning of the carriers that transports La- into the cells of organs that dispose it by oxidation.

The increase of La- production during the sub-maximal exercise is due to various causes. First, we have to consider that in the chain of reactions of glycolysis there are three reactions distant from equilibrium: they are reactions that generate uni-directional flow of substrate to products because, being very far form equili-

brium, the direction of the reaction can not be easily reversed by changing the ra-tios between products and substrates. In addition their activity is deeply and effec-tively regulated by allosteric factors. These reactions are those catalyzed by glyco-gen phosphorylases, phosphofructokinase-1 (PFK) and pyruvate kinase (PK). With the increase of exercise intensity, the concentration of ATP slightly decrea-ses and the ones of ADP, Pi, AMP, derived from ADP, and NH4+ slightly increase. These signals are powerful allosteric activators of PFK. In addition, also the in-crease in the cytoplasmic concentration of Ca++ released during the excitation-contraction cycle of the active muscles activates PFK and glycogen phosphoryla-ses. Furthermore, the increase in sympatho-adrenergic activity during exercise leads to an increase in glycogenolysis and a greater availability of glucose 1-pho-sphate.

We must also consider that, as the intensity of exercise increases, the partial pres-sure of O2 may decrease. Within an active muscle the capillary flow is not homo-geneously distributed from the spatial point of view: the blood flow is different in the superficial and deep zones of the muscle and it also depends on the distribu-tion and the relative density of the type I fibers and IIa, as the muscle areas whe-re type I and IIa fibers are most represented are more perfused. This fact leads to an inhomogeneity of the relationship between muscular O2 delivery and O2 con-sumption (Q’aO2/V’O2). The areas characterized by low ratios would become mo-re and more numerous and extended with increasing exercise intensity. In areas characterized by low ratios, the muscle partial pressure of O2 (PmO2) might there-fore decrease markedly. In this case, oxidative phosphorylation would become more dependent on O2 and the ATP / (ADP · Pi) ratio should decrease progressi-vely to ensure an adequate oxidative phosphorylation. One consequence of the increase in ADP and Pi concentrations is the further increase in substrate flow through the glycolytic pathway, since Pi and AMP are two powerful allosteric acti-vators of PFK.

It is also known that at medium-low exercise intensities, the slow-type (S) motor units consisting of type I muscle fibers are mainly recruited; with the increase of the intensity, the rapid fatigue-resistant motor units (FR), consisting of type IIA fibers, and the rapid (FF) fibers formed by type IIx fibers are recruited. Since the tendency to produce lactate increases in the same order as the recruitment of the motor units, also this phenomenon contributes to higher rate of La- prodiction.

The conversion of a glucose molecule to two of pyruvate in the course of glycoly-sis generates two NADH molecules and consumes two NAD+. Since the stores of NAD+ in the cytoplasm are limited, it is essential to reform it in order to allow the

17

continuation of glycolysis. With increasing exercise intensity and the flow of sub-strates through the glycolytic pathway, the NADH/NAD+ ratio and the pyruvate concentration in the cytoplasm increase. At this point, the only way to allow glycolysis to continue is to restore a normal NADH/NAD+ ratio. Normally this condition is achieved by means of the NADH/NAD+ exchange between cytoplasm and mitochondria ensured by the shuttle mechanisms of the malate-aspartate and glycerol-sulfate, which helps to maintain a normal redox state. At these exer-cise intensities, however, the two shuttle mechanisms reach saturation due to the obvious limitations of the Krebs cycle and of oxidative phosphorylation. Then, the only way to replenish the cytoplasmic stores of NAD+ remains the conversion of pyruvate into La- through the reversible reaction at equilibrium catalyzed by the lactic dehydrogenase (LDH):

Pyruvate + NADH ⇄ Lactate + NAD+ 11

Therefore, the acceleration of the flow of substrates through the glycolytic pathway with accumulation of pyruvate and NADH favors the production of La- and NADH.

Because the lactic anaerobic pathway is less efficient than the oxidative one in terms of ATP production (3 moles of La- per glycosidic unit, or 1.5 ATP per La-, Table 1) the muscle fibers in which the production of La- increases due to the ac-centuated activation of the anaerobic glycolysis deplete more quickly their glyco-gen stores.

The La- produced in the muscle fibers is transported in the interstitium by means the facilitated transport system of the monocarboxylic acid transporters (MCT) and then diffuses into the blood. La- is co-transported with an H+ and approxima-tely 80% of the La- produced in muscle is supposed to be carried by this system. The remaining 20% diffuses in the un-dissociated form of lactic acid and in the form La- exchanged by means of Cl-/La- and bicarbonate/La- antiports.

There are at least two MCT isoforms: i) MCT1, correlated with oxidative metabo-lism indices; it plays a major role in La- uptake; ii) MCT4, correlated with glycolytic metabolism indices; it is more important for the release of La-. The La- moved from the place of production to the interstitium is taken up and oxidized by adjacent muscle fibers and in part it is transported by the circulation to other muscle areas and to organs where it is oxidized or, to a lesser extent, used as a substrate for glycogenosynthesis. This mechanism is called lactate shuttle.

Other factors, in addition to the intensity of the exercise, affect the production and disposal rates of La- during exercise. For example, a low blood pH stimulates the uptake of La- from the muscles and inhibits the exit from those muscles characteri-zed by intracellular concentrations of La- greater than the one in the blood-inter-stitium. The composition of the muscle also conditions the relationship between production and disposal speeds. IIa muscle fibers have the lowest threshold for La- re-uptake, followed by types I and IIx. Oxidation is the main faith of La- in type I fibers, whereas incorporation into glycogen is the route mainly used in ty-pe IIa and IIx fibers. Finally, the progressive increase in the activity of the ort-hosympathetic system in parallel with the increase in the intensity of exercise leads to an accentuated vasoconstriction of the splanchnic and hepatic circula-tion, and the liver is a site where oxidation of La- and glycogen synthesis take pla-ce. Also for this reason, the speed of disappearance of La- in the blood decreases as the intensity of the exercise increases.

Resistance training leads to a decrease in the accumulation of La- as a consequen-ce of the phenotypic modification of the muscle and of the increase in the speed of disposal and utilization due to a larger density of MCT membrane transporters. For example, 9 weeks of aerobic resistance training increase MCT1 by 60-90% and MCT4 by 47%. Inactivity, on the contrary, induces a reduction in the expres-sion of MCT.

A prolonged exercise carried out while maintaining a constant concentration of La- in the blood corresponds to a situation of complete aerobiosis. This means that it is possible to quantify the metabolic power expressed during exercise only by measuring the volume of O2 consumed even if the concentration of La- in the blood is higher than the one at rest. More details about the model that justifies this conclusion are presented in the Recommended Readings (di Prampero & Fer-retti, 1999).

4 Alactic acid mechanisms

The anaerobic alactacid pathway is able to provide high metabolic power for very short times.

In the case of very intense, supra-maximal exercises, the metabolic power developed by the muscles can reach values of 200 W per kg of

18

body mass in power athletes during a vertical jump that lasts about 0.25 s. Taking into account that the muscles involved in the exercise correspond to about 25% of the total body mass, we can easily calculate that the muscular metabolic power increases by about eight hundred times compared to the metabolic rate at rest (1 W kg-1):

12

This vey rapid increase of the metabolic rate of the muscles cannot be sustained by the oxidative or lactacid mechanisms, as the powers that they can develop are very far from those expressed in this type of exerci-se and their kinetics of intervention are too slow. Thus, the energy for ATP resynthesis is provided by the hydrolysis of PCr, the only process able to keep the pace of the splitting of ATP even during these extreme conditions. The muscular energy of this type of muscular activity - anaerobic alactic - is described by:

13,

where the maximum resynthesis speed of ATP ( ) and the maxi-

mum splitting rate of PCr ( max) are equal.

The maximum anaerobic alactic power ( ) and its counterparts,

the maximum mechanical power ( ) and the peak mechanical

power ( ), are useful parameters used to evaluate the physiologi-cal characteristics of power athletes and are they are significantly diffe-rent in the various categories of athletes (Table 2). Furthermore, they are different in both sexes because they mainly depend on the muscle mass and they decay with age (Table 3).

Table 4 shows the synoptic data of maximum power and capacity of the three energy mechanisms illustrated in this chapter.

Recommended readings

1. Brooks GA. The Science and translation of lactate shuttle theory. Cell Metab 27(4):757 – 785, 2018.

2. Cerretelli P. Fisiologia dell’esercizio - Sport, ambiente, età, sesso. Roma: SEU, 2001.

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3. di Prampero PE. Energetics of muscular exercise. Rev Physiol Bio-chem Pharmacol 1981; 89: 143-222.

4. di Prampero PE. La locomozione umana su terra, in acqua, in aria. Fatti e teorie. Seconda edizione, Milano: Edi.Ermes, 2015.

5. Di Prampero PE, Ferretti G. The energetics of anaerobic muscle metabolism: a reappraisal of older and recent concepts. Resp Physiol 1999; 118: 103 – 115.

6. Gladden LB. Lactate transport and exchange during exercise. In: Rowell LB, Shepherd JT, eds. Handbook of physiology. Section 12. Exercise: regulation and integration of multiple systems. New York (NY): Oxford University Press, 1996: 614-48.

7. Hultman E, Greenhaf PL. Food stores and energy reserves. In: Shephard RJ, Åstrand PO, eds. Endurance in sport. Oxford: Blackwell Scientific Publication, 1992: 127-35.

8. Tonkonogi M, Sahlin K. Physical exercise and mitochondrial func-tion in human skeletal muscle. Exerc Sport Sci Rev 2002; 30: 129-37.

9. Venables MC, Achten J, Jeukendrup AE. Determinants of fat oxi-dation during exercise in healthy men and women: a cross-sectional study. J Appl Physiol 2005; 98: 160-167.

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CHAPTER 2

Cardiovascular and ventilatory responses to exercise

Carlo Capelli, M.D.Norwegian School of Sport SciencesNIH - 2018

PREMISES

At steady state, the volumes of oxygen and carbon dioxide transported in the unit of time to and from the lungs through the airways (equations 1a, 1b), diffusing through the alveolar-capillary membrane (equations 2a, 2b), transported by the circulatory system (equations 3a, 3b ) and consumed and produced at peripheral level in a given period of time are the same.

During maximal exercise, total O2 uptake and CO2 output of the body can increase twenty-twenty-five times the ones prevailing at rest. This remarkable increase is made possible by a series of adaptations undergone by the respiratory and cardiovascular systems. This chapter describes the adaptations: i) of the ventilation, ii) of the alveolar-capillary diffusion of O2, iii) of the cardiovascular transport of the gases that allow to support the increase of the gas exchanges observed during exercise. Finally, the effects of training and disuse on the main cardiovascular responses to exercise will be schematically illustrated.

SEZIONE 1

Cardiovascular and ventila-tory responses to exercise

1. Convective transport of oxygen in the inspi-red air

The increase of expiratory ventilation - ( , l min-1) during exercise is the product of the increases of the tidal volume (VT, liters) and of the respiratory frequency (FR, breaths per minute):

4

VT can reach values well above 3 l, corresponding to about 65% of the vital capacity. The amplification of VT occurs at the expense of the pro-gressive erosion of the inspiratory and expiratory reserve volumes. FR can increase from 12-15 breaths per minute at rest up to 50-60 per

minute during maximal exercise. This means that can increase by about twenty-five to thirty times the value at rest: in élite athletes, it can easily reach values of 160-180 l min-1 during maximal exercise in respect to the resting value of 7 - 8 l min-1.

The pattern and the amplitude of the ventilatory response depend on the intensity of exercise. For exercises of moderate intensity - up to

about 50% of the maximum consumption of O2 ( ) - is a li-near function of O2 and CO2, i.e. of the metabolic rate - and this increa-se is due to an increase of both VT and FR.

For medium-high intensity exercises, when the VT has already attained

about 60-65% of the vital capacity, the increase of is mainly due to a further increase in FR, since VT has reached a sort of plateau. Higher FR entails greater viscous resistances to the respiratory flow with a rela-tive increase of the mechanical work of respiration.

In the case of high intensity or maximal exercises, increases signifi-cantly and in excess of the metabolic demands. Therefore, a clear hyper-ventilation is established.

22

This concept is better illustrated if we express as:

5

assuming, for simplicity, that and are identical. In turn, the tran-

sformation of equation 5 makes it possible to express as a function of as:

6.

Figure 1 shows as a function of during exercise at sea level. On the same graph, starting from the origin of the axes, the isopletes along which the differences (FIO2 - FEO2) are constant are also reported. The

slope of these functions corresponds to the ratio between and , - the ventilatory equivalent for O2 -, and is the reciprocal of the diffe-rence (FIO2 - FEO2).

For moderate intensities of exercise (low ), the relation between the two variables lies on a line corresponding to a constant value of

(FIO2 - FEO2). The increase of is therefore able to keep FEO2 unchan-ged compared to the value at rest, a clue that the alveolar gas exchan-ges remain efficient. As the metabolic rate increases, the relationship

between and tends to correspond to lower values of (FIO2 - FEO2). For instance, it is possible to observe values of the difference (FIO2 - FEO2) equal to 0.03, in turn corresponding to values of the venti-latory equivalent for O2 larger than 30. This indicates that the ventilato-ry efficacy, i.e. the ability to extract O2 form the inspired air, decreases when the metabolic intensity increases.

Figure 1: Ventilation (V’E) as a function of oxygen consumption (V’O2) during walking. The thinner lines that radiate from the origin indicate values of difference between the inspiratory and expirato-ry fraction of oxygen (FIO2 - FEO2) constants (redesigned by Cerretelli, 2001).

V’E is equal to the sum of the ventilation of the physiological dead space (VDphysiol) and of the alveolar ventilation (V’A). Consequently, in analogy with equation 4, it is possible to express V’O2 as a function of V’A as:

7a

7b

where FAO2 now corresponds to the alveolar fraction of O2. Thus, all the observa-tions made before on the relation among V’E, V’O2 and (FIO2 - FEO2) apply also to V’A, V’O2 and (FIO2 - FAO2).

The ratio VDphysiol/V’E is equal to about 0.35 at rest and it normally decreases du-ring exercise to attain values around 0.18-0.20. Therefore, V’A becomes more effi-cient as the intensity of exercise increases and it constitutes a progressively lar-ger fraction of VT. This contributes to maintaining constant alveolar oxygen (PAO2) and carbon dioxide (PACO2) partial pressures, both proportional to the cor-

23

responding fractions. This preserves the efficient diffusion of the gases through the alveolar-capillary barrier in response to the greater metabolic demands.

1.2. Control of ventilation during exercise

Ventilation in humans seems to be conditioned by different physiologi-cal control mechanisms and more dictated by the need to eliminate CO2 than by the need to keep PAO2 absolutely stable: exercise in hu-mans is essentially a condition characterized by isocapnia in a wide range of exercise intensities.

This behavior is evident if one examines the ventilatory response du-ring incremental exercise in parallel with the gas exchanges, the alveo-lar gas composition, the plasma acid-base state and the blood lactate concentration (Figure 2).

During moderate intensity exercise, the concentration of La- in blood, the pH and the concentration of plasma bicarbonate remain almost identical to the ones prevailing at rest. As already stated, with the in-crease of the metabolic power, an isocapnic response occurs during

which increases in proportion to (and ).

As the exercise intensity increases, the concentration of lactic acid in the blood increases too. Because of its pK, lactic acid is almost comple-tely dissociated into La- and protons (H+) in plasma. The addition of H+ is buffered by the plasma bicarbonate system by means of the reac-tion:

8.

Figure 2

:Breath-by- breath ventilation (V’E), carbon dioxide output (V’CO2), oxygen consumption (V’O2), ventilatory equivalent for O2 (V’E/V’O2) and CO2 (V’E/V’CO2), end-tidal partial pressures of oxygen and carbon dioxide (PETO2, PETCO2); arterial concentrations of lactate ([La-]) and bicarbonate ([HCO3-]); arterial pH during an incremental exercise at the cycle ergometer in which the load increases every minute by 15 W. The lactic threshold (vertical left line) coincides with the increase of [La-] and is generally accompanied by a decrease of [HCO3-] and an increase of V’E/V’O2. The isocapnic buffer term refers to the period in which V’E/V’CO2 and PETCO2 remain constant. At the end of the iso-capnic buffer period, the decrease in PETCO2 reflects the ventilatory compensation of lactic metabo-lic acidosis; at this point also V’E/V’CO2 increases. This instant is defined as respiratory compensa-tion point of (vertical line on the right) (redesigned by Wassermann, 1999).

24

Lactic acid plus sodium bicarbonate gives rise to sodium lactate and carbonic acid (H2CO3). The carbonic acid then dissociates to water and CO2 in a reaction catalyzed by the carbonic anhydrase:

9.

From this moment forward, the respiratory CO2 originates from two sources: one is the metabolism, as CO2 is produced during oxidation of the energetic substrates; the second is the amount of CO2 produced by buffering the H+ added by the increase of lactic acid in the blood.

The excess of CO2 generated by the buffer reaction stimulates the pe-

ripheral chemoreceptors and induces an increase of proportional to

the increase of , but in excess of . The increase in leads

also to the increase of , which becomes even more efficient thanks

to the reduction of the ratio VDphysiol/ . Also for this reason, the ratio

between and remains constant and, as a consequence, also the alveolar (FACO2) and end-tidal (FETCO2)1 CO2 fractions (Figure 2) do not change in compliance with the equation of the alveolar air for CO2:

10

In this case, therefore, increases while the ventilatory equivalent for

CO2 ( / ), FACO2, FETCO2, and the corresponding end-tidal par-tial pressure (PETCO2), do not change compared to the values prevai-ling at lower exercise intensities or at rest.

1FETCO2 is considered to be a reliable estimate of FACO2 in absence of lung diseases

Conversely, the ventilatory equivalent for O2 ( / ) increases in excess of the metabolic demands, so much so that the relationship

between and progressively changes from linear to curvilinear.

It follows that the function vs. tends toward lower values of the differences (FIO2 - FEO2) (Figure 1). This obviously entails an increase of the alveolar (FAO2) and end-tidal (FETO2) fractions of O2 (and, of course, of PETO2). We then move to a hyperventilatory response. This phase of the ventilatory response has been called isocapnic buffering to indicate the buffering of the acidosis occurring during this phase.

As the intensity of the exercise increases, the strict linear proportionali-

ty between and disappears too: increases in excess to the production of CO2 and a clear hyperventilation is established. The sti-

mulus for the further increase of is represented by the progressive addition of H+ derived from the splitting the lactic acid whose presence in the plasma increases in proportion to the intensity of the exercise. The acidotic stimulation of metabolic origin is sensed by the peripheral chemoreceptors with consequent and further reflexed activation of the respiratory centers. Due to the increase in the intensity of the ventilato-

ry stimulus, / now increases and FACO2, FETCO2 and PETCO2 decrease, reflecting the mechanism of ventilatory compensation of the metabolic acidosis caused by addition of H+ to plasma. At the same time, the alveolar (FAO2) and end-tidal (FETO2) fractions of O2 , PETO2

and / undergo a further increase.

The ventilation control mechanisms are therefore able to compensate for the increased production of CO2 and H+ occurring during exercise.

1.3. Phases of ventilatory responses

The evolution over time of the ventilatory response at the onset of exer-cise is divided into various phases determined by central neurogenic processes and reflex mechanisms (chemo- and mechanoreflexes) (Figu-re 3).

25

Figure 3 :The three phases of the ventilatory response to the exercise. Phase I: rapid increase due to the central command and to input from mechano-receptors; Phase II: slower exponential increase; the central action continues in parallel with that of peripheral origin with the addition of the effect of the short-term potentiation; Phase III: mechanical and chemical peripheral inputs contributes to fine-grain adjustments of ventilation. The gray area represents the contribution to the ventilatory response due only to the short-term potentiation and to the peripheral acidotic - caliemic stimuli (From Eldridge FL Central integration of mechanisms in hyperpnea exercise Med Sci Sports Exerc 1994; 26: 319-).

The initial, anticipatory or phase I, increase of , is relatively short, appears before the exercise starts and it is completed within the first

10-20 s of activity. During this phase, increases because of an antici-patory mechanism of central origin – central command - that origina-tes from the cerebral cortex reinforced by stimuli deriving from muscu-lar mechanoreceptors.

After a brief plateu of about 20 seconds, the second phase appears (pha-

se II); it is characterized by a progressive increase of that reaches a steady state whose amplitude is proportional to the intensity of the exercise. In the first moments of this phase, there is a rapid adaptation

of in response both to the persistence of the central cortical com-mand and to reflexes induced by stimuli from articular, tendon and mu-scular mechanoceptors. The continuous activity of the respiratory neu-rons of the encephalic trunk also causes the so-called short-term poten-tiation. Thanks to it, the ventilatory response induced by the persisten-ce of stimuli increases, as the neurons become more sensitive, although

the level of stimulation does not change. Thereafter, undergoes a more gradual increase until it reaches the steady state. Stimuli that act

on the control of in this later stage come from the central and pe-ripheral chemoreceptors able to monitor arterial partial pressures of oxygen and carbon dioxide (PaO2, PaCO2) and pH.

If we perform high intensity exercise, a third response appears (phase

III) characterized by a fine regulation and a possible increase of . In this case, the stimuli for hyperventilation continue to come from the peripheral and central chemoreceptors, but they are also further poten-tiated by chemical stimuli induced by the increase of kaliemia, of the concentration of the plasma catecholamines, of the body temperature and by the intensification of the cortical command in response to the perception of central fatigue.

At the end of the exercise, declines rapidly in response to the prompt shutdown of the central command. Subsequently, the decline is related to the decay of the stimuli coming from the central and periphe-ral chemoreceptors whose activity progressively decreases as a func-tion of the normalization of the PaO2, PaCO2 and pH values during reco-very.

2. Oxygen flow through the alveolar-capillary barrier

At steady state the volumes of gas exchanged through the upper airways (equations 1a-1b) are equal to the volumes that cross by diffu-sion the alveolar-capillary barrier in the same interval (equations 2a-

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2b). The diffusion of O2 across the alveolar-capillary barrier is also faci-litated by the increase in pulmonary diffusion capacity.

In the course of muscular exercise, the lung's diffusion capacity for O2 quadruples, since lung capillaries that were closed at rest are recruited. At the end of a maximal exercise, the diffusion capacity of O2 slightly decreases compared to the one at rest. This seems to be due to the on-set of mild reversible edema at the peribronchial and/or alveolar level.

In subjects characterized by elevated maximal cardiac outputs (Q’max), we can see an evident decrease of the partial pressure of O2 in the arterial blood (PaO2) du-ring maximal exercise and, as a consequence, of the percentage of saturation of the oxyhaemoglobin (% SatHbO2). This phenomenon, defined Exercise-Induced Arterial Hypoxemia or EIAH, is caused by the reduction of the transit time of the blood in the pulmonary capillaries occurring in the presence of high values of Q’max. The transit time, given by the ratio of capillary volume of the lungs (Vc) to Q’, passes from about 0.75 seconds at rest to about 0.25 seconds during maximal exercise since Vc more or less doubles while Q’ can quintuple. Therefore, the blood that flows along the pulmonary capillaries has no longer enough time to reach the equilibrium with the alveolar partial pressure of O2 (PAO2, equal to 100 mm Hg at sea level) and, as a consequence, arterial hypoxemia necessarily occurs. This phenomenon is even more evident in hypoxia because the rate of increase of the partial pressure of O2 in the capillary blood during diffusion is slower and in the case of a pathological decrease in the diffusion capacity for O2.

3. Transport of oxygen and carbon dioxide by the cardiova-scular system

At the steady state, the volumes of gas exchanged through the upper airways and those that pass through the alveolar-capillary barrier must be equal to the volumes transported by the cardiovascular system (equations 3a-3b). The cardiovascular system responds to higher meta-bolic demands by increasing the convective transport of O2 and CO2.

3.1 Cardiac output

Cardiac output ( ), equal to the product of heart rate (HR) and ventri-cular systolic volume (Vs), is roughly a linear function of the intensity

of exercise (Figure 4). can increase by about six to eight times com-pared to the value at rest and it can reach values above 25-35 l min-1 at maximum exercise intensity in athletes who excel in endurance sports.

Figure 4: Cardiac output (Q’) as a function of oxygen consumption (V’O2) at rest and during exercise in various groups of subjects. The values of the maximal oxygen consumption (V’O2max) of the va-rious groups (arrows) are also indicated. The straight lines starting from zero describe functions corresponding to constant values of the artero-venous oxygen difference ((Ca-Cv)O2) constant (re-designed by Cerretelli, 2001).

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3.2 Heart rate

Also HR is a linear function of the intensity of the exercise (Figure 5) and the slope of the relationship between HR and , in each indivi

Figure 5: Heart rate (HR) as a function of oxygen consumption (V’O2) at steady state in different types of exercise. The oxygen pulse lines are also indicated (in ml O2 / beat) (redesigned by Cerretel-li, 2001).

dual, depends on the type of exercise. For example, if an exercise is per

formed with the upper limbs, HR increases, due to a powerful sympat-hetic activation, much more markedly than in an exercise of identical intensity, but performed with the legs (Figure 5).

Maximal heart rate (HRmax) depends on the age of the subject: young subjects can reach higher HRmax values than elderly subjects.

3.3 Ventricular systolic volume

Systolic volume (Vs) at rest is equal about to 60-70 ml and doubles al-

ready for exercise intensity equal to 50-60% of (Figure 6). A residual increase occurs if the exercise intensity further increases.

Figure 6: Ventricular systolic volume (Vs) as a function of oxygen consumption (V’O2). Values are obtained from various sources (redesigned by Cerretelli, 2001).

The most important determinants of the increase of Vs during exercise in humans are the increases of cardiac contractility and of the venous return to the heart. The increase in cardiac contractility is caused by the augmentation of the activity of the orthosympathetic system. Venous return to the heart immediately increa-ses at the beginning of dynamic muscular exercise performed with large muscle groups due to the effect of the muscular and diaphragmatic pumps. This surge of the venous return to the heart leads to an increase of the end-diastolic volume and hence of preload. Thus, in accordance with the Frank-Starling law of the heart, Vs increases immediately; it can practically double. However, it can be ob-served that, in spite of the increase of venous return , the end-diastolic volume

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does not continue to grow and the end-systolic volume even decreases during exercise performed in orthostatic position (Figure 7). This is due to the increase in cardiac contractility that allows us to eject larger and larger Vs preventing the excessive filling of the ventricula. The Frank-Starling mechanism, therefore, can continue to operate even during exercise and the ventricles can respond to the in-crease in preload.

Figure 7 : Ventricular volumes at rest and during muscular exercise of different intensity perfor-med in supine (a) and orthostatic position (b). Note that the end-diastolic volume increases during exercise. In orthostatic position, the systolic volume decreases according to the intensity of the exercise. R, rest; 1, exercise of mild intensity; 2, moderate; M, maximal. The graphs reports mean values ± standard deviation (redesigned by Rowell, 1993).

Since during maximal exercise HR can increase up to three-four times in respect with the resting value and Vs practically doubles, it is

obvious that the may increase by about six to eight times above its value at rest.

The product of and the arterial concentration of O2 (CaO2) is called

O2 transport ( aO2). Since CaO2 in a healthy subject at sea level is

about 0.21 l of O2 per liter of blood, aO2 at rest it is about 1 l O2 min-1.

During maximal exercise, it can reach 6-7 l O2 min-1 in high-level athle-

tes. aO2 is the main limiting factor of at sea level.

3.4 Artero and venous concentrations of oxygen

The arterovenous difference of O2 increases as a function of the metabolic demand (Figure 8) due to decrease in the concentration

of O2 in mixed venous blood ( ). increases three times as many from about 5 ml O2 100 ml-1 to 15 ml O2 100 ml-1 in the transi-tion from rest to maximal exercise.

Figure 8: Concentration and total oxygen transport capacity in arterial and mixed venous blood as a function of exercise intensity expressed as consumption of oxygen (O2) in men (left) and in women (right) (redesigned by Åstrand, 2003).

The theoretical maximal carrying capacity of the arterial blood for O2 (CaO2max, true only in the case of 100 % SatHbO2) can indeed even increase during exercise due to the increase of the haematocrit induced by the squeezing of the spleen, likely caused by thehigher sympathetic tone, and to the haemoconcentration oc-curring during high intensity exercise. This phenomenon, however, is not able to compensate for the decrease in PaO2 associated with EIAH and, as a matter of

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fact, the effective CaO2 decreases during high intensity or maximal exercise, the more so in hypoxia.

The decrease of is due to the increase of the peripheral extraction

of O2 in the active muscles and to the redistribution of from organs that extract a small amount of O2, such as the liver, guts, to tissues that extract large volumes of O2, as the muscles recruited during exercise (Table 1 and Figure 9).

At rest, the heart and muscles receive about 30-40% of the total . Du-ring maximal exercise, the active muscles and the heart receive 95% of

; the splanchnic district, which at rest receives about 20% of , recei-

ves only 3-5% of total during exercise.

The causes of the redistribution of are the increase of the orthosym-pathetic activity, which induces an increase in vascular resistance of the arterioles in the splanchnic districts, and the vasodilatation in the muscular districts involved in exercise.

Figure8: Cardiac output (Q’) and its distribution to skeletal muscles, heart, splanchnic district and other tissues in dogs as a function of exercise intensity, expressed as a percentage of the maximal oxygen consumption (V’O2max). As exercise intensity increases, the fraction of distributed to the muscles increases, while the fraction distributed to the viscera decreases (redesigned by Laughlin, 1996).

The increase in vascular conductance is connected with muscular activity, occurs very rapidly at the beginning of the exercise and is the consequence of muscle con-traction and of the subsequent metabolic-dependent and flow-dependent vasodila-tations. The first prompt increase of vascular conductance is of mechanical origin and it appears as the muscle start contracting – relaxing generating a pump ef-fect that quickly increases muscle perfusion and conductance. The subsequent me-tabolic-dependent vasodilatation is responsible for a large part of the functional muscular hyperemia, is mediated by the local variation of metabolites that have a vasodilating action (adenosine, potassium ions, H+, decrease of PO2, increase of PCO2, histamine, phosphate, prostaglandins, quinines) and its effect is proportio-nal to the metabolic intensity. The flow-dependent vasodilatation is due to the re-lease of NO from the endothelial cells of the vessels induced by the increase of the shear stress resulting from a larger flow. The orthosympathetic vasomotor con-trol is still impinging during exercise on the arterioles and muscular veins. The effect of this stimulation, however, is clearly attenuated by the vasodilatory ac-tion of local mechanisms, so much so that we speak of sympatholysis to describe

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the abolition of the sympathetic vasoconstrictive effect on the muscular vessels due to the powerful action of the local mechanisms. Many of the metabolites di-rectly involved in vasodilatation interfere at the postjunctional and prejunctional level with the sympathetic vasoconstriction mechanism. Therefore, the central vasomotor control seems to modulate peripheral mechanisms rather than to be directly responsible of muscular vasomotor regulation. Thanks to these phenome-na, the flow of blood that goes into the active the muscles is nearly a linear rela-tionship of the muscular O2 uptake.

It is now clear how the cardiovascular responses and the modification of O2 extraction at the peripheral level can justify the increase of occurring from rest to maximal exercise. If we apply the equation 3a to

the conditions ( = we can understand

that the eightfold increase of max and the triplication of in the transition from rest to maximal bring about a twenty-five fold in-crease of : from 0.2 l O2 min-1 to 5 l O2 min-1.

3.5 Blood pressure

The sharp and rapid fall of muscular vascular resistances that occurs during a dynamic exercise causes only a small increase of mean arte-rial pressure. In fact, the increase in systolic blood pressure, which oc-curs in direct connection with the rise of Vs, is compensated by the de-crease in diastolic pressure due to the fall of total peripheral resistan-ces (TPR) (Figure 10).

Figure 10: Systolic, mean and diastolic pressures during cycling. The intensity of the exercise is expressed as a percentage of the maximal oxygen consumption (V’O2max). The systolic pressure in-creases significantly, the mean pressure increases less and the diastolic pressure decreases (redesi-gned by JD MacDougall, 1994)

Also during isometric exercise HR and mean arterial pressure increa-se. However, the increase of mean arterial pressure and HR is signifi-cantly larger in this type of exercise compared to what is observed du-ring dynamic exercise of equal metabolic intensity. The higher mean arterial pressure is mainly caused by the marked increase in diastolic pressure and the magnitude of the increase is a function of the muscle mass involved in the contraction. Furthermore, if the isometric exerci-se is intense, the variables do not reach the steady state (Figure 11). The accentuated pressure response is due to mechanical causes. Na-mely, the isometric contraction hinders blood flow. Furthermore, a che-moreceptive reflex of muscular origin (metaboreflex), triggered by the accumulation of metabolites, induces a reflex increase of TPR and of HR. Conversely, pulse pressure increases slightly compared to the rest condition because the high cardiac afterload impedes large increases of Vs.

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Figure 11: Top: systolic, mean and diastolic pressures in humans as a function of the intensity of the isometric exercise expressed as a percentage of the maximum voluntary contraction (% MCV). As the exercise intensity increases, the systolic and mean pressures increase and the increase is greater than in dynamic exercise (Figure 10). In the case of isometric exercise, the diastolic pressure also increases. Bottom: Mean arterial pressure in humans as a function of the duration of isometric contraction. The pressure is greater in the case of a weightlifting exercise and is lower during hand grasp exercise. Furthermore, the pressure increases with time. The dotted lines represent the hypothetical adaptation of the average pressure during the first minute of exercise. The graphs show mean values ± standard error (redesi-gned by Rowell, 1993).

3.6 Control of cardiovascular response to exercise

There are three main mechanisms involved in the neural regulation of the cardiovascular system during exercise (Figure 12).

Figure 12: Diagram of the autonomic pathways and mechanisms of cardiovascular control and rela-ted target organs.

The first mechanism is defined central command: the regions of the brain responsible for the recruitment of the motor units involved in exercise send also excitatory signals to the cardiovascular control cen-ters located in the encephalic trunk. These signals would determine the changes in the sympathetic and parasympathetic efferent activities re-sponsible for the cardiovascular responses that occur immediately at the beginning, or even before, the onset of the exercise.

The second mechanism involves reflexes originated at the level of the active muscles. According to this mechanism, nervous signals resulting from the stimulation of receptors sensitive to mechanical deformation of the muscles-joints (mechanoreceptors) and to the accumulation of local metabolites (metaboreceptors) would activate the areas of the car-diovascular control centers in the encephalic trunk. This mechanism is

32

defined as a pressure reflex or muscular metaboreflex and it is respon-sible for the increase of HR and blood pressure. The receptors present in the muscles are constituted by free terminations of nervous fibers present in somatic afferent nerves (group III fibers, mechanical affe-rents, group IV fibers, chemoreceptor afferents).

The third mechanism is represented by the arterial baroreceptor re-flex, which plays a permissive role, as it allows a simultaneous increase in blood pressure and HR, in opposition to what happens in rest condi-tions, when an increase in pressure is usually followed by a decrease in HR.

The rapid and marked increase of Q’ that occurs at the beginning of the exercise is only able to induce a slight increase of blood pressure since TPR decrease rapidly. This slight increase in pressure corresponds, however, to the prompt increase of HR, which, in the case of moderate exercise, jumps rapidly from the resting va-lues of 60-70 beats per minute to values close to 100 beats per minute due to the sudden withdrawal of vagal tone. Thus, a contradictory condition is established if we consider the physiological behaviour of the baroreceptor reflex observed at rest: an increase in pressure corresponds to cardio acceleration and not to bra-dycardia. It is therefore believed that the baroreceptor reflex (Figure 13) is acti-vely reset so as it can operate around higher-pressure values. More precisely, it is assumed that the response interval of the stimulus-response curve moves rapidly upwards (towards higher values of HR) and that the operative interval moves towards the right (towards higher carotid sinus pressure values). The operating point also climbs on the stimulus-response curve and repositions itself on a sec-tion closer to the threshold and characterized by a lower gain. This shift has an important functional meaning, since it reduces the gain of the response to hyper-tensive stimuli thus increasing the efficacy of the reflex in counteracting any in-crease of pressure during exercise. This is important because the baroreflex re-mains able to limit the effects of the hypertensive stimulus caused by the muscular metaboreflex decreasing the risk of incurring in hypertensive crises during exerci-se. The concept of resetting implies that the baroreceptive reflex can continue to operate maintaining the ability to oppose excessive increases of pressure over a new operative interval.

Figure 13: Schematic representation of the sigmoidal stimulus-response curve of the carotid barore-flex and its operational parameters. The curve is drawn from experimental data obtained by ap-plying negative and positive pressure on the carotid with a cervical collar. HR, heart rate; a, mean arterial pressure. Baroceptive reflex threshold: value of distension pressure below which it is not possible to induce any reflex response; saturation: value of the distending pressure above which no correction is possible; operating range: interval of the distending pressure between threshold and saturation; responding range: the interval between maximum and minimum values of the depen-dent variables; central point: barycenter of the curve; at this point it is possible to induce hyperten-sive or hypotensive responses by applying variation of the distending pressure of identical absolute value; in correspondence of this point the maximum gain of the reflex is obtained; operating point: it defines the couple of values of distending pressure of the carotid and HR or mean arterial pressu-re, around which the reflex usually operates in physiological conditions; it is also called equilibrium point or set point. (redesigned by Raven, 2006).

3.7 Adaptations induced by training and inactivity

Aerobic training induces the expansion of the circulating volume and an increase (plus 20%) of the haemoglobyn mass, which is well correla-

ted with the maximum consumption of oxygen ( ).

Aerobic training also induces an increase in the volume of the ventricu-lar chambers (the end-diastolic volume increases). This eccentric hy-

33

pertrophic response is the structural basis of the functional increase of Vs induced by the larger cardiac preload to which also the plasma ex-pansion contributes.

It has been recently suggested that in the early phases of endurance training, however, the thickness of the cardiac septum and walls may increase. This early adaptation would be subsequently followed by a frank eccentric hypertrophic re-sponse.

Isometric training, on the contrary, is a stimulus for inducing the so-called concentric cardiac hypertrophy, characterized by increased car-diac mass and thickening of ventricular walls without increment of the ventricular size. The myocardial structural modifications respond to the protracted increase of afterload occurring isometric exercise and the increase of the thickness of the ventricular walls contributes to maintain a normal parietal tension in the presence of a persistent pres-sure overload

Aerobic training induces also muscular modifications that justify part

of the increase of . After training, the muscles show a better uti-lization of the O2 transported to the periphery by the circulatory sy-stem.

The modifications described above have obvious consequences on

, HR, Vs, , aO2, and during exercise (Figure 14).

After three weeks of inactivity (bed-rest), decreases compared

to control values; after seven weeks of intense training, has again increased to reach even higher values than the ones present befo-re inactivity.

Figure 14: Effects of twenty-one days of forced inactivity in bed (bed-rest) and of the subsequent training lasting fifty days on the maximal consumption of oxygen (V’O2max) in five subjects. The ar-rows indicate the moments in which the data shown in Figure 15 were obtained (redesigned by Åstrand, 2003).

After inactivity, max is significantly lower than before; conversely, after training, it may increase up to values higher than the ones exi-sting prior to training (Figure 15).

The variations of max found after inactivity and after training are attributable to the corresponding changes undergone by Vs: Vs is lower after inactivity and greater after training than in the control condition at all exercise intensities.

The variations of Vs during sub-maximal intensity exercise are compen-sated for by mirror changes in HR: HR is higher after inactivity and lower after training compared to the control condition at the same

. Since HRmax has not changed, it is evident that the variations of Vs found after inactivity and after training determine the correspon-

ding modifications of max.

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Figure 15: Cardiac output (Q’), artero-venous difference of the oxygen concentration ((Ca-Cv)O2), systolic ejection volume (Vs) and heart rate (HR) as a function of exercise intensity during cycling expressed in terms of oxygen consumption (V’O2) determined in the subjects of the study illustrated in Figure 14 (redesigned by Åstrand, 2003).

The adaptations of try to compensate the decrease of indu-

ced by inactivity: max is greater after inactivity than in the control, but the increase is not able to compensate for the decrease of max. Changes in the opposite direction of are observed after training.

The ventilatory system undergoes less important modifications. After

training, increases during maximal exercise, whereas it decreases during sub-maximal exercise. These modifications are accompanied by an increase in VT and a decrease in FR. The adaptation results in more efficient ventilation, since the dead space-to tidal volume ratio and the respiratory work against the viscous resistance to flow reduce. The ven-

tilatory equivalent for O2 ( / ) during sub-maximal exercise de-creases as evidence of a more efficient extraction of O2. Also the resi-stance to fatigue of respiratory muscles improves.

The increase in fatigue resistance of respiratory muscles can drastically reduce the vasoconstrictive effect on the locomotor muscles recruited during exercise of the metaboreflex of diaphragmatic origin. Respiratory muscle training is able to extend the time limit and improve the lactic threshold.

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Recommended readings

1. Åstrand P, Rodahl K . Textbook of Work Physiology, New York (NY), McGraw-Hill, 1970; chapt. 6, 9, and 12, p. 117 – 183, 279 – 318, and 375 – 430.

2. Cerretelli P. Fisiologia dell’Esercizio Fisico, Roma, Società Editri-ce Universo; 2001; p 57 -124, 383 - 424.

3. Dempsey JA, Wagner PD. Exercise-induced arterial hypoxemia. J Appl Physiol 1999; 87: 1997 – 2006.

4. Dempsey JA, Romer L, Rodman J, Miller J, Smith C. Consequen-ces of exercise-induced respiratory muscle work. Resp Physiol Neuro-biol 2006; 17: 242 – 250.

5. Eldridge FL. Central integration of mechanisms in exercise hy-perpnea. Med Sci Sports Exerc 1994; 26: 319-.

6. Iellamo F. Neural control of the cardiovascular system during exercise. It Heart J 2001; 2: 200 – 212.

7. Joyner MJ. Baroreceptor function during exercise: resetting the record. Exp Physiol 2006; 27 – 36.

8. Laughlin MH, Korthuis RJ, Duncker DJ, Bache RJ. Control of blood flow to cardiac and skeletal muscle during exercise. Handbook of Physiology. Exercise: Regulation and Integration of Multiple Systems. Bethesda, MD: Am. Physiol. Soc., 1996; sect. 12, chapt. 16, p. 705 – 769.

9. Laughlin MH. Cardiovascular responses to exercise Am J Physiol (Adv Physiol Edu 22) 1999; S244 - S 259.

10. MacDougall JD. Blood pressure responses to resistive, static, and dynamic exercise. In: Cardiovascular Response to Exercise. Mount Ki-sco, NY: Am. Heart. Assoc., 1994; chapt. 9, p. 155 – 173.

11. Mitchell JH. Cardiovascular control during exercise: central and reflex mechanism. Am J Cardiol 1985; 55: D34-D41.

12. Mitchell JH. Neural control of the circualtion during exercise. Med Sci Sports exerc 1990; 22: 141 - 154.

13. Raven PB, Fadel PJ, Shigehiko O. Arterial baroreflex during exer-cise: a current perspective. Exp Physiol 2006; 91: 27 – 49.

14. Rowell LB. Human cardiovascular control. New York (NY), Ox-ford Univerity Press 1993.

15. Rowel LB, O’Leary DS. Reflex control of the circualtion during exercise: chemoreflexes and mechanoreflexes. J Appl Physiol 1988; 69: 4017 - 418.

16. Saltin B, Blomqvist G, Mitchell JH, Johnson RL, JR, Wildenthal K, Chapman CB. Response to Exercise After Bed Rest and After Trai-ning. A Longitudinal study of adaptive changes in oxygen transport and body composition. Circulation 1968; 38: VII - 1.

Sawka MN, Convertino VA, Eichner EA, Schneider SM, Young AJ. Blood volume: importance and adaptations to exercise training, envi-ronmental stress and trauma/sickness. Med Sci Sports Exerc 2000; 17: 332 – 348.

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