Theme 2: Exercise

Question 1

Give a summary of the main respiratory stimuli (i.e. factors that affect breathing).

Answer 1

• Stimuli may be nervous or humoral
• Nervous stimuli include conscious central pathways and reflex pathways
• Humoral stimuli include chemical and physical stimuli

Question 2

Give some experimental evidence for how ventilation changes with exercise.

Answer 2

(Douglas, 2013):

• Collected breath samples as he walked at various intensities through Oxford
• Ventilation increased approximately linearly with O₂ consumption and CO₂ production up to a “break point” where the ventilation increases rapidly
• This rapid increase is thought to be perhaps due to increased lactic acid production at this point
• The increase is mostly due to tidal volume at first and then due to respiratory rate

Question 3

Describe the different stages of breathing during exercise.

Answer 3

• Phase 1 -> Rapid increase in breathing within seconds of starting the exercise
• Phase 2 -> More slow increase in breathing later
• Phase 3 -> Plateau in breathing

Question 4

Does blood pH, PaCO₂ and PaO₂ change during exercise? What is the implication of this?

Answer 4

• Not with mild to moderate exercise. The homeostasis is very effective.
• This means that feedback mechanisms on ventilation cannot work via chemoreceptors for these signals, since they do not change.

Question 5

What are some hypotheses for why the ventilation increases rapidly at the very start of exercise (phase 1)?

Answer 5

• Central command -> This would allow a faster response since there is no need to wait for feedback. Learning plays a major role in this
• Peripheral chemoreceptors:
  
  • Mean PaCO₂ does not change majorly, but there are oscillations in PaCO₂, which increase during exercise. Chemoreceptors could detect this increased oscillation.
  • Lactate, potassium and adrenaline all stimulate peripheral chemoreceptors.
• Reflex feedback from muscle ‘work receptors’ via the spinal cord (experiments in dogs suggest this is the case, but experiments in paraplegics suggest it is not)

After these fast responses, the feedback mechanisms, such as from the peripheral chemoreceptors, can also assist in ventilation control.

Question 6

Give some experimental evidence for the role of central command in increasing ventilation dueing exercise.

Answer 6

(Krogh and Lindhard, 1913):

• Proposed the concept of “cortical irradiation” to account for anticipatory hyperventilation prior to exercise
• Found that alterations in perceived load transiently affected ventilatory responses

(Eldridge, 1985):

• Studied a paralysed cat
• Stimulated the hypothalamic locomotor region
• This led to activity in not only the bicep femoris nerves but also in the phrenic nerve
• This shows that anticipation of exercise influences ventilation

Question 7

Give some experimental evidence for/against the importance of muscle feedback onto ventilation during exercise. How can these contradictory results be explained?

Answer 7

FOR

(Kao, 1963):

• Connected the circulatory systems of two dogs so that one dog (the neural dog) received all of its perfusion from the other dog (the humoral dog)
• Stimulated the neural dog’s hind legs to make them exercise artifically
• The neural dog breathed harder even though all of its metabolic needs were met by the humoral dog
• If the spinal cord of the dog is cut, the increase in breathing is lost
• Therefore, this is evidence of afferent feedback from the muscle onto control of breathing

(McCloskey, 1972):

• Severed the dorsal roots related to the muscles that were exercising in a cat
• When the cat exercised, the ventilation did not increase as much as it normally would
• Therefore, this is evidence of afferent feedback from the muscle onto control of breathing

AGAINST

(Adams, 1984):

• Used transcutaneous stimulation to exercise leg muscles in healthy and paraplegic patients
• Plotted a graph of ventilation against carbon dioxide production for both groups, which showed that both groups had similar ventilatory responses to exercise
• This suggested that afferent feedback from muscles is not necessary for a normal ventilatory response to exercise

EXPLANATION

It seems that the ventilatory response to exercise includes a lot of redundancy. This means that removing one component (e.g. the muscle feedback) is not sufficient to lose the response, but if we remove all other components, then removing the last component will indeed lead to loss of the response.

Question 8

What is the name for the increase in ventilation caused by increased blood flow?

Answer 8

Cardiodynamic hyperpnoea

Question 9

Give some experimental evidence for/against the importance of cardiodynamic hyperpnoea in increasing ventilation during exercise. How can these contradictory results be explained?

Answer 9

FOR

(Wasserman, 1974):

• Injected 4 micrograms of isoproterenol into the vena cava of an awake dog
• Observed increased cardiac output and an associated increase in ventilation, despite no change in P_CO2
• This provides evidence for cardiodynamic hyperpnoea.

AGAINST

(Banner, 1988):

• Plotted ventilation and oxygen consumption against cardiac output during 30 seconds of exercise in normal patients and those who had undergone heart or heart-lung transplants
• All subjects had similar increases in ventilation and oxygen consumption, despite the fact that the transplant patients had much smaller increases in cardiac output
• This suggests that cardiodynamic hyperpnoea is not necessary for ventilatory increases during exercise.

EXPLANATION

It seems that the ventilatory response to exercise includes a lot of redundancy. This means that removing one component (e.g. the cardiac output increase) is not sufficient to lose the response, but if we remove all other components, then removing the last component will indeed lead to loss of the response.

Question 10

Give some experimental evidence for/against the importance of CO₂ flux (i.e. increased CO₂ production) in increasing ventilation during exercise. How can these contradictory results be explained?

Answer 10

Experiments studying this are difficult because ventilation should increase when arterial CO₂ is increased (due to central chemoreceptors). However, this blood CO₂ increase is not seen in exercise, so any response due to increased CO₂ production must be observed separate to increased arterial CO₂.

AGAINST

(Fordyce, 1980):

• Passed arterial blood from anaesthetised dogs through a gas exchanger to pump it full of CO₂, then released the blood into the venous circulation
• Found that ventilation increased, but the increase was alongside an increase in arterial CO₂, meaning that the effect could be explained by central chemoreceptor feedback
• Thus, this was not mimicking the increase in ventilation that you get without increase in arterial CO₂ during exercise

FOR

(Phillipson, 1981):

• Passed venous blood from sheep through a gas exchanger to pump it full of CO₂, then released the blood into the venous circulation -> This is better than an arterio-venous exchanger because it doesn’t increase cardiac output and thus lead to cardiodynamic hyperpnoea
• In each of the four sheep, there was found to be a linear relationship between the rate of CO₂ production and ventilation, regardless of whether CO₂ production was increased by exercise, venous CO₂ infusion, or combinations of both procedures.
• This increase in ventilation was seen even though arterial CO₂ remained constant.

EXPLANATION

There are too many technical complications to these experiments, so there is no definitive answer.

Question 11

Do the carotid bodies generate an increase in ventilation during exercise?

Answer 11

FOR

(Perret, 1960):

• Made subjects breathe 21% oxygen
• Switched the gas to 40% and 60% oxygen surreptitiously during the study period
• Each time the oxygen increased, there was a transient drop in ventilation before it returned to normal
• This suggests that the carotid bodies detect the lack of oxygen and lead to reduced breathing, before redundant mechanisms return ventilation to normal -> Thus, the reverse could happen during exercise

(Yamamoto, 1960):

• Modelled the changes in alveolar CO₂ that occur during exercise and showed that alveolar CO₂ fluctuates much more rapidly during exercise
• This means that the arterial blood and therefore carotid bodies experience rapid fluctuations in CO₂, even though mean CO₂ stays the same
• This is a possible model for how the carotid bodies could lead to increased ventilation during exercise

(Wasserman, 1975):

• Compared the responses to exercise of normal subjects and those who had undergone carotid body resection
• Below the anaerobic threshold, there was little difference between the arterial CO₂ in the groups
• Above the anaerobic threshold, the difference became more pronounced
• This suggests that the carotid bodies may play a role in increasing ventilation above the anaerobic threshold only

Question 12

Summarise what the role of the carotid bodies might be in control of ventilation during breathing.

Answer 12

• There is mixed evidence about whether the carotid bodies are involved in increasing ventilation during exercise
• However, it is likely that they are involved in augmenting feedback mechanisms depending on the size of the disruption (e.g. a small/large partial pressure disturbance) -> This is known as load compensation
• (Cunningham, 1966):
  
  • Found that there is little difference in ventilation at rest between hypoxia and hyperoxia
  • However, during exercise this difference becomes much larger, which could be explained by the carotid bodies augmenting feedback mechanisms on ventilation

Question 13

Summarise the main stimuli to breathe during exercise.

Answer 13

Feed-forward mechanisms:

• Blood gas oscillations (at the carotid bodies)
• Cardiac output (cardiogynamic hyperpneoa)
• Carbon dioxide fluxes
• Muscle afferents
• Signals from higher centres

Feed-back mechanisms:

• P_CO2
• H⁺
• P_O2

Feed-forward mechanisms show a degree of redundancy, while feedback mechanisms do not.

Question 14

How are feed-forward mechanisms of increasing ventilation during exercise calibrated? Give experimental evidence.

Answer 14

• Somjen (1992):
  
  • Proposed that the brain “knows” exactly how much O2 is demanded and CO2 produced by the level of exercise being undertaken, and has learned to anticipate the corresponding increase in VE that is necessary to avoid any changes in arterial blood gases. He hypothesised that the brain has learned how to do this over a period of many years, from early in infancy, by a process of “trial and error”.
• (Martin, 1993):
  
  • Studied the ventilatory response of goats -> These tend to become slightly hypocapnic during exercise
  • Made the goats undergo repeated exercise, except each time the goats were administered with CO₂ to increase feedback
  • After the experimentation period, even without the CO₂ administration, the goats had learned to breathe harder during exercise and thus became more hypocapnic
• (Robbins, 2003):
  
  • Measured the end tidal CO₂ changes during exercises in 3 tests groups
  • Exposed the 3 groups to different interventions 10 times a day for 7 days:
    
    • 4 minutes of exercise and increased airway CO₂
    • 4 minutes of exercise
    • 4 minutes of increased airway CO₂
  • End tidal CO₂ increased less during exercise in the exercise and increased airway CO₂ group, but not the other two groups
  • This shows evidence of learning from feedback

Question 15

Describe the origin of fuel and fuel consumption after 24 hours of fasting in a normal subject and in a subject adapted after 5-6 weeks of fasting. Give a reference.

Answer 15

(Cahill, 1970):

• Normal subject:
  
  • Every day 75g of muscle are broken down, which is used in gluconeogenesis
  • 180g glucose is used per day, mostly by the brain
• Fasted subject:
  
  • Every day only 20g of muscle are broken down, which is used in gluconeogenesis
  • Only 80g glucose is used per day, mostly by the brain
  • Ketone are largely diverted to the brain instead of the heart, etc.
• The reduced muscle break down is enabled by the diversion of ketones to the brain. This extends survival from 10 to 50 days without food. This sort of adaptation can be considered normal and healthy.

Question 16

How much do each of these increase during exercise:

• Ventilation
• Cardiac output
• Skeletal muscle blood flow
• Factorial aerobic score (how much oxygen you take up between rest and exercise)

Answer 16

• Ventilation -> 17x
• Cardiac output -> 6-7x
• Skeletal muscle blood flow -> 30x
• Factorial aerobic score (how much oxygen you take up between rest and exercise) -> 10x

Question 17

What body failures can be diagnosed via exercise?

Answer 17

Several types of failures become exposed during exercise, which can help with diagnosis of these.

Question 18

What is the main energy store in the human body? Give experimental evidence.

Answer 18

(Cahill, 1970):

• Fat is overwhelmingly the main energy store at around 140,000kcal stored
• Glycogen only stores about 900kcal
• Protein also stores a moderate amount but energy storage is not the primary function

Question 19

The body stores approximately … times more energy as fat than as carbohydrate.

Answer 19

500

Question 20

What makes fat a good energy store?

Answer 20

• Light (energy dense) and readily available
• Used by all organs (except the brain, which is why the use of ketone bodies evolved)
• Efficient

Question 21

What features are required of energy transduction (i.e. the use of fuels)? How is each of these achieved in human cells during exercise?

Answer 21

• Immediate/Fast
  
  • There is some existing ATP already in cells, ready for the start of exercise
  • Creatine is a source of phosphate so that ATP can be very rapidly regenerated during the first few seconds of exercise
  • Glycolysis enables anaerobic respiration during the first 40-60s of exercise
• Sustainability
  
  • After 40-60s, aerobic respiration takes over, which is enabled by the TCA cycle and ETC
  • Both glycogen, protein and fatty acids can feed into the TCA cycle
• High flux
  
  • Due to the TCA cycle

Question 22

What is the use of the TCA cycle as the end-point of the oxidation of multiple types of fuel?

Answer 22

It provides a drain for the end products of the previous processes (such as glycolysis), making them non-linear. This means that glycolysis, etc. can proceed without their products building up.

Question 23

Draw how glycogen and fatty acids feed into the TCA cycle.

Answer 23

Question 24

What is the limiting factor of submaximal exercise? Give some experimental evidence.

Answer 24

• Glycogen availability is the limiting factor
• (Bergstrom, 1966):
  
  • Fatigued one leg by cycling at a moderate pace while resting the other leg
  • Measured glycogen in each leg via biopsy in the 3 days following fatigue
  • The glycogen concentration was much lower in the exercising leg at first but rose to be much higher after 3 days (the exercising leg preparing for future exercise)
• (Bergstrom, 1967):
  
  • Measured muscle concentration of glycogen over time in steady exercise
  • Muscle glycogen concentration steadily decreased to close to 0, at which point exercise that was perceived as easy at the start became impossible
  • The rate at which muscle glycogen decreases is approximately proportional to the pulse rate (i.e. a measure of exercise intensity)

Question 25

Why is glycogen the limiting factor for submaximal exercise when there is abundant oxygen and abundant fuel (fat) remaining?

Answer 25

* Glycogen is required for anaplerotic reactions that restore the intermediates of the TCA cycle -\> The intermediates are depleted by cataplerotic reactions * This means that when glycogen runs out, even though there is plenty of fat left to use, it cannot be used efficiently because there is not enough TCA cycling happening to facilitate the burning of the fat * Thus, running out of glycogen is often called "hitting the wall" in running

Question 26

Give some experimental evidence for the importance of anaplerotic reactions in maintaining oxidation of fuels during exercise.

Answer 26

(Ashworth, 1966): * Studied a mutant E. coli strain * The mutant E. coli could not grow without the addition of TCA cycle intermediates. * Analysis in comparison to the wild type revealed that the mutant lacked PEPCK (catalyses conversion and shuttling of cytosolic PEP to oxaloacetate (4C in the late TCA cycle). * This shows that the TCA intermediates are essential for fuel use (and so they must be generated by anaplerotic processes). (Gibala, 1998): * Plotted TCA cycle intermediate pool size against TCA cycle flux at rest and during exercise * The larger the intermediate pool size, the larger the flux

Question 27

What are the three main factors affecting fuel selection during exercise?

Answer 27

* Intensity of exercise * Organ/Tissue/Fibre type * Diet and training

Question 28

Give some experimental evidence for how fuel usage changes depending on exercise intensity.

Answer 28

(Romijn, 1993): * Studied the usage of different fuels after 30minutes of exercise at 25, 65 and 85% of VO_2Max * Fat usage is highest at moderate intensity * Glycogen usage is highest at high intensity * The gross amount of fuel coming from the plasma remains approximately constant regardless of the intensity -\> It is the muscle-stored fuel usage that increases at high intensity

Question 29

How does organ/tissue type affect fuel selection during exercise?

Answer 29

* Muscle: * Red (slow twitch) muscle has lots of capillaries and so it is involved in aerobic respiration * White (fast twitch) muscle has more glycolytic intermediates and so it is involved in glycolysis * Heart: Uses mostly fat * Brain: Uses mostly glucose (and ketones)

Question 30

How does diet and training affect fuel selection during exercise?

Answer 30

* If you deplete your glycogen stores during exercise and then eat large amounts of carboydrates in the following days, your glycogen stores will be much larger next time * If you train in a low-glycogen state for a long time, your body will become better at using fat as fuel In other words, your body adapts to the state you place it in.

Question 31

Give some experimental evidence for how diet and training affect fuel selection during exercise.

Answer 31

(Philp, 2012): * Performed a review of the literature * Concluded that frequent training in a low carbohydrate state results in improved fat oxidation during steady state sub maximal exercise. * Discussed the existence of carbohydrate response elements, which alter transcription depending on whether carbohydrates are present

Question 32

What are the US and UK guidelines for physical activity each week?

Answer 32

Question 33

Define exercise.

Answer 33

A subset of physical activity that is planned, structured, and repetitive and has the final or an intermediate objective to **improve or maintain physical fitness**.

Question 34

Draw the spectrum of the types of adaptation that can occur in response to exercise.

Answer 34

This is a broad topic, so we will focus mainly on the adaptation on the left of the spectrum.

Question 35

Define physical fitness.

Answer 35

A set of attributes that are health- or skillrelated. The degree to which people have these attributes can be measured with specific tests

Question 36

What is VO_2Max and how is it usually quoted?

Answer 36

* The maximal amount of oxygen the body can use in 1 min (L/min). * Typically adjusted for body weight (mL/kg/min). * VO_2Max implies a maximal physiological limit is achieved, but in reality exercise capacity may be limited by other symptoms. Thus, the term VO_2Peak is commonly employed, which is the peak average oxygen consumption during a 20 second period.

Question 37

What is the clinical importance of VO_2Max/Peak?

Answer 37

* It represents the cardiac, circulatory and respiratory function and muscle oxygen use. * A ‘normal’ VO_2Max/Peak implies that the individual has no major limitations to cardiac output, its redistribution, or skeletal muscle metabolism or function. * Cardiorespiratory fitness (measured as VO_2Max/Peak) is consistently shown to be inversely associated with CVD and all-cause mortality. * Association is as strong as several conventional modifiable risk factors, including cigarette smoking, hypercholesterolaemia, obesity and hypertension.

Question 38

Give some experimental evidence for the importance of VO_2Max as a clinical predictor of health.

Answer 38

(Khan, 2017): * Studied the association between VO_2Max and heart failure in 1,873 men aged 42-61 years. * This was a prospective study looking at the number of heart failures in each quartile of VO_2Max. * There was a direct inverse relationship between cardiorespiratory fitness and incident heart failure rates (P \<0.05 for linear trend). * The highest quartile had 73% lower incidence of heart failure than the lowest quartile (in model 1, which adjusted only for age). * The study used several models, each of which adjusted for different factors.

Question 39

Exercise leads to adaptations that increase VO_2Max. What are the main categories of adaptation that enable this?

Answer 39

The pulmonary diffusing capacity and O₂ carrying capacity are not discussed here because they are covered in the altitude lectures.

Question 40

Describe cardiac adaptation to exercise.

Answer 40

* Resting and sub-maximal heart rates fall by 5-20 beats per minute. * Stroke volume is increased by ~20%. * Myocardial contractility is enhanced. * All four chambers of the heart increase in volume and thickness This constellation of adaptations is known as the "athlete's heart".

Question 41

Give some experimental evidence for how the heart adapts to exercise.

Answer 41

(Wilson, 2015): * Performed a meta-analysis and systematic review of various measures of cardiac function * Multiple of these measures (such as left ventricular mass, etc.) were higher in endurance trained individuals compared to resistance trained individuals. Controls were lower than both.

Question 42

Describe how the endothelium adapts to exercise.

Answer 42

* In response to changes in shear stress (caused by exercise), the endothelium produces several vasoactive hormones (principally NO) that alter the tone (vasoconstriction vs. vasodilation) of conduit and resistance vessels. * This leads to an initial upregulation in flow-mediated dilation. * After some time, structural modification of the endothelium occurs. * Structural modifications enhance the lumen size, which normalizes shear stress and normalizes flow mediated dilation (one of many examples of an ‘athlete’s paradox’). * In other words, structural modifications take over from flow-mediated dilation after some time.

Question 43

Give some experimental evidence for how the endothelium adapts to exercise.

Answer 43

(Rowley, 2011): * Examined the brachial arteries on the dominant and non-dominant upper limbs of of elite racquet sportsmen and compared them to matched healthy inactive controls. * Found larger resting arterial diameter in the athlete's dominant vs. non-dominant hands (~0.5 cm difference) and vs. both arms of the control subjects (~1 cm difference). * Similar differences observed in brachial artery dilatory capacity in response to glyceryl trinitrate (which is converted to nitric oxide, the major simulator of vasodilation). This suggests that this luminal adaptation is not a temporary diameter increase due to vasodilators but is instead a more permanent structural adaptation.

Question 44

Describe how skeletal muscle adapts to exercise.

Answer 44

* Increased angiogenesis * Increased expression of transporters for glucose and fats * Increased expression of key enzymes in glycolysis, beta oxidation and the Krebs cycle * Increase in mitochondrial density and mitochondrial proteins * Increase in antioxidant enzymes (since more respiration leads to more ROS production) * Increase in the expression and activity of key transcription factors for metabolic and mitochondrial enzymes These adaptations provide a robust defense against metabolic perturbation, resulting in increased fatigue resistance.

Question 45

Is it central or peripheral factors that limit VO_2Max? Give experimental evidence.

Answer 45

Central factors (i.e. the cardiorespiratory system). It is estimated that 70-85% of the limitation is linked to maximal cardiac output. Evidence for this: * (Saltin, 1968): * Compared maximal oxygen uptake during bedrest, when sedentary, and after training. * Found that increased VO_2Max when sedentary compared to bedrest was due to increased cardiac output, while the highest VO_2Max after training was largely due to increased cardiac output and partly due to increased a-v O₂ difference. * (Saltin, 1985): * Compared cardiac output and muscle blood flow during an isolation and compound exercise. * When a small muscle mass is over perfused during during exercise, it has an extremely high (2-3 times greater) capacity for consuming oxygen. * Demonstrates that muscle’s capacity to utilise oxygen is greater than the pumping capacity of the heart, so the cardiorespiratory system is the limiting factor.

Question 46

What is the purpose of metabolic and oxidative enzymatic adaptations in skeletal muscle?

Answer 46

* Because of the increase in mitochondria and metabolic enzymes activity/expression, exercise at the same work rate elicits smaller disturbances in the trained muscles. * This means that exercise at a given percentage of VO_2Max can be sustained for a longer time.

Question 47

What is the best measure of skeletal muscle adaptation to exercise?

Answer 47

* The anaerobic threshold during an incremental exercise test is the point at which the ventilation begins to increase more rapidly with V_CO2 * The closer the AT is to the V_O2Peak, the better the skeletal muscle is adapted to using the oxygen that is delivered to it

Question 48

How does skeletal muscle adaptation to exercise occur? Give experimental evidence.

Answer 48

* Repeated, transient increases in the expression of exercise-responsive genes in skeletal muscle confer exercise adaptations over time. * (Perry, 2010): * Made participants undergo a seven-session, high-intensity interval training period * Muscle biopsies were obtained 4 and 24 h after the 1st, 3rd, 5th and 7th training session * PGC-1α is a protein thought to be involved in controlling skeletal muscle adaptation and citrate synthase activity is a measure of TCA cycle activity * PGC-1α mRNA levels spiked after every training session, but the spikes became progressively smaller * This was confirmed by the plateau in PGC-1α protein levels across visits * However, citrate synthase activity continued to increase across visits * These results suggest that the same stimulus leads to progressively smaller transcriptional changes, explaining why training usually leads to a plateau over time

Question 49

Draw out the simple signal transduction hypothesis of exercise adaptation.

Answer 49

Question 50

Give an example of a signalling protein in this signal transduction hypothesis of exercise adaptation.

Answer 50

AMPK: * Mammalian AMPK is a heterotrimer comprised of two α subunits (catalytic), two β and three γ subunits (regulatory). * Activation of AMPK occurs in response to increased cellular AMP concentrations, which arise during cellular metabolic stress -\> AMP binds to the γ-subunit, which allosterically activates the AMPK complex. * An exercise intensity \>60% VO2 Peak is required to activate AMPK. * Once activated, AMPK restores cellular energy balance by activating catabolic ATP-producing pathways and inhibiting anabolic ATP-consuming pathways. * AMPK also alters the metabolic phenotype of muscle to enhance ATP production capacity.

Question 51

Give some experimental evidence for what causes AMPK to be activated.

Answer 51

(Chen, 2003): * Compared how the AMP:ATP ratio and AMPK subunit activity change from resting to low, medium and high intensity exercise * Found that the AMP:ATP ratio was significantly increased in the medium and high intensity groups * AMPK α1 and AMPK α2 subunit activities increased from low to medium intensity, and AMPK α2 activity increased further from medium to high intensity.

Question 52

What adaptation regulators does AMPK activate to enable skeletal muscle adaptation to exercise?

Answer 52

* Transcription factors (e.g. p53): * Modulates aerobic respiration by directly regulating the promoter regions of many metabolic and mitochondrial genes. * p53 is typically rapidly degraded by ubiquitin -mediated proteolysis. Post-translational modifications, including phosphorylation, prevent degradation. * This enhances DNA -binding activity at regulatory promoter regions. * AMPK is a p53 kinase. * Transcriptional co-repressors (e.g. Class IIa HDACs): * Deacetylation compacts chromatin structure (heterochromatin), meaning promoter regions are inaccessible to transcriptional machinery. * Class IIa HDACs associated with several DNA-binding transcription factors, acting as transcription co-repressors. * AMPK phosphorylates HDAC5 causing its dissociation from transcription factors and nuclear export. * Transcriptional co-activators (e.g. PGC-1α): * Master regulator of oxidative metabolism through co-activation of transcription factors that control metabolic and mitochondrial gene expression. * Associates with DNA -bound transcription factors and recruits histone acetyltransferase. * Histone acetylation (euchromatin) exposes promoter region to the transcriptional machinery. * Overexpression = marked increase in muscle oxidative capacity and performance. * Phosphorylation = increased expression. * AMPK is a PGC-1α kinase.

Question 53

What does CPET stand for?

Answer 53

Cardiopulmonary Exercise Testing

Question 54

How is CPET testing done?

Answer 54

* Different set-ups may be used, but commonly a bike is used * At first, there is 0 workload, but this is progressively increased * Various variables are measured, including oxygen consumption * When oxygen consumption is at its peak, this is the VO_2Max

Question 55

What are some limitations of CPET testing?

Answer 55

* The value is specific to that exercise (since it depends on which muscles are being used) * The peak oxygen consumption may not be the highest the individual could achieve

Question 56

Give an equation for VO₂.

Answer 56

Question 57

Give some experimental evidence for cardiovascular fitness being a predictor of mortality.

Answer 57

(Myers, 2002): * Studied the cardiovascular fitness and mortality of normal subjects and subjects with cardiovascular disease * Used peak exercise capacity as a measure of cardiovascular fitness * Grouped the participants into groups based on peak exercise capacity and peak exercise capacity adjusted for age * Patients with better fitness showed much lower mortality over 14 years than those with worse fitness * However, it is not clear whether exercise is the cause for this or whether it is just an association

Question 58

Draw a modern setup for CPET testing.

Answer 58

Question 59

What are some difficulties with this setup for CPET testing?

Answer 59

* The time-point at which each flow, gas composition and power reading is taken must be perfectly aligned * The pulse oximeter may not read accurately during the exercise if the subject starts to, for example, grip harder

Question 60

During CPET testing, what is measured and what is calculated?

Answer 60

Measured: * Oxygen uptake (VO₂) * Carbon dioxide production (VCO₂) * Oxygen saturation (SpO₂) * Ventilation (VE) * Heart rate Calculated: * Oxygen pulse * Respiratory exchange ratio (RER) * Anaerobic threshold * Ventilatory equivalents (VE/VCO₂ and VE/VO₂) * Respiratory compensation point

Question 61

How is the data from a CPET test often presented?

Answer 61

Wasserman's nine panel plot

Question 62

What does the VO₂ data from a CPET test tell us?

Answer 62

* Typically around 250 ml/min at rest * Dependent on age, gender, body habitus * VO₂ max (ml/kg/min) ≈ 50 – (0.4 x age in years) * Normal value (\>80%) is very reassuring * VO₂ max \< 20 ml/kg/min low * VO₂ max \< 15 ml/kg/min moderately impaired * VO₂ max \< 10 ml/kg/min severely impaired

Question 63

What does the heart rate data from a CPET test tell us?

Answer 63

* Maximum heart rate typically 220 - age beats/min * Normal to reach (\>80%) maximum heart rate, since cardiovascular system normal limits exercise * Low heart rate (i.e. high HR reserve) is abnormal, suggesting non-cardiovascular limitation

Question 64

What is oxygen pulse and what does it tells us in a CPET test?

Answer 64

* Oxygen pulse = VO₂ / HR ≈ oxygen uptake per beat * Used as an indirect measure of stroke volume, which increases early in exercise, but usually not in later stages * Maximum oxygen pulse less than 10 ml/beat is abnormal

Question 65

What does the minute ventilation data from a CPET test tell us?

Answer 65

* There is initially a rise in tidal volume, then respiratory rate * Overall ventilation not normally a limiting factor in exercise, so should be \<70-80% predicted at max * Maximum ventilation can be predicted by (FEV1 x 20) + 20 * Ventilation can also be affected

Question 66

What does the oxygenation data from a CPET test tell us?

Answer 66

* Oxygenation should remain constant during exercise * Desaturation during exercise is suggestive of respiratory or pulmonary vascular disease (or intracardiac shunt) * The best way of measurement is measuring the A-a gradient, which requires invasive arterial blood gas analysis.

Question 67

What is the anaerobic (lactate) threshold and what does it tell us during a CPET test?

Answer 67

* The anaerobic (lactate) threshold is the point at which aerobic respiration becomes insufficient and so lactate begins to accumulate in the blood. Ventilation increases as a result but this is a later event. * On a CPET test, it is the point at which VCO₂ exceeds VO₂ * VCO₂/VO₂ is known as the respiratory exchange ratio (RER), so the anaerobic threshold is when RER \> 1. * Low anaerobic threshold suggests poor oxygen delivery, due to cardiovascular or pulmonary vascular limitation.

Question 68

What is ventilatory efficiency and what does it tell us on a CPET test?

Answer 68

* Ventilatory efficiency is how much gas you need to move to clear carbon dioxide (or take up oxygen) * Increased VE/VCO₂ implies reduced ventilatory efficiency (or hyperventilation for another reason, e.g. acidodis, anxiety)

Question 69

What is the respiratory compensation point and how is it different to the anaerobic threshold?

Answer 69

* Lactic acid is produced once the working skeletal muscle cells reach the anaerobic threshold. * Usually circulating bicarbonate compensates for this lactic acidosis to begin with. This period is called the isocapnic buffering stage * However, beyond a certain point work intensity becomes so great that lactic acid production can no longer be compensated by circulating bicarbonate and hyperventilation begins. This point is called the respiratory compensation point (RCP).

Question 70

Give an example of a diagnostic table that could be used to diagnose patients after a CPET test.

Answer 70

Question 71

How does cardiac output change from rest to exercise and how does the distribution change?

Answer 71

* Cardiac output increases from 5 to 17.5L/min * The distribution changes due to vasoconstriction of vessels that supply non-exercising tissues and vasodilation of those that supply exercising tissues

Question 72

How does the systolic, diastolic and mean blood pressure change during isotonic (non-static) exercise?

Answer 72

* Systolic increases due to increases in cardiac output * Diastolic decreases due to mass vasodilation * Mean increases very slightly

Question 73

How does the systolic, diastolic and mean blood pressure change during isometric (non-static) exercise?

Answer 73

* Systolic increases due to increases in cardiac output * Diastolic increases due to vasoconstriction * Mean increases as a result of the former two

Question 74

Compare and explain how these variables change during dynamic and static exercise: * VO₂ * Cardiac output * Heart rate * Stroke volume * Arterial blood pressure * Total peripheral resistance

Answer 74

* VO₂ increases a lot less in static exercise because the body fatigues much more easily * Stroke volume and therefore cardiac output increase a lot less in static exercise because venous return is impeded * Total peripheral resistance decreases in dynamic exercise (due to vasodilation) but increases in static exercise (due to vasoconstriction) -\> Arterial blood pressure therefore increases a lot more in static exercise

Question 75

Are stroke volume increases important during exercise? Give experimental evidence.

Answer 75

(Donald, 1964): * Studied the response to exercise of normal dogs and those with cardiac denervation * No deterioration in the capacity for exercise was noted after cardiac denervation * In normal dogs, the increase in cardiac output was achieved by an increase in heart rate, whilein the denervated dog the increase was principally due to an increase in stroke volume * This suggests that cardiac output is normally mostly increased by sympathetic drive increasing heart rate and inotropy, but when this is not possible due to denervation (e.g. after a transplant), Frank-Starling means that stroke volume increases compensate

Question 76

Give a summary of the neural control of organs during exercise.

Answer 76

Question 77

Give some experimental evidence for the role of central command in the cardio-respiratory response to exercise.

Answer 77

(Krough, 2013): * Studied the concept of anticipatory hyperventilation, heart rate and blood pressure -\> These variables start to increase before exercise does * Found that the ventilation, heart rate and ABP increase more if the participants are told that the exercise is more vigorous * Regardless of the intensity they are anticipating, the exercise is the same intensity and the variables return to the same point (FIND REFERENCE - Arvidsson?, 1970): * Compared patients undergoing real exercise with those imagining exercise in a hypnotic state * Cardiac output increased and peripheral resistance decreased in the hypnotised group, despite much smaller increases in VO₂ * This suggests that there is a large degree of central control over cardiac function * However, other studies have not been able to replicate these results (Gandevia, 1993): * Studied subjects during curare-induced whole body paralysis * Told the subjects to attempt to contract muscles * This led to increases in heart rate and arterial blood pressure * However, the resting heart rate was very high (120bpm), which is because the patients were artificially ventilated, so the results could be altered due to this (Eldridge, 1981): * Identified the sub-thalamic nucleus as a key sub-cortical site for cardio-respiratory control, independent of afferent feedback from muscles * Stimulated the sub-thalamic nucleus in decorticate cats, which produced locomotion and increases in ABP, ventricular pressure, heart rate and phrenic nerve activity (controls the diaphragm) * When the cat was paralysed and the experiment was repeated, the cat did not move but there was an increase in blood pressure and phrenic nerve activity (controls the diaphragm) * This is therefore evidence for sub-thalamic control of the cardio-respiratory system independent of afferent feedback -\> This is technically not central command since it is not cortical * A problem with this study was that the sub-thalamic nucleus is tiny in cats and so the electrode tip that the scientists used may have been larger and there could've been accidental stimulation of the surrounding areas too

Question 78

How is the baroreflex involved in exercise?

Answer 78

* When blood pressure increases, the baroreflex decreases heart rate * This would be a problem during exercise, because it would prevent the heart rate increasing, so the baroreflex must be inhibited during exercise * Imaging of the brain shows increased activity in the left insular cortex during imagined exercise * The left insular cortex causes GABAergic inhibition of the nucleus ambiguus, which is one of the main vagal output tracts -\> Thus, this inhibition leads to decreased vagal control of the heart

Question 79

Name two important sub-cortical sites involved in cardio-respiratory changes during exercise.

Answer 79

* Sub-thalamic nucleus * Periaqueductal grey

Question 80

Give some experimental evidence for the importance of the sub-thalamic nucleus in cardio-respiratory control during exercise.

Answer 80

(Basnayake, 2012): * Repeated the classic experiment of (Goodwin, 1972), which involved measuring blood pressure and heart rate changes during bicep contraction and bicep contraction with stimulation of the triceps tendon -\> The stimulation of the tricep tendon increases the load on the bicep * Inserted an electrode into the sub-thalamic nucleus to study activity * As expected, arterial blood pressure was significantly increased in the tricep tendon stimulation group compared to the normal contraction group (although blood pressure was not significantly different) * STN activity was highest at rest, lower during bicep contraction and lowest during bicep contraction with tricep tendon stimulation -\> This suggests that STN activity is like a handbrake and cardio-respiratory increases occur when the STN activity is lowered

Question 81

What is the role of the periaqueductal grey in cardio-respiratory changes during exercise? Give experimental evidence.

Answer 81

* Stimulation of lateral column leads to hypertension * Stimulation of ventrolateral column leads to hypotension * (Green, 2005): * Used electrodes to stimulate the ventral and dorsal sides of the periaqueductal grey * Stimulation of the ventral electrodes led to a fall in blood pressure * Stimulation of the dorsal electrodes led to a rise in blood pressure * This suggests a role of the PAG in reciprocal control of blood pressure * (Green, 2007): * Used a similar set-up in an exercise setting, except used the electrodes for measurement rather than stimulation * Anticipation of exercise led to increased activity in the PAG compared to rest * During exercise, the activity was even higher * (Basnayake, 2011): * Measured blood pressure and PAG activity (via electrodes) changes during rest, exercise, muscle occlusion and recovery * Found that PAG activity was increased during exercise and muscle occlusion * This suggests that the PAG is involved in the muscle pressor reflex

Question 82

What does removal of the periaqueductal grey lead to?

Answer 82

* Immediate loss of consciousness * Mutism * Attenuation of CO₂ sensitivity * Loss of muscle pressor reflex * Respiratory failure

Question 83

Give some experimental evidence for the role of peripheral feedback in the cardio-respiratory response to exercise.

Answer 83

(Alam, 1937): * Studied subjects who performed isometric exercise (weightlifting) and occluded the subject's blood flow in the arm * The systolic blood pressure rose and remained high until the occlusion was removed * The increase in blood pressure was greater when the weight lifted was higher * This suggested some peripheral feedback to the brain due to accumulating metabolites (that activate C fibres in the muscle) (Rowell, 1981): * Performed a very similar study to (Alam, 1937), except this time it was the thigh that was occluded * After the exercise stopped, arterial blood pressure remained high until occlusion was stopped, but heart rate and ventilation fell * This is arguably an artefact of the fact that exercise was stopped, which led to the decrease in HR and ventilation that would otherwise not happen (Coote, 1971): * Provided direct evidence for the pressor response to muscle stimulation * Stimulated a muscle via the cut ventral root, which led to an increase in contraction and also increase in blood pressure * When the dorsal root was cut and the ventral root was stimulated again, the muscle still contracted but the blood pressure did not increase * This provides evidence for the role of the muscle afferents in blood pressure increases during exercise (Matsukawa, 1994): * Stimulated a triceps muscle via the ventral root and observed how blood pressure, heart rate, cardiac sympathetic nerve activity and tension all increased * Cut the L4-S1 ventral and dorsal spinal roots and repeated this * Observed that tension was the only one that increased * This provides evidence for the role of the muscle afferents in blood pressure and heart rate increases during exercise

Question 84

Give some experimental evidence for how epidural anaesthesia affects cardio-respiratory responses during exercise. What does this tell us?

Answer 84

(Fernandes, 1970): * Compared subjects undergoing exercise at increasing work intensities until exhaustion * During dynamic exercise with epidural anaesthesia, blood pressure was lower than in control experiments, but ventilation and heart rate were not affected. * The results indicate that afferent neural activity from the working muscles is important for blood pressure regulation during dynamic exercise in man but may not be necessary for eliciting the ventilatory and heart rate responses.

Question 85

What is the muscle/exercise pressor reflex?

Answer 85

When a muscle contracts leading to afferent signals that cause cardiovascular changes, such as an increase in arterial blood pressure.

Question 86

Draw a summary diagram of cardiovascular control during exercise.

Answer 86

* Afferent and efferent pathways converge on the cardiovascular control centre in the medulla. * Cortical areas (central command), the PAG and sub-thalamic nucleus influence the cardiovascular control centre. * Afferent fibres from the muscles also influence the cardiovascular system during exercise, which is known as the exercise pressor reflex.

Question 87

Summarise the role of the PAG and sub-thalamic nucleus in cardio-respiratory changes during exercise.

Answer 87

The PAG and STN integrate information from central command (in the cortex) and muscles, after which they pass it on to the medulla, which in turn affects cardiovascular and respiratory changes.

Question 88

Name some conditions that pre-term birth increases the risk of.

Answer 88

* Hypertension * Heart failure * Ischaemic heart disease * Mortality * Pulmonary vascular disease

Question 89

How does pre-term birth affect VO_2Max?

Answer 89

* A systematic review found that pre-term birth led to a VO_2Max that was 5.72ml/kg/min lower than normal births. [FIND REFERENCE] * This was done in non-athletes.

Question 90

Compare how the left and right ventricles are affected in pre-term birth. Give experimental evidence for this.

Answer 90

(Lewandowski, 2013): * Used MRI to study the hearts of adults who were born pre-term and adults who were born at term * Found that the left ventricular mass was significantly increased in pre-term births * Were able to produce models for the average heart of those who had been born pre-term and those born at term (Lewandowski, 2013): * Studied the right ejection fraction of adults who were born pre-term and adults who were born at term * Found that the pre-term individuals had a significantly lower right ejection fraction * 6 of the pre-term individuals had a right ejection fraction under 45%

Question 91

Describe how cardiac hypertrophy and fibrosis may be affected in pre-term birth. Give experimental evidence.

Answer 91

(Bensley, 2010): * Using sheep, pre-term birth was induced at 0.9 of term and hearts were examined at 9 weeks after term-equivalent age, when cardiomyocyte proliferation and maturation have ceased. * In pre-term lambs, cardiomyocytes of both ventricles and the interventricular septum were hypertrophied. * There was also a 6 to 7-fold increase in collagen deposition. (Bertagnolli, 2014): * Studied a rat model of pre-term birth and normal birth * Compared control hearts with those exposed to oxygen before term * At 16 weeks, the oxygen-exposed hearts showed much greater collagen levels than the control hearts * This suggests that oxygen exposure may play a role in cardiac remodelling that occurs with pre-term birth (Lewandowski, 2021): * Compared the hearts of individuals who were born pre-term and at term * Left ventricular structure and function were quantified by cardiovascular magnetic resonance and echocardiography * Found that preterm-born young adults have greater extracellular volume fraction in the left ventricle, which suggests a greater degree of diffuse myocardial fibrosis * The higher the degree of diffuse myocardial fibrosis, the worse the diastolic function (i.e. the ability to relax)

Question 92

Give a some experimental evidence that gives a summary of the effects of pre-term birth on the cardiovascular system.

Answer 92

(Telles, 2020): * Conducted a meta-analysis that found that pre-term born individuals have: * Smaller ventricular dimensions from birth to young adulthood * Lower left ventricular diastolic function across all developmental stages * Lower right ventricular systolic function across all developmental stages, that worsens with ageing * An accelerated rate of left ventricular hypertrophy from childhood to young adulthood

Question 93

What could explain why pre-term born individuals have a higher risk of early heart failure? Give experimental evidence.

Answer 93

(Leeson, 2017): * Suggested that pre-term born individuals have a reduced myocardial functional reserve * This would mean that an infection, etc. would make the individual more likely to drop down into the disease zone (Huckstep, 2018): * Calculated the VO_2Max of subjects * 40%, 60% and 80% workload were determined from this VO_2Max * Echocardiography was performed at each workload after two minutes (once reach desired work intensity, determined by HR) * Found that as workload increased, the difference in ejection fraction between term born and pre-term individuals increased * This suggests less of a reserve in pre-term individuals (Huckstep, 2020): * Found that the difference in ejection fraction from rest to 40% or 60% workload was positively associated with the % of peak VO₂ that was achieved -\> In other words, the more ejection fraction increased with exercise, the better the peak VO₂ was * Found a similar relationship with heart rate recovery -\> In other words, the more ejection fraction increased with exercise, the faster the heart rate recovered after exercise These factors suggest that pre-term born individuals may have a higher risk of early heart failure due to reduced myocardial functional reserve.

Question 94

Give a summary of the cardiac and vascular changes that may be present in pre-term born individuals.

Answer 94

From review: (Lewandowski, 2020)

Question 95

What are the screening considerations for adults born pre-term?

Answer 95

Question 96

Does VO_2Max change with altitude? Give experimental evidence.

Answer 96

* Yes, VO_2Max decreases with altitude, which is not that intuitive since at sea level it is the cardiovascular system (i.e. oxygen delivery, not uptake) that is the limiting factor. * (West, 1983): * Studied maximal exercise at multiple points during an ascent of Everest. * Measurements were carried out at sea level, 6,300 m during air breathing, 6,300 m during 16% O2 breathing and 6,300 m during 14% O2 breathing. The last PO2 is equivalent to that on the summit of Mt. Everest. * Plotted a graph of maximal oxygen uptake against inspired pO₂, which shows that maximal oxygen uptake falls greatly with altitude * The results were similar to a study by (Pugh, 1964)

Question 97

What limits VO_2Max at altitude?

Answer 97

It is not clear. It could be any of the points along this sequence. The evidence for each will come in the following flashcards.

Question 98

Is ventilation the limiting factor for VO_2Max at altitude? Give experimental evidence.

Answer 98

(West, 1983): * Plotted a graph of maximal exercise ventilation against inspired pO₂ during an ascent of Everest * Ventilation increased as pO₂ decreased from sea-level (150mmHg) to 60mmHg, but decreased at higher altitudes * This could suggest that ventilation becomes the limiting factor for work capacity, but it could also be the opposite, where work capacity is reduced at altitude and therefore ventilation does not need to be as high * Ventilation may decrease at very high altitudes because excessive ventilation diverts blood away from the muscles, but the counter-argument to this is that ventilation should be easier at high altitudes due to the reduced air pressure (Schoene, 1984): * Another factor to consider in this question is whether the ventilation at high altitude is being affected by acclimatisation * This study found that individuals with greater HVRs (hypoxic ventilatory responses) performed better at high altitudes and were able to ascend higher up Everest

Question 99

Is gas exchange at altitude diffusion limited? Give experimental evidence.

Answer 99

(West, 1983): * Found that at the height of Mt Everest, gas exchange is diffusion limited * This is largely because the gradient across the alveoli is much smaller (Wagner, 1987): * Conducted a simulated ascent of Mt Everest * Used multiple inert gas elimination technique (MIGET) to study the V/Q ratio at barometric pressures equivalent to various altitudes * Based on this, plotted the expected and actual alveolar-arterial pO₂ difference against the oxygen uptake * At altitude, there was a significant difference between the expected and actual alveolar-arterial pO₂ difference, which indicates a degree of diffusion limitation

Question 100

Is oxygen carrying capacity a limiting factor to VO_2Max at altitude? Give experimental evidence.

Answer 100

(Calbet, 2002): * Allowed subjects to acclimatise to altitude and thus have high haemoglobin concentrations * Then they carried out haemodilution by removing some blood and infusing saline (to reduce haemoglobin concentration) * They compared the VO₂ before and after the haemodilution at two different intensities -\> The isovolaemic haemodilution had no effect on exercise capacity

Question 101

Is cardiac output a limiting factor to VO_2Max at altitude? Give experimental evidence.

Answer 101

LEFT VENTRICULAR: (Wagner, 2010): * Produced a theoretical prediction model for the VO_2Max as a function of the cardiac output at 3 different altitudes (sea level, 15,000ft and summit of Everest) * Used 3 defined data points from the Operation Everest II study to assist with this * The model suggests that at the summit of Everest the VO_2Max plateaus at a relatively low cardiac output -\> This means that increasing cardiac output is unlikely to be a limiting factor if the exercise is of any significant intensity RIGHT VENTRICULAR: (Groves, 1987): * Plotted graphs of pulmonary vascular pressure gradient (essentially the pulmonary resistance) against cardiac output at 3 different barometric pressures * Found that the relationship became steeper at lower barometric pressures and a lower maximal cardiac output was achieved * This suggests that hypoxic pulmonary vasoconstriction may be responsible for reducing right ventricular cardiac output, which is what ultimately limits VO_2Max (Naeiji, 2010): * Studied the decrease in VO_2Max during chronic and acute hypoxia when the patient is given a placebo or sitaxsentan (endothelin receptor antagonist) * The sitaxsentan acts as a pulmonary vasodilator * Found that the sitaxsentan led to a smaller decrease in VO_2Max during both chronic and acute hypoxia compared to the placebo * This suggests that right ventricular cardiac output may be what limits VO_2Max at altitude

Question 102

What is a drug intervention that could be used to improve cardio-pulmonary performance at high altitude? Give experimental evidence.

Answer 102

Iron (Holdsworth, 2020): * Found that iron: * Attenuated fall in arterial O2 saturation * Improved right ventricular function * Improved index of stroke volume * No effect on pulmonary artery pressure

Question 103

Name some metabolic changes that occur at altitude. Give experimental evidence.

Answer 103

(Levett, 2012): * Studied subjects who climbed Mt Everest * Found that the ascent led to: * Loss of mitochondrial density * Early increase in UCP3 expression (which could explain weight loss at altitude) * Later increase in PPARa expression, which mediates a switch away from oxidative metabolism (Formenti, 2010): * Compared individuals with Chuvash polycythaemia with controls by subjecting them to a maximal exercise test * Found that the Chuvash polycythaemia subjects had much higher blood lactate levels during the exercise and had to stop earlier because of this, which is indicative of a shift to glycolysis instead of oxidative phosphorylation

Question 104

Does peripheral diffusion limitation occur at altitude, limiting VO_2Max? Give experimental evidence.

Answer 104

(Hogan, 1991): * Studied the gastrocnemius muscle in normal dogs and dogs who had been given sodium thiocyanate (which shifts the haemoglobin dissociation curve to the left) * Plotted a graph of VO_2Max against venous pO₂, which shows that the left-shifted dogs had a lower VO_2Max at a given pO₂ * This suggests that peripheral diffusion limitation may occur at altitude

Question 105

Name some chronic adaptations that may enable high altitude populations to exercise better at altitude. Give experimental evidence.

Answer 105

(Gilbert-Kawai, 2014): * Produced a review that identified the adaptations shown in the diagram (Petousi, 2014): * Found that Tibetans have a lower pulmonary artery systolic pressure (PASP) and lower experession of HIF2α than Han Chinese (Horscroft, 2017): * Compared PPARa expresssion in lowlanders and sherpas * Found that the sherpas had much lower PPARa expression at baseline and altitude, which suggests that they maintain more oxidative respiration rather than glycolysis

Question 106

Give some statistics for the scale of the problem of physical inactivity.

Answer 106

* Adults are at least 20% less active than in 1960s. By 2030 it’s predicted that we will be 35% less active. * Physical inactivity contributes to: * 1 in 6 UK deaths * Up to 40% of many long-term conditions * Around 30% of later life functional limitation and falls * The estimated annual cost to the UK is £7.4 billion * Physical inactivity is the 4th biggest non-communicable disease risk factor for mortality in high income countries

Question 107

What are the UK Chief Medical Officers Guidelines for physical activity?

Answer 107

* Muscle-strengthening activity on at least two days a week * 150 minutes of moderate intensity activity or 75 minutes of vigorous intensity activity or a combination of both * Minimise sedentary time and break up periods of inactivity * For older adults (65+) - Balance and flexibility activities at least two days a week

Question 108

Name some conditions that physical activity reduces the mortality and morbidity from.

Answer 108

Question 109

Describe a mechanism for how physical activity is protective against various conditions. Give experiment evidence.

Answer 109

(Kushner, 2010)

Question 110

Draw a graph of how strength and balance change over time in successful (i.e. activity-rich) and unsuccessful ageing. Give experimental evidence.

Answer 110

(Skelton, 2018)

Question 111

Does all physical activity have benefits? Give experimental evidence.

Answer 111

(Ekelund, 2019): * Systematic review and meta analysis covering 8 studies and 36,383 people * All physical activity regardless of intensity associated with substantially reduced risk of death * Magnitude of association about twice as great as previously reported from self-report * Aligns with UK CMOs’ guidance that “Any activity is better than none, and more is better still”

Question 112

What is the danger of sedentary behaviour?

Answer 112

* Sitting or lying awake is an independent risk factor for health by disrupting metabolism (muscle, lipid, glucose) and circulation * Many adults spend \>7 hours per day sedentary (increasing with age or limiting illness) * Just two minutes walking has a physiological effect.

Question 113

Who gains the most from doing more exercise per week? Give experimental evidence.

Answer 113

(Moore, 2012): * Studied the number of years of life gained after the age of 40 depending on the leisure time physical activity each week * The greatest benefit is seen in people who do no exercise and then start to do some

Question 114

How active are people in the UK? Give experimental evidence.

Answer 114

(Health survey for England, 2016)

Question 115

Draw a graph to show how the proportion of the population meeting aerobic and muscle-strengthening guideline changes with age in men and women.

Answer 115

Question 116

What are the perceived barriers that people with long-term health conditions see as preventing them from exercising?

Answer 116