Skeletal Muscle and Exercise in Chronic Disease

Question 1

What is the limiting factor to exercise in VO2max test in healthy people?

Answer 1

Leg fatigue

Question 2

What is the limiting factor to exercise in VO2max test in people with COPD?

Answer 2

1/3 d/t SOB, 1/3 leg fatigue, and 1/3 both leg fatigue and SOB

Question 3

What happens to exercise capacity if a person receives a single lung transplant?

Answer 3

• Single lung transplant (50% lung capacity): Exercise capacity in the 40-50% range

Question 4

What happens to exercise capacity if a person receives a double lung transplant?

Answer 4

• Double lung transplant: have about double the lung capacity of single lung recipients BUT have a similar 50% exercise capacity demonstrating the importance of non-ventilatory factors in exercise limitation.

Question 5

How can pulmonary function affect exercise performance?

Answer 5

1. Limiting maximal achievable ventilation (SOB)

2. Peripheral muscle detraining due to inactivity

Question 6

How can nutritional status affect exercise performance?

Answer 6

1. A loss of muscle mass

2. Diminished muscular quality

Question 7

How is ventilation calculated?

Answer 7

tidal volume x respiratory rate

Question 8

What is tidal volume?

Answer 8

Volume of air you take in one breath

Question 9

Explain the relationship between tidal volume and ventilation

Answer 9

• Early on in exercise, there is a rapid rise in tidal volume (bigger breaths) which then plateaus

Question 10

Explain the relationship between breathing frequency (respiratory rate) and ventilation

Answer 10

Respiratory rate increases in almost a linear fashion with an increase in ventilation

Question 11

How much of tidal breath is dead space ventilation at rest?

Answer 11

• At rest, about 30% of tidal breath is dead space ventilation

Question 12

How much of tidal breath is dead space ventilation at max exercise?

Answer 12

• At maximal exercise, dead space only about 15-20% of tidal volume

Question 13

Why does dead space decrease with exercise?

Answer 13

• As I take bigger breaths, dead space decreases because airways increase in size and alveolar volume is increased. Dead space-to-tidal volume ratio will go down

Question 14

How is alveolar ventilation calculated?

Answer 14

Alveolar ventilation = Alveolar volume x Respiratory rate

Question 15

Describe the relationship between CO2 output and ventilation

Answer 15

+ve correlation between CO2 output and ventilation –> Arterial CO2 stays flat

Until a point when there is a faster rise in ventilation than CO2 production. It is at that point that there is hyperventilation and arterial PCO2 decreases –> Respiratory threshold/Lactate threshold (NOT anaerobic threshold)

Question 16

What is the vital capacity (VC)?

Answer 16

The maximal amount of volume available in the lungs excluding residual volume

Question 17

What is the residual volume? What is it usually in healthy adults?

Answer 17

Air left in your lungs after complete exhales (you will never completely empty your lungs. Usually about 25% in healthy adults. In older adults, some of the lung elastic recoil is lost, so residual volume goes up to ~33%.

Question 18

How does tidal volume increase during exercise?

Answer 18

In healthy subjects this is achieved by using some of both the Inspiratory and Expiratory Reserve Volumes.
Thus, in healthy subjects the end-expiratory lung volume goes below the resting end expiratory lung volume, known as the Functional Residual Capacity (FRC).

Question 19

What is the functional residual capacity?

Answer 19

From the resting end-expiratory lung volume to the end of residual volume

Question 20

How does the flow-volume loop look like in COPD?

Answer 20

Trouble getting air out; obstructive disease; expiratory loop is curved (“scooped”). Air does come out, but it takes a long time.

Question 21

How does the flow-volume loop look like in pulmonary fibrosis?

Answer 21

Pulmonary fibrosis (stiff lungs); restrictive disease 
Air comes out very fast; not much comes off and not much comes in. Small total volume that comes out quickly

Question 22

In restrictive disorders like lung fibrosis, how does end expiratory lung volume change with exercise?

Answer 22

• End expiratory lung volume (EELV) is typically reduced even at rest
o It is also NOT further reduced on exercise.
o The only place to recruit volume from in this situation is the Inspiratory Reserve Volume.

Question 23

Why do people with restrictive disorders like lung fibrosis have trouble exercising?

Answer 23

The problem that comes with taking more from the Inspiratory Reserve Volume to take bigger breaths is that the lungs get stiffer with more volume. People with restrictive disorders already have stiff lungs.
• A lot of elastic work of breathing = get very SOB
• Dyspnea: Feeling of increased effort/work of breathing

Question 24

How does expiratory flow differ in COPD as opposed to normal patients?

Answer 24

• In COPD, expiratory flows are lower than normal particularly at lower lung volumes.
Even at rest, they have trouble exhaling resting tidal volume

Question 25

How does end expiratory lung volume change in COPD?

Answer 25

• Since the air comes out so slowly, more air is left in at the end of exhalation. End expiratory lung volume increases.  dynamic hyperinflation
• To compensate and be able to take big enough breaths quickly, they can breathe higher up in the envelop by dynamically increasing functional residual capacity (FRC). Higher flow at higher volumes
• This allows them to take advantage of the higher flows that occur at larger lung volumes because the airways are stretched open and so have less resistance.

Question 26

What is the disadvantage of breathing at higher lung volume above the FRC in COPD?

Answer 26

The cost of breathing at lung volumes above FRC is that the inspiratory work of breathing dramatically goes up as the end expiratory pressures are now positive relative to outside  BIG elastic work of breathing!

Question 27

How does ventilation (deadpace, alveolar and total) change in obstructive disease?

Answer 27

• Deadspace ventilation is higher
• Alveolar ventilation (important for CO2 removal) is normal
This results in elevated total ventilation.

Question 28

How does maximal voluntary ventilatory capacity (MCV) change in obstructive disease?

Answer 28

Reduced Maximal Voluntary Ventilatory Capacity

• Normally, healthy humans use 60-70% of MVC; lung disease use about 80-100%

Question 29

What is the relationship between cardiac output and oxygen consumption in healthy adults? In CVD?

Answer 29

Cardiac output is generally tightly linked (linearly) with oxygen consumption such that if oxygen consumption is increased cardiac output will follow in most cases. This is not the case where there is cardiac disease or significant cardiopulmonary interaction.

Question 30

How do HR and stroke volume change with exercise (increasing O2 intake)?

Answer 30

More exercise = more O2 consumption = HR goes up linearly; stroke volume goes up fast then slows down (exponential)

Question 31

What drives the increase in cardiac output with exercise?

Answer 31

At the beginning of exercise, the increase in cardiac output is being driven by increased stroke volume, then later on it is being driven by increased HR while stroke volume is maintained.

Question 32

How does endurance training affect stroke volume and HR during exercise?

Answer 32

With endurance training (shown in bold) there is an increase in the stroke volume response, lower resting heart rate, and a slower slope of heart rate response.
Q stays the same, but it is achieved with a larger stroke volume and lower HR.

Question 33

How does cardiac output differ in mitochondrial disorders or inability to breakdown glucose (PFK deficiency) ?

Answer 33

although patients with these disorders have lower oxygen consumption and lower oxygen extraction, they have normal cardiac output and elevated increases in cardiac output for increases in oxygen consumption (with increased muscle capillarization)

Question 34

What occurs when cardiac output is redistributed in more working muscles?

Answer 34

Blood flow to first muscle group is decreased but oxygen extraction increases

Question 35

How does blood flow distribution differ in chronic lung disease during exercise?

Answer 35

This possibility of an alteration in blood flow distribution has been raised in chronic lung disease, where the increased work of breathing steals blood flow from the leg muscles to supply the respiratory muscles. This may be due to excessive work of breathing in some patients.

Question 36

In heart failure patients, how do cardiac output and oxygen extraction differ from mild diseases?

Answer 36

With loss of cardiac function defined by heart classifications for people with heart failure, there is a progressive inability to increase cardiac output for oxygen consumption.
However, there is no difference in oxygen extraction between these groups. This suggests that the peripheral muscle in this case is unable to adapt to a decrease in oxygen delivery by an increase in oxygen extraction. This signifies that the pathology is not limited to central causes.

Question 37

How does oxygen extraction differ in people with mitochondrial dysfunction vs. HF patients?

Answer 37

• In HF patients, peripheral muscles are unable to extract more oxygen. As opposed to people with mitochondrial dysfunction who are able to increase capillary density in the muscles, these people do not.
• In order to increase O2 consumption, Krebs cycle or mitochondrial enzymes must increase activity, and people with HF don’t necessarily have this increase in activity. They have both central and peripheral problem

Question 38

When exercising, how does stroke volume change in mild pulmonary fibrosis patients?

Answer 38

• Mild pulmonary fibrosis (TLC>60%), stroke volume did not increase. Thus, the only way for them to increase their cardiac output is to increase their HR, but there are limits to that

Question 39

When exercising, how does stroke volume change in severe pulmonary fibrosis patients?

Answer 39

• Severe pulmonary fibrosis (TLC<60%), stroke volume decreased significantly. Will have a very hard time to increase cardiac output.

Question 40

How does stroke volume differ in healthy vs anorexia nervosa patients? Why?

Answer 40

Reduced stroke volume with lower weight.

• This may be due to reduced cardiac muscle mass, or perhaps reduced venous return.

Question 41

Explain the relationship between short-term work capacity and muscle mass

Answer 41

Muscle short-term work capacity depends on muscle mass

• Correlation is seen on graph

Question 42

How does short term starvation or anorexia affect muscle force, relaxation and fatiguability?

Answer 42

In humans, short term starvation or anorexia increases the relative force that can be developed at low stimulation frequencies, slows muscle relaxation, and increases fatiguability. Similar changes can be seen in an animal model.
• Relative importance of slow twitch fibers/oxidative fibers becomes increased in starvation or muscle mass loss state.
• Muscles relaxed slower and fatigue was higher in those populations –> Due to change in relative muscle mass

Question 43

Nutritionally, what can help malnourished patients to restore force at low frequency and increase relaxation rate?

Answer 43

This can be reversed with a 48-hour infusion of potassium and glucose. It is unclear which or both elements were required. This suggests that malnutrition may partly affect function through changes in energy balance and ability to maintain membrane potential.
• IV sugar and potassium restored membrane potential in muscle and helped with action potential propagation in undernourished patients

Question 44

What occurs to exercise capacity in refeeding after AN?

Answer 44

despite muscle mass still being low at 45 days, exercise capacity has normalized. –> energy and electrolyte balance was restored, thus AP can propagate properly and exercise can be regained even without normal muscle mass

Interestingly, in the graph we see that oxygen consumption for work done is reduced. –> More efficient at performing work.

Question 45

What could possibly cause the decrease in O2 consumption for the work done in AN patients undergoing refeeding?

Answer 45

• Possible causes for this reduced oxygen consumption could be restoration of type II glycolytic fibers, or reduced catecholamine production resulting in reduced stimulation of futile energy cycles.

Question 46

What are the causes of muscle mass loss in COPD?

Answer 46

o	Malnutrition (partly, but not always)
o	Loss of muscle mass is a component of systemic inflammation (unable to use calories and protein to make muscle) --> leading to cachexia

Question 47

Explain the relationship between weight and work capacity in healthy adults. What about COPD patients?

Answer 47

• In control, there is a positive correlation between weight and 30-sec work. As your weight increases, generally 30-sec work increases.
• In COPD, subjects had reduced short-term work capacity regardless of weight

Question 48

In which condition do inflammatory markers rise disproportionately with exercise?

Answer 48

Cystic fibrosis

Question 49

How does muscle mass relate to inflammation?

Answer 49

Chronic renal dialysis = malnutrition + chronic systemic inflammation
•	Patients had high IL-6 
o	High IL-6 = Low muscle force
•	Patients had high CRP
o	High CRP = Low muscle force

Question 50

Why is it difficult for lung disease patients to maintain their muscle mass or weight?

Answer 50

Hypoxia induces production of ROS and Hypoxia Inducible Factor-1 (HIF-1) which stimulates glycolysis and can stimulate leptin production which suppresses appetite.

Hypoxia can have a myriad of effects, including the induction of the production of reactive oxygen species (oxidants), pro-inflammatory cytokines, and Hypoxia Inducible Factor-1, which can stimulate glycolysis but also lead to leptin production, which suppresses appetite.

They also have a decreased appetite due to SOB.

Question 51

Why do CF patients have lower muscle strength?

Answer 51

Systemic corticosteroids can also have a negative impact on muscular performance, here demonstrated in patients with Cystic Fibrosis at modest doses eg 5 mg/day of Prednisone.
= Corticosteroids decrease muscle function

Question 52

Which compound can reduce muscle fatigue?

Answer 52

N-acetylcysteine (NAC)

Question 53

How does N-acetylcysteine (NAC) reduce muscle fatigue?

Answer 53

• NAC = cysteine donor; helps make glutathione (major intracellular antioxidant + scavenges free radicals)
• Fatigue was decreased using NAC
• Side effects include flushing, increased BP, nausea…

Question 54

How can we increase glutathione levels?

Answer 54

whey-based supplement
can increase muscle function/performance
Non-pasteurized, ultrafiltrate

Question 55

What are the advantages of using fat for energy?

Answer 55

For every molecule of oxygen used to burn fat, less CO2 is produced. This means less ventilatory demands, which may be important in patients with ventilatory limitation. Aerobic training shifts preferential fuel utilization towards fat, so that patients with ventilatory limitation can benefit from aerobic training.

Question 56

What occurs with lactate buildup in aerobically trained individuals? How much lactate is produced comparatively to untrained individuals?

Answer 56

o Metabolic enzymes are better and can use pyruvate, produce less lactate.
o Serum lactate goes up more slowly than in untrained individuals
o However, maximum amount of lactate produced is the same than in untrained people! It just appears at a higher % of max exercise capacity, and max exercise capacity is higher.
This is partly due to less lactate production due to enhanced aerobic enzyme activity and preferential use of fat. Remember, if Pyruvate does not enter the TCA cycle it is converted to lactate.

Question 57

What happens to lactate after it is produced?

Answer 57

• When it comes in the blood, lactate is taken up by RBCs, and also non-exercising muscles can take this lactate and use it as fuel (–> pyruvate–> Krebs cycle)
• Thus, lactate goes down in aerobic training both due to decreased production + increased clearance

Question 58

Name some adaptations to endurance training

Answer 58

• More reliance on fat
o Less CO2 production
o Glycogen sparing (Side note: low glycogen stores =  exercise ability)
• Increased aerobic capacity
o Less lactate production
o Improved lactate clearance
• These both lead to less circulation of lactate

Question 59

Why are CF patients recommended to exercise?

Answer 59

• Those who are most active had a better preservation of FEV1 than those who are less active.  PA seems to slow the progression of lung disease in CF patients
o Preserves lung function
• Regular moderate to vigorous activity is recommended

Question 60

Which 2 factors can predict exercise ability observed in a progressive exercise test?

Answer 60

lung function and muscle function

Question 61

Which parameters differs between single lung transplant and double lung transplants?

Answer 61

Single lung recipients have much lower lung function than double lung recipients.
However, there is no significant difference in exercise capacity and leg function between the groups.
You will note that the double lung recipients use less of their ventilatory reserve.
However even the single lung recipients do not use up a large percentage of their reserve.