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106 Cards in this Set

  • Front
  • Back


Inter-tissue communication: ‘metabolic cross-talk’


Adipose tissue acts as a major endocrine organ (energy storage organ) which releases signaling proteins known as Adipokines in order to communicate with the other organs. Adipose tissue is an insulating and cushioning organ.

- The expansion of adipose tissue as a result of obesity, via hyperplasia, changes adipokyne secretion which in turn leads to the development of metabolic disorders.

- The adipokynes have autocrine (lipid/ glucose transport via adiponectin and regulation of insulin sensitivity via IL-6), paracrine (immune cell attraction adipokine secretion via TNF- alpha) and endocrine effects (regulation of satiety/ appetite via leptin, inflammation via resistin, insulin sensitivity via adiponectin).

Major adipokines released the adipose tissue

discovery of leptin - parabiosis experiment with ob mouse (no hormone production) and db mouse (no receptor).

Proinflammatory substances such as (IL-6, TNF-1alpha), IL-10, TGF-beta, adiponectin/ resistin (positive metabolic effects à reduced in levels during obesity)


Vascular function-

Regulation of bone and cartilage mass-

Central action in terms of hormonal regulation of food intake and energy expenditure (satiety hormone which generally works to reduce hunger)-

Increase in leptin causes increase in blood pressure and heart rate.


Adiponectin (low levels of adiponectin are associated with high insulin resistance and BMI. Inverse relationship with BMI. It reduces hepatic glucose production and increases glucose uptake and fatty acid oxidation on skeletal muscles. It also reduces inflammation and atherosclerosis. Increasing exercise may cause an increase in adiponectin levels in overweight patients)-

TNF-alpha (directly associated with insulin resistance and involved in apoptosis and inflammation. It causes increase in hepatic glucose production and uptake of fatty acids and thus increases insulin resistance. Exercise protects against TNF-alpha induced insulin resistance)-

Leptin (increases with increase in BMI. Regulates energy intake and expenditure. Diabetic patients can reduce their leptin levels via strenuous exercise as it reduces body fat)-

IL-6 (chronic secretion of IL-6 as an adipokyne causes reduction in insulin dependent glucose uptake and impairs insulin secretion. Acute production of IL-6 as a myokine improves lipid oxidation, insulin signaling and secretion. Exercise cause increase in muscle derived IL-6 which is correlated with muscle mass and exercise intensity.)


Exercise training remodels subcutaneous adipose tissue and improves glucose homeostasis.

In sedentary mice, presence of white Adipose tissue, some blood vessels and mitochondria.

Increased blood vessel, increased number and size of mitochondria, and the development of beige or BRITE cells dispersed in between the white adipose tissue.

Adipokines also release factor x which increases glucose uptake in oxidative skeletal muscle and brown adipocyte.


Released from the skeletal muscle with exercise. Muscle release IL6 in response to contraction. - Meet metabolic demands of the host by increasing glucose uptake, fat oxidation and lipolysis-

Exercise (HIT >> LIT) causes dramatic increase in IL6 response. This causes an increase in glucose infusion rate and increases insulin sensitivity.-

The response of inflammatory elements as observed during exercise is the same as that observed during sepsis, minus the presence of TNF-alpha.-

Crosstalk of muscle with other organs such as liver, pancreas, adipose tissue, provides a framework to help us understand how exercise mediates many of its whole body beneficial effects. Provide a feedback loop for the muscle to regulate its own growth and regeneration for adaptation to exercise training.


Muscle release IL6 in response to contraction. - Increases glucose uptake and GLUT4 translocation in a manner similar to insulin via activation of the fuel sensing kinase AMPK. IL-6 stimulates phosphorylation of AMPK which increases transport of GLUT4 to the surface and increase glucose transport. Also involved in lipid oxidation and lipolysis. - IL-6 when released acutely as a myokine increases insulin sensitivity and lipid oxidation.


Cell culture muscle does not have the same proteins found in vivo in skeletal muscle (does not have the same composition). - Techniques used to measure myokines levels is the AV (arterio-venous) balance, or muscle biopsy. - Can also detect or study C2C12 myotubes, stimulated via electrical pulses, then screen the media which is storing the muscle to check for the release of chemicals. Electrical stimulation can be damaging to the muscle as it is an artificial stimulus and it can artificially release proteins that are normally not released.


The type I transmembrane protein FNDC5 is upregulated in muscle during exercise in both mice and humans.- Irisin levels increase in the mRNA level in response to exercise. - During physical activity, the protein’s extracellular portion, irisin, is cleaved and released into the bloodstream. This protein induces WAT browning into BRITE cells. Also improved glucose uptake. - Irisin does not have a normal transcriptional start codon ATG – has ATA

Running induces systemic cathepsin B (new myokine) secretion which is associated with memory function. It enhances neutrophin levels in adult hippocampal progenitor cells




1) Consider the stimulus (primary game, event, competition, training session etc) --> mode (single vs. team sports), duration (marathon vs sprint), intensity (low vs high intensity training) and repetition or bouts of the exercise (relay race), as well as the work rate (continuous vs. stochastic)

2) What are the energy requirements (Energy systems used, and demands on stored energy and whether there is a possibility of fueling before, during or after the event, as well as the food source available)

3) Training vs competition (Whether the exercise session or training is for competitive or a part of daily exercise. Training for a competition is more intense and specific. In some cases, optimal levels of nutrition and adaptation for performance may not be the goal, and certain competitions with weight divisions may require the gain or loss of weight within a short amount of time. If weight loss is required, more protein portion is added to the diet even if there is a reduction in food intake, in order to avoid protein breakdown in the muscle).


Endurance (in general cases, a much lower effort than the maximal effort is given, and it largely involves an element of fatigue. This element of fatigue requires a significant amount of reduction in maximal effort in order to make a certain distance or time which, however, can still be short in duration. Endurance exercise is also relatively continuous with little or no amount of breaks in the work rate and if it is continued for a long duration it may involve a significant reduction or depletion of available nutrients such as electrolytes, water and stored energy substrates)

Sprint/strength/power- short duration (They still involve an element of fatigue, but in this case, the absolute work rate would not be too much lower than the maximal effort that can be given. In this case, endogenous fuels may be depleted, but the loss of water and electrolytes is generally not considered a problem. Examples include sprint running or cycling or power lifting)

· Mixed/ stochastic (Most team sports, some typically endurance events- long overall workout, short intermittent high intensity work bouts. Team sports, bodybuilding, mixed martial arts


Observe the effects of nutrition on optimising the gradient achieved from training response (stimulus → fatigue → compensation → overcompensation → involution).

- As exercise intensity increases, the use of extracellular slow burning foods (fat oxidation increases)-

Events that require a short burst of energy, such as sprinting, have an increased dependence on intra-myocellular fast access fuels-

Nutrition also works to optimize work and adaptation by increasing gene transcription in order to produce proteins required for tissue growth, mitochondria and oxidative components, receptors, chaperones and structural elements.

Energy systems used for exercise of different durations:

6 seconds → CP (50%), anaerobic glycolytic (44%)

30 seconds → anaerobic glycolytic (60%), aerobic glycolytic (40%)

60 seconds → anaerobic glycolytic (50%), aerobic glycolytic (50%)

120 seconds → aerobic glycolytic (65%), anaerobic glycolytic (35%)

1 hour → aerobic glycolytic (92%)

4 hours → aerobic lipolytic (50%), aerobic glycolytic (50%) .


- Female athletic triad, which involves amenorrhoea, osteoporosis and eating disorders, must be avoided as well as a relative energy deficiency in sport due to a decrease in nutrition amount.

- A balance between health vs performance vs sanity must be maintained in the diet.-

A healthy body and diet must be maintained while developing training adaptations or a sickness as nutrient deprivation can cause no training which leads to no adaptation.

- Optimal performance usually depends on leanness. -

For endurance exercise performance, carbohydrate diet is important, as well as muscle glycogen content. To maintain performance, a carbohydrate diet is important. -

If a high fat diet was conducted, no real improvement in performance is observed. However, significantly more fat storage is used.


- The recommendations for events involving prolonged high intensity work requires consumption of greater than 7g/kg/d to maximize exercise performance -

Maximizing pre event glycogen storage maximizes competition performance -

AMPK levels increase when AMP concentrations increase when muscle is stressed during intense prolonged work. AMPK levels increase dramatically significantly when exercising at 70% VO2


Muscle Activation, Fatigue and Fiber Types

How movement works (sequence):

Supraspinal activation (brain)

Neural activation (alpha motor neorons)

Neuromuscular transmission

Muscle contraction

Fatigue can occur in any of these steps.


- Motor neuron axon connects to the muscle fibers.-

The axon terminals are in neuromuscular junctions

Graduation of muscle force:

There are two key strategies used by the motor system to increase the force in a muscle:

-       Increase in firing rate (frequency) of motor units (known as rate coding).

-       Recruitment of additional motor units (muscle fibres) smallest ...

There are two key strategies used by the motor system to increase the force in a muscle:

- Increase in firing rate (frequency) of motor units (known as rate coding).

- Recruitment of additional motor units (muscle fibres) smallest ones are recruited before the larger motor units (tetanus is when you have the highest twitch summation)-

The brain can use both strategies at the same time

Motor unit recruitment:

A motor unit is an efferent motor neuron and all the muscle fibers it innervates.

The number of muscle fibres in each motor unit (motor unit size) varies dramatically both between different muscles and within the same muscle.

As more force is required recruitment begins with small/slow units, progressing to large/faster units·

Larger motor units tend to have faster, LESS fatigue resistant fibres·

Smaller motor units tend to have slower, MORE fatigue resistant muscle fibres

The initial motor units continue to fire throughout the process

How ALS occurs

The aquaporins is expressed outside the endfeet does not localize correctly in ALS, causing astrocytes to not work with microglia to clear the debri, which leads to formation of inclusions and improper usage of microglia

How the neuromuscular junction works:

Action potential in the NMJ, and it triggers the opening of the voltage gated calcium ion channels.

Calcium binds to the vesicles containing acetylcholine. The moves to the motor neuron end plate and release the acetylcholine. The ATCH binds to the nicotinic receptors, and passes the action potential to the muscles.

Myasthenia Gravis (disease)

• Autoimmune condition antibodies block the nicotinic receptors

• Congenital condition- genetic defect in any component of the receptor



Cross bridge cycle occurs (myosin heads split → myosin heads bind to actin forming cross bridges → myosin heads rotate toward center of sarcomere → as myosin heads bind to ATP, cross bridges detach form actin.)

Motor Unit feedback and modulation via Afferent neurons (from muscle)

- Muscle Proprioceptive neurons:-

Golgi tendon organ (type 1a neurons): Orientation & Ligament Tension interpreted to aid balance, body spatial awareness etc..

- - Muscle Spindle (type 1b neurons): Muscle length and velocity to allow the brain to measure muscle stretch.


Muscle fatigue occurs, which is an exercise induced reduction in maximal voluntary muscle force.


- Central Fatigue: “A reduction in force capacity that occurs due to insufficient neural activation of the muscle” Maximal voluntary effort is less than that achieved when the muscle is stimulated directly by electrical stimulation of the motor nerve

Examples of central fatigue – hyperthermia, hypoxia, chronic fatigue syndrome, low blood glucose and age-

Peripheral Fatigue: “A reduction in force capacity that occurs despite optimal activation of the muscle” Muscle force drops despite electrical stimulation of the motor nerve

How fatigue can affect the steps of movement:

Supraspinal activation (brain) due to hyperthermia, hypoxia, chronic fatigue syndrome, low blood glucose and age

Neural activation (alpha motor neurons) → Reduced excitation of motor neurons (firing freq.), due to Inhibition by reflex pathways (eg. muscle spindle afferents) and Group III or IV muscle afferents (pain due to lactic acid buildup, pH, temperature)

Neuromuscular transmission → Occurs due to Motor axon “Branch failure”, Fatigue at Neuromuscular junction, Nerve A.P., Muscle A.P., Pre-synaptic: ACh release from vesicles, Post-synaptic: Sensitivity to ACh

Muscle contraction → Sensitivity of Contractile Proteins to Ca2+. Action potential disruption via an increase in [K+ ] during exercise.Myofibril damage. Metabolic Factors such as decrease in energy Supply (CHO) in endurance events, inorganic Phosphate accumulation, Insufficient O2 (eg. intense isometric flexing, endurance events) and increase in Acidosis.


Lactic acid – provides energy over short distances via the lactic acid system. Glucose ----> 2 pyruvate ---> 2 lactate (large amounts of lactic acid is catastrophic) exercise trained people have less lactic acid comparatively.


People who are sprinters have fast twitch, high force and fast fatigue (fast, type 2a and 2b fibres)

People who are marathon runners have slow twitch, low force and is fatigue resistant. (slow type 1 fibres)


Type 1 → slow speed of contraction, small fibre diameter, low force capability, many mitochondria, slow rate of fatigue.

Type 2a → fast speed of contraction, intermediate fibre diameter, medium force capability, many mitochondria, intermediate rate of fatigue.

Type 2b → fast speed of contraction, large fibre diameter, high force capability, few mitochondria, rapid rate of fatigue.

ACTN3 is a gene for speed produces fast twitch (encode for fast filament actn3)

Some people have mutations R577X (very common) which prevents you from running faster.

· Fatigue and fibre types:

- Type 1 < Type IIA < Type IIB/X-

The difference in fatigue resistance is derived from 3 characteristics: - Contractile economy, Oxidative capacity, Relative training status

Power output of muscle:

Contraction and shortening of muscle against a load is done via external work.Work = force x distance Power = force x velocity. Maximum power is achieved when the muscle is contracting with about 1/3rd maximum force and 1/3rd maximum velocity of s...

Contraction and shortening of muscle against a load is done via external work.Work = force x distance Power = force x velocity. Maximum power is achieved when the muscle is contracting with about 1/3rd maximum force and 1/3rd maximum velocity of shortening


Fine motor control: low activation threshold fibres, very small motor units, type I fibres e.g eye muscles, finger movements…high dexterity tasks.

Intermediate control (normal): Low (type I) and intermediate (type IIa) fibre recruitment. Power: All of the above, most power supplied by the late recruitment of motor units driving type IIb fibre contraction.

Exercise: Cross country skiing recruits more motor units than sprinting. Why?.


Fine motor control: low activation threshold fibres, very small motor units, type I fibres e.g eye muscles, finger movements…high dexterity tasks. Intermediate control (normal): Low (type I) and intermediate (type IIa) fibre recruitment. Power: All of the above, most power supplied by the late recruitment of motor units driving type IIb fibre contraction. Exercise: Cross country skiing recruits more motor units than sprinting. Why?.


(Mechanisms of Muscle Damage and Adaptation)

• Understand the different types of muscle injuries

- Ligament Rupture: Avulsion, result from severe hyperextension of a joint and complete tear in the stabilising ligaments-

Ligament and muscular Tears: Partial tears on ligament and/or muscle resulting from serious hyperextension, stretching, rapid changes in length and trauma.-

Ligament and muscle Strains: Result from mild hyperextension and stretching.-

Whole muscle cell damage: Numerous mechanisms such as trauma, toxins (such as tetanus), denervation/ muscle wastage, eccentric exercise.-

Sarcomere damage: eccentric exercise, over stretching.

Eccentric exercise

when you use your muscles as brakes. It increases delayed onset muscle soreness (DOMS) compared with concentric exercise.

Types of muscle contraction:

- Isometric exercise: No movement push against a static object, no joint movement during the muscle contraction phase. No lengthening or shortening of the muscle. Can be used in resistance training.-

Isotonic exercise: The muscle length changes; shortens is concentric contraction, lengthens is via eccentric contractions.-

Concentric contraction: e.g. biceps curl, bicep shortens (load less than total muscle force)-

Eccentric contraction: e.g. slowing the arm going from shoulder to leg direction with a force greater than muscle contraction. The muscle lengthens during the contraction. Muscles can adapt and respond to eccentric exercise

Running downhill is eccentric (higher number of sarcomeres), and running on an inclines hill is concentric (lower number of sarcomeres). The most damaging exercise type increases sarcomere numbers and strength.

Eccentric exercise damage depends on muscle length ( short length → less damage)

Muscles adapt and respond to eccentric exercise (damage) by leading to improved strength, improved angle and reduced soreness.

Markers of muscle damage

functional, chemical, nociceptive.

Length tension relation and damage

Descending limb of the tension and sarcomere length causes sarcomere instability.

• Understand how muscles adapt and regenerate following injury

Muscles can adapt and respond to eccentric exercise-

When muscle is damaged in eccentric contraction, damaged signals induce differentiation of satellite cells (heterogenous population of stem and progenitor cells required for growth, maintenance and regeneration of skeletal muscle), and they act to repair damaged muscle.-

• Integrate your new knowledge on muscle adaptation into your understanding of muscle structure and activation

- Myc5 negative when muscles are not damaged. Pax7 is always expressed.-

When damage occurs, MYF5 levels increase prior to the need of differentiating.-

Allows conversion of satellite stem cell to a committed satellite cell.-

Increase in MYOD occurs which causes proliferation and formation of myoblasts.-

Differentiation occurs which causes decrease in PAX7 and myogenin and increases MRF4 and MYHC

Replenishing stem cell pool:

– can undergo symmetric expansion using WNT7A (self renewal).

WNT7A can bind to FZD7 receptor which leads to activation of VANGL2 which leads to planar cell polarity pathway leading to division. Asymmetric expansion can also occur.

Stem cells may run out before they are replenished which happens in muscular dystrophy.

Muscular dystrophy:

Inherited conditions of progressive muscle weakness and wasting

• Limb girdle muscular dystrophy (Proximal wasting, Hip and shoulder girdles)

• Congenital muscular dystrophy (Infantile hypotonia, Regeneration degeneration cycles on muscle biopsy).

MD can be heterogeneous even in the same gene

Cause of MD:

Involves the complex DGC (dystrophin associated glycoprotein complex). The complex acts as a shock loader, without which muscles will detach. It is a glycoprotein complex because LAMA2 (attached with collagen sheets) binds to the DGC via glycoproteins (binds to alpha DG which is heavily glycosylated). DMD is the molecule that is generally associated with muscular dystrophy.

Another complex, integrin associated complex is also involved.

LAMA2 mutants display ultra-structural defects at the MTJ

It was found out that MD is not all about active force, involves passive tension as well.

Interventions to reduce or prevent muscle damage:

Ice bath to cool hot muscles

Anti-inflammatory drugs (ibuprofen, NSAIDS)

Cooldown exercises


Isoleucine/ leucine is a legal mTOR pathway stimulator (leucine inhibits TSC1/TSC2 and thus indirectly stimulates the mTORC1 which produces proteins such as S6K, 4EBP1 which lead to protein synthesis.

Muscle adaptations to damage are similar to those induced via exercise & resistance training:

Overload principle: high tensions are required for ­an increase in growth

Hypertrophy = increase in muscle fibre size (main mechanism) via the mTOR pathway

Hyperplasia = increase in muscle fibre (cell) number. However, limited evidence this occurs in short term

Optimisation of muscle fibre distribution → increased fast twitch)

-May be initially a 20-40% increase in strength without a noticeable increase in size (cross-sectional area) of the muscle.

Hypertrophy comes later and contributes to long term strength increases by increasing muscle cross sectional area.

It is likely that some of the training response is driven by muscle damage and activation of anabolic repair mechanisms

Neuromuscular adaptations to exercise: ‘Neurological training’

Occurs independent of muscle hypertrophy. Enhanced capacity to activate motor units. Improved coordination of motor unit firing. Improved ability to recruit motor unit firing. Results in large increase in power prior to hypertrophy.

Muscles respond and adapt to many stimuli.

Aerobic training markedly enhances the oxidative capacity of muscle fibres

Muscle also adapts to a lack of stimuli or activity. Reduction in tension, stretch, damage and work decreases mTOR and calcineurin, increases FOXO and increases aptogenic pathways

How Muscles respond and adapt to stimuli:·

Structural / Mechanical: (detection of force, stretch, damage)- Activation of repair mechanisms; satellite cells- Remodelling; fibroblasts, Extracellular matrix, fibre restructuring- Catabolic pathways stimulation (mTOR, calcineurin). ·

Neurological (Motor Units):- Greater efficiency in neuronal recruitment patterns- Improved rate coding and recruitment- Lowering of neural inhibitory reflexes (afferent nerves) ·

Metabolic: - Increased mitochondria - Improved control of metabolic pathways etc



How does the body detect & respond to muscle damage?

Via Neural pathways, when afferent nerves detect changes in metabolites, chemicals, stretch, length etc, and respond accordingly. Causes decreased motor unit function, sensation of pain, reduced performance and change in blood flow.

Via muscle cell intrinsic pathways, which activates stress pathways within the muscle cells

Via the immune pathways, which detect and respond to alarm signals from damaged muscles. Involves factors such as DAMPs and PAMPs, receptors of the innate immune pathways, and shows responses via repairing/ fibrosis and cytokines.


The evidence that the immune system is involved in responding to muscle damage is that Type 1 interferon pathways, indicative of TLR/ inflammasome recognition of nucleic acid, are activated in muscles during exercise. This presents a strong immune signature. Exercise drives expression of multiple immune and remodelling genes in working muscle

Why are immune signatures appearing after exercise?

Exercise is a key inducer of reactive oxygen species (ROS) -> cell damage. Excess ROS causes NFkB activation, which activates proinflammatory mediators. ROS also causes apoptosis. Damage and infectious agents activate the immune system. -

Exercise and particularly muscle cell damage is a DANGER SIGNAL for the immune system. Stressed cells give off alarm signals known as Alarmins or DAMPs. (IL33, ATP outside the cell instead of being inside the cell, histone modifiers such as HMGB1). Detecting these signals are detected by immune system which initiates an inflammatory cascade.

How are Danger signals detected?

• Danger signals are detected by the innate immune system (primary response of muscle damage.

• This is an ancient arm of the immune system that detects and removes pathogens before they cause problems. Evolved to recognise pathogens or damage. It is driven by quite specific recognition of conserved motifs present within most pathogens and also our own cells.

DAMPs are released from dead and damaged cells, and they bind to the toll like receptors (TLRs) in the immune cells which releases cytokines and chemokines such as IFN-alpha.


They detect bacterial, viral and other pathogenic compounds such as LPS, bacterial DNA, pathogen proteins etc. they trigger very potent immune responses and activate or license immunity.

They recognize a variety of substrates because they have a leucine rich repeat structure that creates a large pocket for binding different structures

They constantly monitor the cellular environment for danger signals.

- TLR signaling help build immune system specificity and they are constantly monitoring the cellular environment for danger signals

INFLAMMASOME (makes decisions on how the cell is going to die):

TLR receptors monitor the cellular environment. If a pathogenic or stress signal is detected they initiate a highly inflammatory reaction and activate a cascade that includes upregulating the proteins involved in the inflammasome pathway such as Pro-IL1β. Very large inflammasome complex activates caspases and cleaves Pro-IL1β to active IL-1β Also IL-18 and others. The inflammasome is one of the key intracellular responses to severe cellular stress.

Mutation which causes overactivation of these proteins can lead to fibrosis

Inflammasome activated via cellular and pathogenic factors.

what happens after detection of danger signal

Once the danger signal is detected, you get immune cell recruitment such as neutrophils, monocytes, dendritic cells and macrophages, which regulate subsequent muscle repair/recovery (repair, phagocytosis, adaptation and transient loss of performance) or pathology (inflammation, fibrosis, death, permanent loss of performance)

Role of neutrophils:

Blocking neutrophil infiltration decreases initial regenerative response-

Can cause neutrophil mediated release of cytokines, proteases to lead to pathogenesis of damaged cells.-

Can lead to increased macrophage invasion and satellite cell activation (for repair)

Role of macrophages (both proinflammatory and anti-inflammatory):

Key regulators of muscle repair or pathology.-

M1 macrophages → pro inflammatory → classical activation → Th1 cytokines, IFN gamma, TNF alpha are common markers → have cytolytic and phagocytic responses-

M2 macrophages → anti-inflammatory → alternate activation → IL4,10,13, TGF-Beta, Arginase, Th2 cytokines are common markers → leads to Muscle repair, growth and fibrosis

How do monocytes and macrophages mediate muscle repair:

Blocking of recruitment cells delay repair of muscles. Ccr2 deficiency causes reduced muscle inflammation, delayed phagocytosis and impaired muscle regeneration following muscle injury. One of the key things generated by Ccr2 is IGF1 which induces muscle growth (key growth factor in the body that regenerates tissue).

Monocytes/macrophages produce factors that help Satellite Cells survive and differentiate. Satellite cells also secrete factors that recruit monocytes to them. Monocytes (macrophages) are important modulators of satellite cell activity, presence of monocytes enhance satellite cell survival. Differentially activated macrophages regulate myogenic precursor cell fate during human skeletal muscle regeneration.

Macrophages secrete factors that can interact and promote myeloid stem cell survival and differentiation

Macrophages activated by cell damage release TNF which drives apoptosis of cells expressing fibrogenic activating protein (FAP) (TNF blocks TGF-beta- classical repair protein)


Increase in TGF-beta causes increases in arginase levels which increases collagen levels and TIMP1 (protease that breaks down existing damaged tissue) for repairing. Too much can lead to fibrosis.

Switch from M1 to M2 involves TGF alpha. Increase in TGF alpha causes increase in collagen and TMP1 and too much can lead to fibrosis

SIDE NOTE: IL-10 is an anti-inflammatory cytokine which plays a role in the repairing process. Blocking IL10 blocks muscle repair (partially inhibiting m2 macrophages).


Stress/ Damage → DAMPs (HMGB, HSP) released → sensed by TLR → activates innate pathways → inflammasome activated if too much damage/ infection → inflammasome causes recruitment of neutrophils (brought by IL8, IL6), monocytes and M1 Macrophages (CCr2) → phagocytosis occurs to remove damaged cell and debris → CCr2 activates IGF1 (for muscle regeneration) and sometime TNF (inhibits FAP cells and fibrosis). → if there is no ongoing muscle damage and clearing out area, IL10 released → M2 macrophages activated → activate satellite cells, extracellular cell repairing → functional muscle

Implications for exercise?

Muscle repair pathways need time to establish, so rest is required. The Initial inflammation (M1, neutrophils) are pro adaptive/ anti-fibrotic. However, constant inflammation via repeated damage may cause M1 macrophages to suppress repair (conversion to M2 macrophages).

Muscle Cell Stress can be induced due to Metabolic reasons (prevented by eating well), Direct damage (exercise, toxins), Neurologic reasons (helps to keep your fluid and electrolytes up).

Optimal rest between training allows muscles to repair



• Understand the differences between innate and adaptive immunity

Innate immunity: first line of defense, no memory effect, antigen independent, specific recognition of DAMP/PAMPs. They include Natural killer (NK) cells, Neutrophils, Macrophages, Dendritic cells. A series of receptors expressed in the innate immune cells detect stress molecules, pathogen products and dying cell factors and initiate cytokine and mediator production that orchestrates and initiate repair, killing and immunity.

Adaptive immunity: acquired (takes time), long-lasting, highly specific for antigens (both protein and lipid), involves clonal selection. They include T lymphocytes and B lymphocytes (to make specific antibodies)

• Understand some of the basic principles of immunity:

Cytokines are the key effector proteins in immunity, produced by immune and non-immune cells and effect on immune cell growth, development, activation, recruitment.

Lines of defense include physical barriers (skin, mucus, etc), innate immunity and then acquired immunity.

The cascade of immunity:

Release of DAMPs → Detection by innate immune cells → Production of cytokines and modulators (e.g prostaglandins, catecholamines etc. → Response within tissue; immune cell recruitment, inflammation, repair → Response at lymph node = adaptive immunity → B and T-cell activation and differentiation further refining the immune response

B-cell: antibody immunity

B-cells produce a single antibody which forms part of the B-cell receptor (responds to single pathogen)-

If the antibody portion of the BCR binds strongly to an antigen the B cell differentiates and proliferates to produce more of the antibody.-

B-cell differentiation involves increasing specificity of the antibody and Isotype switching of the antibody (driven in part via T-cell help).


T-cells are activated by fragments of antigens on dendritic cells and macrophages-

Secrete an array of cytokines that direct immunity-

Produce specific cytokines depending on differentiation pathways activated-

Many types: -

T-helper cells (CD4+): Help B-cells differentiate and produce cytokines to promote immunity-

T-regulatory cells (CD4+, CD25+): Produce IL-10 and other anti-inflammatory cytokines-

Cytotoxic T-cells (CTLs, CD8+): Produce granzyme and pro-apoptotic molecules that kill infected cells-

Natural Killer Cells (NK-Cells, CD56+): Similarities to innate cells and CTLs.

• Be able to discuss the impact of exercise on immunity: cell types and functions

Moderate exercise is anti-inflammatory.

Acute proinflammatory responses occur in the muscles to promote repair. Systemic effects generally anti-inflammatory (due to inhibition of TNF-alpha) unless high exertion and serious damage occurs.

Acute exercise is inflammatory. Causes a decrease in blood NK cells (no decrease in number, rather relocation to other areas such as peripheral vein walls and tissue) and lymphocytes. There is also a decrease in soluble IgA post high intensity and duration exercise.This lead to the hypothesis that immunity is decreased for a short period after exercise → open window hypothesis

More prone to get infections post exercise.

Functional effect on different cell types:

A decrease in NK cells, T cells and B cells were observed. Studies have shown that the NK cells don’t change in number, rather they relocate to areas such as peripheral vein walls and tissue following exercise. Also causes a decreases in cytotoxicity of the NK cells, which causes them to have less effect on infectious agents.

Neutrophils increase during and post exercise in the blood. Adding carbohydrates to it does not change the neutrophil numbers post exercise, but has an effect on neutrophil function.

Increased levels of monocytes in the blood and perturbation with high intensity exercise

Response to exercise (U/J shaped response):

When considering the case of upper respiratory tract infection:

• Sedentary state is maladaptive.

• Moderate physical activity is balanced between pro and anti-inflammatory mechanisms - immunologically beneficial

• High levels of activity and training are detrimental and immunosuppressive

Causes of getting URTI (Upper respiratory tract infection) in exercise:

Found most commonly immediately following high intensity endurance exercise.

Physical and mechanical damage (Caused by prolonged exercise (dry air), and localised to mucosal tissues; nasal passages, mouth, and lungs).

Allergy: (greater allergen exposure if training typically outside, large volumes of inhaled air.)

IgA secretion (Some studies suggest IgA secretion is reduced following prolonged high intensity exercise. It is a mucosal immunoglobulin→ important for initial defence against mucosal pathogens).

Increase in levels of Catecholamines (Adrenaline/noradrenaline)

Increase in levels of Glucocorticoids (Cortisol is immunosuppressive)

Central and peripheral control of immune cell status and immunity

Systemic (HPA-axis) effectors are produced (adrenaline and cortisol) post exercise. In addition there is the localized production of immune modulators (MIPs, IL-8, cytokines etc) that can be released to the systemic circulation post exercise. This alters cell migration and immune parameters (increased leukocytes, decrease in hematopoietic stem cells and functionality of stem cells). An increase in cortisol levels are also observed.

• Thus both central and peripheral pathways are activated by exercise

Role of Catecholamines:

Adrenaline and noradrenaline are produced by high exertion exercise and endurance events. Can be anti- and pro-inflammatory depending on the tissue and stimuli.

Effect of cortisol on the immune system

Cortisol is broadly anti-inflammatory and inhibits both the innate (inhibit prostaglandin production to prevent initial inflammation, Inhibit proinflammatory cytokine production, and decrease mast cell degranulation/ allergy) and adaptive immune systems (inhibit T cell activation and differentiation, inhibit Th1 immune responses → autoimmune, proinflammatory T-cells, and inhibit cytokine production by T-cells)

Effect of glucocorticoids:

· Glucocorticoids can function as potent anti-inflammatory drugs, used to treat inflammation. They increase metabolic recovery, and provide pain relief and they are anti-inflammatory.

Muscle cells produce factors that modulate immunity and the physiological response to exercise

Myokines are factors released by skeletal muscles, which work in a hormone like fashion by exerting specific endocrine effects on other organs via panacrine mechanisms.-

IL6 is produced by muscles. Generally thought to be anti inflammatory. Has beneficial effects on the liver. Acute response improves insulin signaling, increased insulin sensitivity in skeletal muscle, and decreases systemic TNF induction by endotoxin. Chronic response reduces insulin sensitivity in liver and adipose tissue. -

CCL2 → Acute response causes adaptation/repair/hypertrophy in skeletal muscle as well as local metabolic adaptation. Chronic response promotes insulin resistance; important factor for chronic low-grade inflammation in adipose tissue.

Pro-inflammatory and anti-inflammatory pathways and exercise

Typical exercise regimes (low intensity-high intensity) induce transient activation of pro-inflammatory cytokine and myokine mediators. These mobilise innate immune cells to traffic to damaged areas and help initiate repair. Once exercise is finished they rapidly return to normal levels and homeostasis resumes. Muscles adapt and less damage and cytokine output is associated with each recurrent bout. It is still unclear what drives the beneficial effects of exercise on health and immune function. It is likely that better metabolic control, reduced adiposity (decreases systemic inflammation) and a slightly anti-inflammatory phenotype all contribute.

Exercise and gut microbiota:

Exercise influences levels of IgA which controls gut bacteria, Innate Immune system which controls gut microbial composition, and Diet which helps controls gut microbiota. They are all linked with exercise and performance.

What are the long-term effects of exercise on the immune system?

Aerobic training leads to positive effects on natural immune functions, especially in young and old individuals and obese persons during weight loss

Areas of improvement include enhanced functional capacity of natural cytotoxic immune mechanisms (ie. NK cell activity, diminished age-related decrease in T-cell function and associated cytokine production, improved general health


Respiratory Response to Exercise)

• Key aspects of respiratory system nomenclature

V = volume (ml or L)

VT = tidal volume (ml or L)

V̇ = minute ventilation (ml/min) (dot over V → time derivative)

V̇ I = inspiratory ventilation (ml/min)

V̇ E = expiratory ventilation (ml/min)

V̇ O2 = oxygen consumption (ml/min)

V̇ O2max = maximum O2 consumption (ml/min)

TLC = total lung capacity (ml or L)

FRC = functional residual capacity (ml or L)

RV = reserve volume (ml or L)

VC = vital capacity (ml or L)

FVC = forced vital capacity (ml or L)

FEV1 = forced expiratory volume in 1 s (ml or L)

PaCO2 = arterial partial pressure of CO2 (mmHg)

PACO2 = alveolar partial pressure of CO2 (mmHg)

Function of the respiratory system:

Gas exchange (main), also involved in metabolic reactions (Acid/Base regulation, Removal, deactivation of cytokines, hormone activation etc), host defenses and speech (via phonation)

• The properties of the lung that optimise gas exchange

Large surface area for diffusion, PO2 low and PCO2 high and vice versa (creating a diffusion gradient), and little resistance to the movement of gases so they are in close proximity of alveoli and capillaries with thin walls.

Two lungs with 5 lobes to allow for increased surface area, shaping of the lungs to fit in other organs as well, and to allow continued function even if one lobe gets damaged.


Hollow air sacs open to the atmosphere for gas exchange

Surrounded by capillaries and Thin walled (0.4μm) in order to increase Alveolar-capillary surface area (about 85m2) which is a large surface for gas exchange and slow air movement to allow time for diffusion

• Changes occurring in ventilation & respiration during exercise


During Inspiration (Active movement):

- Inspiratory muscles ↑ thoracic volume, causing Pip (intrapulmonary pressure) & Palv (alveolar pressure) to ↓ below Patm (atmospheric pressure). -

contraction of diaphragm (major inspiratory muscle) and the intercostal muscles lower the floor of the thorax and lifts the ribs up and out. Volume of thorax increases and this decreases Pip (intrapulmonary pressure) & Palv (alveolar pressure) to ↓ below Patm (atmospheric pressure). Air then moves into the lungs to equilibrate pressure gradient. -

External intercostals elevate and move outwards 2nd rib and succeeding ribs-

During exercise, inspiration is assisted by upper chest wall muscles, they lift the ribs and clavicle for greater increase in tidal volume.

Changes occurring in ventilation & respiration during exercise


During Expiration:

• Quiet breathing-

Passive movement (elastic recoil). Relaxation of the diaphragm and the intercostal muscles allow rbs to return to original position. Decreases thoracic volume and increases intrapulmonary pressure and forces air out of lungs.

• Exercise (Active movement)-

Internal intercostal muscles contract to pull the ribs back to resting position -

Abdominal muscles push abdominal contents against diaphragm. Forces diaphragm back into thoracic cavity.

Control of breathing:

Involves complex neural mechanisms that involve the higher brain centres (medulla and pons → receives constant feedback from the central and peripheral inputs, respiratory centre of the brain), spinal cord neurons

Peripheral chemoreceptors for O2, CO2 and hydrogen (acidity regulator) and these are the main driver of ventilation at rest. Change in any of these levels lead to activation of neurons in the medulla and the arterial systems which lead to as well as irritant receptors (coughing).

• Processes that drive ventilation during exercise

• Processes that drive ventilation during exercise

The dynamic volumes are IRV and ERV to allow changes in tidal volume (also dynamic) . Static volumes are VC, RV, TLC

The dynamic volumes are IRV and ERV to allow changes in tidal volume (also dynamic) . Static volumes are VC, RV, TLC


• Minute Ventilation (V̇) = volume of air entering the lungs [ml/min]

Variables = V̅T and f (respiratory frequency, breaths/min)

V̇ = V̅T x fAt rest:

V̇ = 500 ml/breath (V̅T) x 15 bpm (f) = 7500 ml/min (7.5 L/min)

Moderate exercise: V̇ = 2-4000 ml/breath x 40-50 bpm = 80-200 L/min = 10-20 fold ↑!

During low intensity exercise, tidal volume (VT) and frequency increase proportionately.

During moderate exercise VT increases much more than ∆freq. This Increases V̇ A (alveolar minute ventilation) for minimal energy cost (increases efficiency!)

At max exercise, V̇ (minute volume) is much less than max voluntary ventilation (maximum volume of air that can be breathed in one minute)

Thus, a ventilatory reserve exists, so ventilation is not thought to be limiting for O2 delivery to exercising muscle.

What determines maximum cardiac output:

Higher CO (cardiac output) is associated with increase in Oxygen consumption. A person can work out harder if he increases his oxygen consumption more.

Factors affecting gas movement:

Ability of O2 and CO2 to diffuse across the alveoli / capillary interface depend on:

Pressure gradient between lungs and blood (high pressure gradient→ in the alveoli PP of O2 is high compared to venous pulmonary circulation. PCO2 is high in the venous system/ pulmonary artery compared to PCO2 in the lungs), Area for diffusion, Distance to travel and thickness of tissue through which gases diffuse, Transit time of gases relatively long due to increase surface area.

How is O2 delivery increased at exercising muscle:

Blood flow varies at different levels in the lungs of an upright person

• Standing – little flow to lung apex (top of the lung) while lung base has continuous flow, due to gravity.

• Exercise – demand for O2 increases up to 20x in heavy exercise. Blood flow to all areas of the lungs increases (4-7x) due to increase in Cardiac Output which causes increase in pulmonary artery pressure and increased capillary distensibility, as well as due to the increase in number of open pulmonary capillaries.

This increases alveolar surface area available for O2 uptake and thus ↑ O2 diffusing capacity of the lung

Role of Haemoglobin and interactions:

Carries O2-

Has 4 protein subunits associated with non-protein haem group, which is a Iron containing transport protein.-

Conformational change occurs as first Hb binds to O2. this change allows the other three haem groups to bind better with more oxygen (cooperative binding, increased affinity). -

By contrast, Co2 is carried by the protein chains of the molecule so it does not compete with O2 for binding at the haem group/ ion binding position. -

Factors that affect Hb affinity for O2 and O2 unloading from the blood are temperature, H+ and PCO2. increase in these factors causes a reduction in Hb Affinity for O2 and increases O2 unloading (more O2 is unloaded at the same PO2) from the blood and vice versa. These parameters are all high in systemic capillaries where oxygen unloading is the goal.


Oxygen unloading:

Exercise increases O2 unloading at muscle, curve shifts from left to right due to an increased hydrogen ions and CO2 (the Bohr effect). This is due to increase in PCO2, H+ (more acidity/ low pH) and temperature.

O2 consumption is increased in active muscles via a combination of an increase in blood flow (vasodilation and recruitment) to active muscles and an increased removal of oxygen from each ml for blood passing through muscle (by an increased arterio-venous O2 difference)

O2 unloading from Hb aided by:

- low muscle PO2 ; high blood H+ (lactate), temp & CO2, which reduces affinity of Hb for O2 (right shift of oxyHb dissociation curve)

What drives increased ventilation during exercise?:

During exercise, VO2 and VCO2 increases about 20 fold, but the ventilation remains matched with VO2-PAO2. This is in order to maintain PaO2, PaCO2 and pH and at fairly constant level. PaO2 only starts to drop at very high intensity exercise. When PaO2 and PaCO2 starts to drop body responds by increasing ventilation rate → PPAO2 increase.

pH starts to drop with high intensity exercise mainly due to metabolic acidosis (production of lactic acid). Also causes decrease in PCo2 during exercise because CO2 is a weak acid, and the body tries to compensate for metabolic acid by trying to eliminate as much CO2 as possible.

Regulation of exercise ventilation (neural- humoral control):

Matching of cardiac output (CO) with ventilation (VE) via elimination of CO2

Neural hormonal control of ventilation during exercise:

• Immediately prior to exercise, VE increases → neural drive (anticipatory) via central command from cerebral cortex. → neural basis.

• During exercise VE rapidly rises (10-20s) on a neural basis. It then rises more slowly via chemical basis. Involves the cerebral cortex (central) and the mechanoreceptors in the muscles and the limbs (peripheral) .

• On cessation VE rapidly falls – neural basis & then stabilizes – chemical basisChemical / humoral factors involved in this which allows fine tuning of VE by peripheral chemoreceptors resulting from rapid small fluctuations in PaCO2 and pH/lactate during severe exercise.

How does the respiratory system adapt to exercise training?

Changes in Skeletal, cardiac muscle (heart and skeletal muscles become stronger and more efficient to allow greater capacity to increase cardiac output cia increase in stroke volume → main limiting factor for VO2max) and capillary structure (greater capacity to deliver oxygen into the tissues) via training

How does the respiratory system adapt to exercise training?

Slight adaptation-

Parameters such as Airway, alveolar and vascular structure, Diffusion capacity, Diffusion surface area, Lung volumes (VC, TLC) remain unaltered.-

ventilatory muscles such as diaphragm and intercostal muscles may become fatigue resistant - yet to be determined. -

Thus the structure and function of the respiratory system is already optimized

Ventilatory Threshold

• The point at which pulmonary ventilation increases disproportionately with O2 consumption. = Tvent. At this point, pulmonary ventilation not related to cellular O2 demand, rather, increased ventilatory drive comes release of CO2 from buffering of lactic acid production which leads to metabolic acidosis, and the body deals with this change in pH by trying to get rid of CO2 from the body, and also via increase in minute ventilation.

How does training affect Tvent?

Depends on two components. -

Normally Ve increases linearly till 50-65% VO2 max after which it increases in a curve.-

In general Ve is higher in untrained than trained individuals, and ventilatory threshold is lower in untrained people. This is an adaptation observed due to training but not at the respiratory level, but rather at the muscular level, to increase lactate threshold. -

The lactate threshold is the exercise intensity at which blood lactate begins to accumulate. This is when lactate clearance no longer keeps up with production, which occurs at the ventilatory threshold. This value varies between individuals and can be increased with training.

• Limitations of the respiratory system to exercise

In general, the respiratory system does not limit performance.

The exceptions are Altitude (Reduced Hb saturation due to reduced PPO2 in the mountains, Hyperventilation – respiratory alkalosis→ shift to left of the curve → increase Hb binding and decreases O2 unloading, Higher CO – reduced blood transit time, Fatigue of respiratory muscles) and Disease.

• Know what drives ventilation

▫ Humoral / Chemical-

Same factors affect this as the oxy-Hb curve!-

Contribute to the slow portion of the increase in ventilation (fine tuning)▫


Drives the large and rapid increase in ventilation upon beginning exercise-

Also causes anticipatory increase in ventilation-

Some unexplained component