Summary of the lectures and articles of the research master course Exercise and Clinical Immunology of the research master human movement science at the Vrije Universiteit Amsterdam. Includes notes of the lectures and summary of the reading material (chapters of book and articles)
Exercise and Clinical Immunology
Lecture 1
Chronic diseases with a low grade of inflammation or compromised immune system: obesity,
diabetes type 2, osteoarthritis, periodontitis, ageing and frailty, cardiovascular disease, interstitial
lung diseases, cancer, Alzheimer, osteoporosis.
Cachexia and loss of muscle mass are associated with aging and chronic disease with low grade
inflammation.
The loss of muscle mass is strongly related to morbidity and mortality.
Exercise is medicine?
Cardiometabolic wellness, improves cognitive performance, and treatment of a variety of health
conditions
Exercise provides protection against (chronic) disease?
Recent research shows that exercising before an injury may lessen the severity of future chronic pain.
Neuromusculoskeletal and cardio-respiratory systems, different phenotypes for both traits.
Molecule (DNA) → Cell → organ in vivo/in situ → organism → movement performance
If you understand the whole chain of molecule, cell, organ and organism, you don’t have to do try
and error.
Epigenetic: if your DNA is more or
less packed → each cell same
genome, but epigenetics make it
into different proteins. More
glucose ect.
Peak power:
• Large muscle fiber diameter
• Fast myosin heavy chains
• Glycolytic metabolism
• Low myoglobin concentration
• Low capillary density
Endurance:
• Small muscle fiber diameter
• Slow myosin heavy chains
• Oxidative metabolism
• High myoglobin concentration
• High capillary density
, Amount of muscle fibers at birth, can’t change that
Oxygen provided by capillaries, endurance athletes have
more capillaries and a shorter diffusion distance. Myoglobin
can easy bind oxygen. The cell can sense oxygen.
Inverse relation between muscle fiber size and oxidative
capacity. So al mitochondria are always supplied with
enough oxygen.
Transcription – nucleus, translation – cytoplasm, post-
translational modification – Endoplasmic reticulum or cytoplasm
Transcription of mRNA → signal is calcium or a low energy state.
Integrins/dystroglycane stick through the membrane it connects the outside with de matrix on the
inside. When muscles contracts there is also a signal along the length of the muscle and it gives
signaling cascade. When you pull on the complexes they undergo a transformation. And the .. binds
to the molecules and that’s where DNA translation starts. NO- gas can also signal and also go outside,
it can change protein transcription
Also stretch factors on the membrane, transformate and calcium can enter the cell. Produces factors
which produces growth factors and they can be thrown in space.
Fibroblasts are cells in the connective tissue and they produce collagen. IL-4 and 6 produced bij
immune system but also by muscle cell. Muscle cell can produce many growth factors.
When we do a 5 min exercise that transcription is increased and rate of translation is increased. By
making a growth factor.
It goes in an indirect way because:
• It allows also signaling to a neighbor like the fibroblast. Allows distribution over the whole
cell and to others cells.
• it can be taken up in the circulation.
Insulin-like growth factor 1 (IGF-1) seems to be a strong anabolic factor in the induction of muscle
hypertrophy.
IGF-1 affects muscle protein content by different signaling systems
• autocrine signaling is a form of cell signaling in which a cell secretes a chemical messenger
(autocrine agent) that signals the same cell
• paracrine signaling is a form of cell signaling in which the target cell is close to the signal
releasing cell
• endocrine regulation is a control system of glands that secrete chemical ‘messengers’ called
hormones that circulate within the body via the bloodstream to affect distant cells within
specific organs
We have all kind of factors:
• hormones
• growth factors
• steroids
• cytokines
• adipokines (originally associated with a… fat cells)
,Growth factors is a naturally occurring substance capable of stimulating cellular growth,
proliferation, healing and cellular differentiation. Usually it is a protein or a steroid hormone. Growth
factors are important for regulating a variety of cellular processes. They typically act as signaling
molecules between cells, cytokines and hormones that bind to specific receptors on theh surface of
their target cells.
Under stress conditions, ER stress may occur and this will affect translation of mRNA within the ER
system
Exocytosis: secreting the factors in the space between the cells.
Endocytosis: secreted to the inside of the cell
Growth factors and cytokines; mechanical load causes; :
1. activation of transcription factors involved in activation or repression of many different
genes
2. expression of
a. growth factors: IGF-1Ea, MGF and myostatin, VEGF, HGF, TGFbeta, GDF11, BDNF
b. cytokines: interleuking-6, IL-4, COX2
By alternative splicing, particular parts are left out and you get IGF-1 like isoforms. Like IGF-1ea and
MGF.
Effects of eccentric, concentric and isometric contractions on the expression of growth factors
Gastrocnemius muscle; 4 days, each day a serie of contractions of the different types.
IGF-1ea and MGF mRNA are upregulated by the different stimulation patterns.
Myostatin is downregulated by the different stimulation patterns.
IGF 1 is a strong anabolic agent -30% hypertrophy without training!
MGF is a muscle repair factor by activating muscle stem cells → myoblast → myotubes, fill gap
where the muscle was broken. Make a new and longer muscle. IGF will enhance the size and … tion.
Myostatin inhibits the process which MGF enhances. Receptor of myostatin is also in other cells.
If you go to the mountains and exercise the amount of VEGF increases and you get more capillaries,
but in case of a tumor you don’t want more capillaries.
Hepatocyte growth factor (HGF) is attached to the ECM of a muscle cell and is released by nitric
oxide. If you damage a muscle cell, it can activate many cells. HGF was shown to be in the blood
stream by injury. Probably communication to all the cells.
HGF stimulates proliferation of satellite cells, whether HGF is taken up into the circulation is
unknown, however HGF activator, which is an enzyme that cleaves HGF is a serum factor which is
known to be taken up in the circulation and will work from one tissue to another.
Endurance exercise induces fatigue and excessive increase in IL-6 – a 100 fold increase. IL-6 is always
been associated with immune system and has many functions on the muscle cell. With a marathon
IL-6 increases. It stimulates protein degradation. Opposite of IGF. It inhibits … it can have multiple
functions. Stimulates also oxidative metabolism.
In elderly it is negative for the size, in marathon runners it’s not such an problem.
, Communication between cells via
exosomes, very small microvesicles. They
are thrown in the space between cells and
can be taken op in de blood stream.
Contain proteins, DNA and RNA. Still
discovering what is in and where it works.
Crucial functions in cell but also in distance.
RNA can be used for a protein, but also for
miRNA and that can bind to messenger
and can block translation. You can regulate
gene expression in other cells.
Myotubes secrete soluble factors that
inhibit osteoclast formation. Cyclically-
strained myotubes modulate osteoclast
formation via IL-6. Our data suggest that
the production of soluble factors by muscle in response to mechanical loading may affect bone
metabolism, likely via IL-6.
Article Pedersen
Physically inactive people have a life span that is 5 years shorter than that of physically active people.
Type 2 diabetes, CVD, colon cancer, breast cancer, dementia and depression constitue a cluster of
diseases which defines a ‘diseasome of physical inactivity’. → different phenotypical presentations,
but share important pathogenetic mechanisms. Inflammation is associated with physical inactivity.
Abdominal adiposity is associated with CVD, type 2 diabetes, dementia, colon cancer and breast
cancer. Same as with physical inactivity, both also inflammation.
Physical exercise is a factor that strongly affects brain plasticity. Higher levels of cardiovascular
fitness are associated with increased hippocampal volume as well as better memory function.
Several meta-analysis demonstrate a positive association between cardiovascular fitness and
cognitive performance in elderly subjects. Protect against dementia.
There are indications in the literature that physical inactivity is an independent cause of abdominal
adiposity and a contributing factor to cognitive decline. It is possible that physical inactivity leads to
the accumulation of visceral fat and consequently the activation of a network of inflammatory
pathways, which not only promote the development of insulin resistance and atherosclerosis but
also lead to neurodegeneration and thereby the development of cognitive impairment.
Myokine concept
Myokines play a role in protection against the diseasome of physical inactivity.
Myokines: cytokines and other peptides produced, expressed and released by muscle fibers and
exert autocrine, paracrine or endocrine effects.
Another source of cytokines is adipose tissue (adipokines).
Contracting human skeletal muscle releases significant amounts of interleukin IL-6 into the
circulation during prolonged single-limb exercise.
IL-6 – the myokine prototype
During exercise increase in plasma concentration of IL-6. Followed by appearance of IL-1 receptor
antagonist and anti-inflammatory cytokine IL-10.
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