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Notes of week 3 MNP
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College 7Block 13 – Fatigue I
In block 12 we have seen that muscle contractile activity itself can lead to an
increase of the force and power output of that muscle: potentiation
However, to intensive (and/or prolonged) exercise will lead to muscle fatigue.
This can be defined either as failure to prolong the activity at a given work load
(or force level in case of isometric contractions) and/or as a decrease of the
maximal force (power) producing capacity.
Fatigue is a very important phenomenon in every day life of many people and
also in patients and athletes. It comes in different forms and many aspects still
are unclear.
Fatigue also will affect the basic contractile relations of skeletal muscle.
Slide 5
Years ago, the coach of the Dutch Olympic Laser team approached me with the
following questions:
- To what extent does the fatigue in Laser sailors depend on their hiking
position?
- Can you develop a test to monitor the physical condition of our sailors and
training progress?
Notes: Laser sailors hike, they lean outward the boat to encounter the pressure
generated by the wind into the sail to keep the boat levelled. They can do so with
flexed or more extended knees and these positions may lead to different levels of
fatigue.
To answer the questions of the coach we have to have fundamental knowledge
about the causes of fatigue.
Slide 6
Longer lasting and/or repetitive muscle contractions, mean that fatigue comes
into play as an additional factor affecting the muscle contractile properties.
We already have seen that with fatigue
- Maximal isometric force (F0) declines
- Vmax declines
- The force-velocity relation becomes more concave (F 0/a declines)
- Power production declines
Notes: In addition we have seen that in genera, with fatigue the rates of force
development and relaxation also will slow down.
Slide 7
Notes: it was already mentioned earlier that fatigue may
directly affect cb function (1).
It was also mentioned that in some conditions, HFF may
occur (involving reduced action potential propagation
over the surface membrane into t-tubuli (2)). This will
lead to reduced Ca2+ release by the SR (3).
It will now first be demonstrated that Ca 2+ release by the
SR can also be reduced more directly during repetitive
contractions.
Finally, the metabolic changes occurring in the muscle in
combination with factors such as an increase in core
temperature, may contribute to a decline of force or power and thereby to a
decline of ATP-consumption. In this way we protect the cells in our body for
getting too low levels of ATP and too low pH, which both would cause serious
damage if these would become too low. So, there is an elaborate network of
,feedback mechanisms that prevent serious damage to occur. If we take doping,
in order to produce more power for longer, and we would succeed in doing so
(e.g. amphetamines) this is very dangerous. An example is the medicine Ritalin
(which is used by people with ADHD), this medicine is known to interfere with our
thermo sensation system. Our core temperature is usually strictly regulated and
if it surpasses 39-40degrees (which may occur when exercising in the heat)
normally we will slow down (are forced to slow down). Exercise intensity will drop,
which prevents core temperature of becoming too high. However, with Ritalin our
body does not sense the core temperature correctly anymore and consequently
we may keep on running at a too high intensity for too long. This is very
dangerous: rats have known to run themselves to death while running in the heat
with Ritalin-like medication.
Comments: when we wouldn’t have fatigue and we keep on exercising, the ATP
levels might end up very low, and then we might end up in rigor. If there is a risk
of ATP-levels going too low, you reduce exercise intensity (fatigue). Regulation is
possible at different levels 1, 2, 3 and 4.
1. Cross-bridge activity metabolites might impact cross bridge function,
this may be lower and energy consumption will go down
2. With too high stimulation frequency we might accumulate potassium in the
t-tubuli and this will prevent action potential conduction across muscle
fibers and therefore reduce calcium release and force production high
frequency fatigue
3. Interfere with calcium release (less calcium) e.g. low frequency fatigue:
damage of the proteins in the excitation-contraction coupling which leads
to decrease of calcium release
4. You may feel the pain which has inhibiting effects on motor neurons
Especially protons and Pi are related to fatigue.
Slide 8 4
2+ Caffeine
Notes: if we now move on to the process of Ca 3
Force (mN)
release, people have seen that during repetitive 2
stimulation of isolated skinned fibers, force
1
declined over several minutes, but that addition of
caffeine (which opens Ca2+ channels independently 0
from any action potentials*) immediately restores 0 1 2 3 4
force to a substantial extent. This indicated that Time (min)
Ca2+ release may become a limiting process during fatigue in this preparation.
*in skinned fibers caffeine directly opens the ryanodine receptors in the SR: Ca 2+
release.
Slide 9
Notes: these are force (bottom) and Ca 2+ traces (top) of skinned
muscle fibers. Ratio on the y-axis indicates how much of the dye is
bound to Ca2+ ions (indication of the amount of Ca 2+). In the fresh
state (left) we see that addition of caffeine also increases Ca 2+, but
not force: thus, the muscle fibers were already maximally saturated
with Ca2+ without caffeine, hence [Ca2+] was not the limiting factor
for force production. However, in the fatigued muscle (after several
minutes of contractions) the decline in force can partly be restored by addition of
caffeine (which increases [Ca2+]). This indicates that Ca 2+ concentration may
become limiting during fatigue (at least in isolated single fibers).
,Comments: in the fatigued state the calcium was not saturated not high enough
to produce maximal isometric force. So it seems, that under certain
circumstances, calcium release from the SR may become a great limiting step in
the whole sequence of events that leads to force production.
Slide 10 A A
a
bb
c
c
Notes: This is another example. When we increase the number [Ca
a
1 2+
2+] 1
] [Ca
i I dd
(M)
of contractions per second (from 1 to 4) over time, we see that 0
( M)
0
at some point (4 contractions per second in c) force declines
rapidly together with [Ca2+]. This example also shows at the B B
400 400 a
a
11 ss
same time that the (limited) reduction of force during the first bb cc
Force Tension
minutes was not caused by a too low [Ca 2+], since the latter (kPa) (kPa)
even increased while force decreased (b). dd
Nevertheless, under certain conditions Ca 2+ release ([Ca2+]) 0 0
may become too low, which will (further) reduce force 11 min
min
production.
Slide 11 400
Sensitivity of troponin C for Ca2+ is probably not reduced (no 300
Force (kPa)
rightward shift) during ‘normal’ fatigue (red) although Sundberg
200
and Fitss (2019) think this does occur.
Note: also during low frequency fatigue a reduction of Ca2+ release 100
and consequently less force, may be a more important factor than 0
reduced sensitivity of troponin. 0.0 0.5 1.0 1.5 2.0
[Ca2+]i (μM)
Notes: there are also suggestions that the binding of Ca 2+ to
troponin-C may become more difficult under conditions of fatigue. However, in
general the Ca2+ force relation in fatigued is not much shifted to the right during
fatigue (red) indicating that Ca 2+ sensitivity is only marginally decreased. Note,
however, that with low frequency fatigue (pronounced in the hours following
repetitive long lasting contraction, especially following eccentric contractions) the
sensitivity of troponin may be reduced more profoundly, although also during LFF
a reduction of Ca2+ release may be a more important factor than reduced
sensitivity of troponin.
The exact causes for the decreases in Ca2+ release during LFF are
unknown, but probably involve some kind of damage to structures
involved in excitation contraction coupling (T-tubuli/SR).
Slide 12 Fresh Fatigued
Ca-pumps are not slowed down during fatigue and cannot
explain the slowing of relaxation
Notes: potentially the Ca2+ pumps could also be affected during
fatigue. When this would occur this may account for the slowing
of relaxation which we often see during fatigue. Indeed, in
0.5s
amphibian (frog) muscle this occurs. However, in mammalian
muscle the Ca-pumps are not slowed down during fatigue and therefore cannot
explain the slowing of relaxation. Dashed line is force, continuous line denote
[Ca2+].
Slide 13 – metabolism and fatigue
- Which metabolites may contribute to fatigue?
- Do these metabolite concentrations change during exercise?
- Via which processes do these metabolites affect performance?
Notes: during high intensity exercise we have to regenerate a large amount of
ATP per unit of time: the metabolic fluxes through the different reactions involved
, in ATP regenerations are extremely high. This will lead to all kinds of changes in
concentrations of the reaction products. In principle these metabolites could
affect the different processes related to peripheral fatigue.
Slide 14
In terms of energy production per units of time, the anaerobic
reactions are the most important. From these we see several
potential candidates that could account for (part of) the force
(and speed) reduction during fatigue. Note that only when PCr
is close to zero, ADP and H+ are expected to increase. In
addition, Pi IMP, NH3 and lactate seem potential candidates.
Lactate itself is just a useful (energy rich) molecule which does
not affect force production during fatigue. However,
peripherally NH3 has no direct effects.
Note: C) this so called stress reaction occurs during very high intensity
maximal exercise.
Comments: in general, that indeed the metabolic changes are linked to fatigue.
All reactions are to minimize the drop in ATP.
With activity ATP is split in ADP, H+ and Pi. To replenish ATP the creatine-kinase
reaction becomes very active. At very high intensity exercise there are the
coupled reactions of C. When more ATP is needed the anaerobic glycolysis is
started. When the energy flux is really high, you get a drop in pH.
Slide 15
Notes: these are the changes measured in isolated muscle fibers
poisoned with cyanide (which blocks complex II in the respiratory
chain, consequently aerobic energy production is no longer possible
in this preparation). With 20Hz stimulation we see several changes
but during the first 30sec the decline in force is limited, whereas the
changes in ATP, PCr and lactate are already considerable in the first
30sec.
We only can conclude that after 60 seconds, PCr was low (and hence
Pi was high), ATP was reduced, and lactate increased. It doesn’t tell us which
metabolite is causally related to fatigue.
Slide 16
Notes: in humans we can make similar measurements
with NMR (Nuclear Magnetic Resonance) we see
decreases in PCr, increase in Pi (and hardly any changes
in the three different ATP peaks).
- Note that the distance between PCr and Pi peak
also increases: this is a measure of the decline in
pH.
- Note that the PCr peak splits: probably indicative
for the greater drop in pH in the fast compared to
the slow muscle fibers.
- Note that the ADP peaks are not visible (they are small and covered by the
ATP peaks)
- Note that there are three ATP peaks, because ATP contains three different
phosphates, which are each slightly different configuration within the
molecule and therefore have a slightly different resonance frequency.
Additional information: note for the exam: phosphate nuclei have a charge and a
spin (rotation), together these lead to tiny magnetic fields pointin into a certain
direction depending on the orientation of the P nuclei: so normally all P-nuclei will
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