Download Skeletal Muscle Fatigue: Lactic Acid or Something Else? Ian Stowe

Skeletal Muscle Fatigue: Lactic Acid or Something Else?
Ian Stowe
University of Florida, PET 5936
November 22, 2013
Abstract
The study of skeletal muscle fatigue during exercise is a complicated endeavor. There
are many physiological changes that occur during exercise and it is difficult to isolate
specific variables. For many years acidosis has been targeted as the primary source of
muscle fatigue; specifically acidosis due to lactic acid. Recent studies, however,
challenge this notion and have demonstrated that acidosis at physiological temperatures
does not have as large of an impact on muscle fatigue as previously believed.
Alternatively, researchers have investigated the role that inorganic phosphate (Pi) and
potassium ions (K+) play in skeletal muscle fatigue. The results suggest that each of
these factors contribute more greatly to muscle fatigue than does lactic acid.
Furthermore, lactic acid has been shown to actually decrease the rate of muscle fatigue by
maintaining muscle force-producing capabilities.
Introduction
In trying to determine whether or not lactic acid causes skeletal muscle fatigue, it
is imperative to first define fatigue and discuss the underlying physiological mechanisms.
Skeletal muscle fatigue can be defined as the temporary decline in muscle forceproducing capabilities associated with an acute exercise bout. For the purposes of the
current study we will not examine persistent fatigue arising from chronic exercise and
overtraining. Such a broad definition does not actually tell us much about fatigue or its
underlying causes. However, it does provide an excellent segue into detailed studies and
experiments aimed at uncovering the phenomenon that is skeletal muscle fatigue. While
vague, there are some concepts that can be extrapolated from this definition. For
example, we can eliminate disease as being the cause of skeletal muscle fatigue because
we know that fatigue is a fleeting condition. An inhibition of force-producing
capabilities due to an illness would be a symptom and not the source of skeletal muscle
fatigue.
To examine fatigue, we must examine the entire skeletal muscle force-producing
process from the onset of excitation thru individual cross-bridge contraction. During
volitional muscle contraction, the initial urge to move originates in higher brain centers in
subcortical and cortical regions. The movement blueprint then undergoes a series of
revision processes as it is passed between various brain regions. Eventually, the motor
cortex “approves” and passes the final plan down to the spinal cord, which puts on the
“finishing touches” and relays the plan to the motor units as an action potential or series
of action potentials. An action potential is an electrical signal that travels through a
neuron or muscle cell in the form of a wave of depolarization and subsequent
repolarization. This impulse is passed on to the next cell via the release of
neurotransmitters, which react with protein channels, allow for the rapid movement of
ions between inter- and intracellular areas, and incite an action potential in the new cell.
When an action potential reaches the myocyte, acetylcholine is released and activates an
action potential in the muscle fiber, ending excitation events.
Excitation-contraction (E-C) coupling, or the events that bridge the gap between
excitation and contraction, commence when the action potential traverses the cell
membrane and down T-tubules triggering the release of calcium ions from the
sarcoplasmic reticulum into the cytoplasm. The calcium binds to troponin and E-C
coupling concludes. Contraction begins when calcium-bound troponin causes
tropomyosin to move exposing myosin-binding sites on the actin. When sufficient
energy is present, in the form of ATP, myosin heads can continually bind to, pull, and
release from actin. This is referred to as cross-bridge cycling and it causes the actin
protein complex to slide past myosin contributing to the subsequent shortening of the
sarcomere and, in turn, the entire muscle; a contraction. When neural activation ceases,
calcium is taken back up by the sarcoplasmic reticulum via calcium-handling proteins
such as parvalbumin and calsequestrin, tropomyosin shifts back to its original position
and contraction is terminated.
Acidosis
The manifestation of any physiological condition that interrupts or retards any
part of the excitation-contraction cascade over the course of an exercise bout contributes
to muscle fatigue. Muscle acidosis has long been considered the major source of skeletal
muscle fatigue during exercise.2,7 An acid is a molecule that when dissolved in water
releases hydrogen ions (H+). In theory, acids can cause damage to myofibrillar proteins
as well as metabolic enzymes resulting in fatigue due to inhibited energy production and
decreased functioning of contractile machinery. Lactic acid, specifically, is regarded as
the primary culprit. Lactic acid dissociates quickly in the blood effectively forming
hydrogen ions and lactate. So, when we question lactate’s contribution to fatigue we are
actually referring to its formation via lactic acid dissociation and not lactate itself.
The exponential accumulation of lactate that begins at the lactate threshold is
quite noticeable. Because lactate accumulation is a major symptom of the lactate
threshold and the lactate threshold is associated with rapid muscle fatigue, a correlational
effect between acidosis and fatigue is evident.3,15 This has led many people to believe that
lactic acid is the source of the large majority of the physiological impediments that occur
at this flexion point. However, other molecules also tend to accumulate during exercise
and may actually contribute to muscle fatigue to a greater extent than lactic acid.
Inorganic phosphate (Pi) and extracellular potassium ions (K+) are just two examples of
molecules that may in fact have such an effect. Pi appears to disrupt cross-bridge cycling
and calcium sensitivity while K+ affects potassium-sodium dependent activation
processes.8,11,24
Many studies on lactic acid acidosis and muscle fatigue have been performed
using in vitro skinned muscle fiber testing. In these studies, experimenters measured
force production and maximal shortening velocity as indicators of muscle fatigue. This
form of testing has shown to be highly temperature-dependent and has skewed our
understanding for years. At lower temperatures, artificially induced acidification caused
a greater decline in force production than at higher temperatures. One study
demonstrated significantly diminished force production in response to acidification at
10˚c and yet another study demonstrated similar findings at 12˚c.17,23 The same
experimenters demonstrated a 20% decrease in muscle maximum shortening velocity at
12˚c.23 One may be inclined to quickly attribute muscle fatigue to lactate acidification
based on this data. However, there is a distinctly important difference between that
which is statistically significant and that which is physiologically significant. As we
know, 10-12˚c is far from being physiologically normal.
As temperatures approach 37˚c (body temperature) these adverse effects are
abated. Acidification at 32˚c, for example, caused a force production reduction of less
than 10% while not significantly reducing maximal shortening velocity.23 Various
experiments conducted at near physiologic temperatures that decreased normal pH by .4.5 units exhibited extremely similar findings, suggesting that acidosis and, by extension,
lactic acid is not the primary source of skeletal muscle fatigue in the working muscle.13,17
Furthermore, some studies have even indicated an association between lactic acid
accumulation and improved force production.18
Inorganic Phosphate (Pi)
Recent studies have demonstrated that some of the effects once attributed to lactic
acid can actually be ascribed to Pi.6,10,24 Like lactate, Pi levels are positively associated
with exercise intensity. Pi is formed when ATP-stimulated myosin heads release ADP
and Pi after ATP is hydrolyzed by myosin ATPase. Pi is also formed as a direct product
of the phosphagen, or ATP-phosphocreatine (PC), system. We know that when Pi is
present in muscle fibers that myosin heads and actin form a relatively weak bond. Only
after Pi is removed is a strong bond established. Theoretically, increased levels of Pi
inhibit cross-bridge force production in this manner. Unfortunately, it has proven very
difficult to isolate the effects of increased Pi on force production because the introduction
of Pi alters various aspects of metabolic functioning. However, one study measured the
effects of Pi by reducing, as opposed to infusing, Pi into muscle cells and was successful
at increasing cross-bridge force-producing capabilities.19 This indicates a direct
relationship between increased Pi and skeletal muscle fatigue. Needless to say, the data is
equivocal and further research in this area would be hugely beneficial.
Two ubiquitous consequences of augmented Pi quantities include decreased
myofilament calcium-sensitivity and inhibition of calcium ion (Ca2+) release from the
sarcoplasmic reticulum (SR).10,14,24 One study in particular demonstrated the deleterious
reactive effects of Pi on calcium. In this study, skinned rat muscle fibers were mixed in
solutions of varying quantities of Pi and various calcium-related processes were adversely
affected.10 A decrease in calcium sensitivity was observed as indicated by a significant
decrease in maximum fiber tension of both fast and slow-twitch muscle fiber types.
Phosphate’s adverse effects on muscle tension were demonstrated in other studies as
well.5 A decrease is cross-bridge force production was also observed. This study also
investigated the mechanisms responsible for inhibited calcium release from the SR.
It has been suggested that Pi leaks into the SR via ATP-sensitive anion channels.1
Once it enters, Pi reacts with calcium stores and forms CaPi and eventually undergoes
precipitation forming CaPi precipitate.12 Precipitation refers to the process of a substance
becoming separated from a solution following the introduction of a reagent and
subsequent reaction. The term precipitation is derived from the visual resemblance of the
chemical reaction to rain. When a reagent is added to a solution and precipitation occurs
the separated substance appears to “rain” down through the solution to the bottom of the
container. Calcium ions in the form of CaPi precipitate are not functional for the
purposes of activating muscle contraction via troponin binding. In addition, this reaction
reduces free Ca2+ availability in the SR thus inhibiting calcium release and, subsequently,
calcium-dependent muscle contraction. To combat this decrease in calcium availability,
the SR undergoes prolonged Ca2+ uptake, which runs counter to the calcium release that
is necessary for muscle contraction.21 Therefore, this calcium “loading” by the SR is
associated with skeletal muscle fatigue.10
Potassium Ions (K+)
The final possible mechanism of muscle fatigue that we will examine is the
exercise-induced rise in extracellular potassium ions (K+). The increase in extracellular
K+ observed during exercise parallels increases in exercise intensity.20 As we know, K+,
sodium ions (Na+), and other various ions play a pivotal role in neural signaling and
communication. As mentioned previously, neural communication is achieved thru a
series of action potentials. The rapid depolarization and polarization that compose an
action potential are the products of the movement of the aforementioned ions across the
plasma membrane via specific ion channels. When excess K+ ions exit the cell, the
resting membrane potential is altered such that the cell becomes hyperpolarized. In other
words, the cell shifts to a state that is further from threshold thereby reducing the speed of
neural activation.4,16 This in turn retards muscle contraction and contributes to fatigue
over time.
Amazingly, studies have demonstrated that lactic acid can actually enhance
muscle contractility previously inhibited by extracellular K+. In one particular study,
experimenters first successfully demonstrated the stifling effects of extracellular K+ on in
vitro slow and fast-twitch rat muscles.11 They demonstrated, using a force transducer, that
increased extracellular K+ does in fact contribute to decreased force production. When
lactic acid was introduced, force production improved significantly. For example, in a rat
soleus muscle exhibiting a 25% decrease in force production due to K+ exposure, the
addition of lactic acid almost entirely restored tetanic force.11 The mechanism for such an
occurrence is not entirely certain. In the working muscle, lactic acid is formed when
pyruvate accepts two hydrogen ions but lactic acid dissociation involves the release of
just a single H+ to form lactate, which actually produces a net removal of harmful ions
from the cell and blood. Theoretically, the formation of lactate can act as an acid buffer
by preventing a rapid decline in pH.22 Here we see that lactic acid formation is not the
cause of muscle fatigue but is actually critical in retarding the fatigue process.
Conclusion
Lactic acid, and by extension lactate, is not the physiological miscreant as once
imagined. It appears as if early studies and popular belief have accused lactic acid of
causing muscle fatigue because of the very strong correlation between increased lactate
accumulation and muscle fatigue. This has given rise to the term “lactate threshold”, or
the exercise intensity at which lactate begins to accumulate and muscle fatigue begins to
manifest. However, many physiological changes occur at this flexion point and it is
difficult to determine isolated effects.
More and more studies are emerging that relieve lactate of its poor reputation,
suggesting that at physiological temperatures acidosis does not play a large role in muscle
fatigue. Furthermore, research has uncovered other suspects such as Pi and extracellular
K+. The data suggests that these chemicals actually contribute greatly to skeletal muscle
fatigue. Lastly, it has been demonstrated that lactic acid can significantly alleviate
fatigue effects caused by K+ which significantly turns the table on previously held
notions regarding skeletal muscle fatigue.
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