07/11/2022

Muscle Fatigue
DOMS (muscle soreness)
Overtraining
Rhabdomyolysis

Muscle Fatigue: Inability to maintain a given exercise

intensity or power output
• Individual is rarely completely fatigued – He/She can
maintain lower intensity output
Muscle fatigue can be classified as:

 Temporary: due to strenuous physical activities. The time to recover from

muscle fatigue will depend on the extent of the intensity and length of the
physical task. On average, the individual should be fully recovered within 3
to 5 days. The usual intervention to speed up muscle recovery involves
massage, cold compression, and light analgesics’ intake. However, muscle
fatigue lasting beyond 2 weeks should require medical attention

 Chronic: related to muscle wasting mediated by aging, immobilization,

insulin resistance, diseases associated with systemic inflammation
(arthritis, sepsis, infections, trauma, heart failure, chronic obstructive
pulmonary disease (COPD)), chronic kidney failure, muscle dystrophies,
muscle myopathies, multiple sclerosis, and, more recently, coronavirus
disease 2019 (COVID-19)
Molecular Mechanisms of Muscle Fatigue - PMC (nih.gov)

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Possible causes of temporary muscle

fatigue:
1. Deficit of ATP production through decreased rate of
energy delivery from the Energy Systems ATP-PCr,
anaerobic glycolysis, and oxidative metabolism Peripheral
Fatigue
2. Accumulation of metabolic by-products, such as
lactate and H+

3. Failure of the excitation-contraction coupling

mechanism
Central
4. Alterations in neural control of muscle contraction Fatigue

1.- Deficit of ATP production. Energy Systems and Fatigue

When we feel fatigued, we often express this by saying “I have no energy.”
Can a deficit of substrates necessary for ATP synthesis cause fatigue during
exercise?

1.1.- PCr depletion

• Biopsy studies of human muscle have shown that during repeated maximal
contractions, fatigue coincides with PCr depletion 
• Causality or Chance?
• Possibly, intracellular accumulation of Pi, which increases during intense
short-term exercise because of the breakdown of ATP, is a potential cause
of fatigue in this type of exercise
• Pi impairs myofibrillar performance altering the crossbridge
turnover and reduces Ca2+ release from the Sarcoplasmic
Reticulum

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1.2.- Glycogen Depletion

• Diverse studies have shown a correlation between muscle glycogen
depletion and fatigue during prolonged exercise.
• As with PCr use, the rate of muscle glycogen depletion is controlled by the
intensity of the activity.
• Increasing the intensity results in a higher rate of muscle glycogen
breakdown.
• During sprint running, for example, muscle glycogen may be used 35 to
40 times faster than during walking.
• The perception of severe fatigue does not occur until muscle glycogen levels
are very low
• Marathon runners experience a sudden onset of fatigue at 29 to 35 km
(“hitting the wall”). At least part of this sensation is due to muscle glycogen
depletion.
• Carbohydrate loading can delay fatigue, thus improving performance,
sparing muscle glycogen levels

Mechanisms of Fatigue With Glycogen Depletion

Probably, glycogen depletion does not directly causes fatigue during endurance
exercise. Rather, muscle glycogen depletion may be the first step in a series of
events that leads to fatigue.

• Glycogen breakdown is necessary to maintain oxidative metabolism of both

carbohydrates and fats through the Krebs cycle.
• Glycogen breakdown is needed for the optimal production of NADH and to
maintain the electron transport system.

• As glycogen is depleting, exercising muscle relies more heavily on the

metabolism of Free Fatty Acids.
• To accomplish this, more FFAs must be moved into the mitochondria,
and the limited rate of transfer may limit FFA oxidation, making the fiber
unable to obtain sufficient ATP to sustain the exercise intensity.

1.3.- Blood Glucose

• At the beginning of exercise blood glucose rises. With prolonged activity,
blood glucose may fall. Fatigue occurs at blood glucose levels below 65
mg/dl (normal: 70 – 100 mg/dl)

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2.- Accumulation of metabolic by-products

2.1.- Pi  Commented previously regarding ATP-PCr depletion

2.2.- Heat
• Energy expenditure results in heat production, causing core temperature to
rise.
• High muscle temperature could impair skeletal muscle function 
• Time to exhaustion is affected by ambient temperature:
• In an study, time to exhaustion was longest at 11º C and shorter at
colder and warmer temperatures
• Precooling of muscles prolongs exercise, while preheating causes
earlier fatigue

2.3.- Lactic Acid and Hydrogen ions

• Activities of short duration and high intensity, such as sprint running and
sprint swimming, depend on anaerobic glycolysis and produce large
amounts of lactate and H+ within the muscles
• Lactate by itself is not responsible for fatigue (in fact, it is a fuel source), but
hydrogen ion is capable of decreasing pH both inside and outside of muscle
cells

• Fortunately, the cells and body fluids possess buffers, such as proteins and
bicarbonate (HCO3―), that minimize the disrupting influence of the H+.
• Because of the body’s buffering capacity, the H+ concentration does not rise
exponentially during the most severe exercise, allowing muscle pH to
decrease from a resting value of 7.1 to no lower than 6.6 to 6.4 at
exhaustion.
• However, pH changes of this magnitude can already affect energy
production and muscle contraction
• An intracellular pH below 6.9 starts to inhibit the action of
phosphofructokinase, an important glycolytic enzyme, slowing the rate of
glycolysis and ATP production.
• At a pH of 6.4, glycogen breakdown is stopped, causing a rapid
decrease in ATP and ultimately exhaustion.
• H+ may displace calcium within the fiber, interfering with the coupling of
the actin-myosin cross-bridges and decreasing the muscle’s contractile
force.

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• Most researchers agree that low muscle pH is the major limiting factor of
performance and the primary cause of fatigue during maximal, all-out
exercise lasting more than 20 to 30 s.
• In addition, blood acidosis affects Central Nervous System:
• pain, nausea, discomfort, disorientation
• and inhibits O2 / Hb combination in lung

3.- Neuromuscular Fatigue

Studies performed one century ago clearly established a failure of nerve
impulse transmission in fatigued muscle. This failure may involve one or more
of the following processes
• The release or synthesis of acetylcholine by the neurmuscular synapse
might be reduced.
• The muscle fiber membrane might develop a higher threshold for stimulation
by motor neurons.
• During the action potential, sodium enters and potassium leaves the
muscle cells. The concomitant intracellular increase in Na and
decrease in K would disrupt normal sarcolemmal membrane potential
and excitability
• Some evidence suggests that fatigue also may be attributable to calcium
retention within the sarcoplasmic reticulum, which would decrease the
calcium available for muscle contraction
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4.- Central Nervous System (CNS) and Fatigue

• The CNS plays a role in most types of fatigue, perhaps limiting
performance as a protective mechanism.
• Indeed, the perceived discomfort of fatigue (psychological fatigue)
precedes the onset of muscular (physiological) fatigue.
• Athletes who feel exhausted can often be encouraged to continue by
various signals that stimulate the CNS, such as listening music or
shouts of encouragement and support.
• Unless they are highly motivated, most individuals terminate exercise
before their muscles are physiologically exhausted.
• The precise mechanisms by which the CNS exert these actions is at
present unknown

5. Heart and Lung as sites of Fatigue

• No evidence that heart and lungs are sites of fatigue
• Arterial PO2 and Cardiac Output are maintained during exercise
• Heart and respiratory muscles can utilize lactate or FFA as energy fuels as
well as glycogen
ECG  no signs of ischemia at maximal effort or fatigue
• If there were signs  heart disease
• With severe dehydration due to prolonged exercise  Cardiac arrhythmias
are possible
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Delayed-Onset Muscle Soreness (DOMS)  Dolor Muscular

Tardío o Agujetas
• Appears 24 - 48 hours after strenuous exercise
• Not due to lactic acid microcrystals!!!!!!!!!!!!!!
• Due to microscopic tears in muscle fibers or connective tissue that results in
cellular degradation and inflammatory response
• Eccentric exercise (running downhill) causes more damage than concentric
exercise (cycling)
• It is interesting to slowly begin a specific exercise to avoid DOMS
• The symptoms of DOMS disappear in a couple of days as the injury is
repaired.
• Muscle damage appears to be a precipitating factor for muscle hypertrophy.

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• Steps leading to DOMS

• Strenuous muscle contraction results in
muscle fiber damage, including membrane and
sarcoplasmic reticulum, as well as surrounding
conective tissue
• Calcium leaks out of Sarcoplasmic Reticulum,
activating proteases in cytosol, which degrade
contractile proteins, especially Z-proteins
• Development of an inflammatory process 
Increase in prostaglandins/histamine release
• Edema and histamine stimulate pain receptors
• This damage is responsible for the localized
muscle pain, tenderness, and swelling
associated with DOMS.
• With DOMS there is a transient increase in
plasma concentration of enzymes and other
proteins from muscle (due to increased
permeability of the sarcolemma), such as
Creatine Kinase, Transaminases and
Myoglobin

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The repeated bout effect

• A bout of unaccustomed exercise results in DOMS
• Following recovery, another bout of the same exercise results in minimal
injury
• Theories for the repeated bout effect
• Neural theory
• Recruitment of larger number of muscle fibers
• Connective tissue theory
• Increased connective tissue synthesis to protect muscle
• Cellular theory
• Synthesis of protective proteins within muscle fiber

Overreaching (Sobrecarga) and Overtraining

(Sobreentrenamiento)
The terms overreaching and overtraining both refer to what occurs in the body
when the training volume -- intensity, duration and frequency – is increased too
quickly without giving the body enough time to recover.

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Overreaching
• An increased training volume without adequate recovery may propitiate the
athlete to fall during a few days or weeks into a state of fatigue called
overreaching.
• This state is relatively common during the training process, and runs parallel
to a decreased performance.
• Done correctly, this allows the body to adapt to the increased training
stimulus, and this transitory decrement in performance lasting several days
to several weeks is followed by an increase in performance
(supercompensation)

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Overtraining
• If recovery is inadequate and/or training loads are still too high, the athlete
can experiment an unexplained decline in performance that extends over
weeks, months or even years.
• This condition is termed overtraining, and its precise causes are not fully
understood. Research has pointed to both psychological and physiological
causes.

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Common Training Mistakes

Common Symptoms of Overtraining

Symptoms of Overtraining
• Elevated heart rate at rest
• Decreased Heart Rate Variability
 Increased sympathetic tone
• Elevated heart rate and blood
lactate levels during exercise
• Loss in body weight  Due to
reduction in appetite
• Chronic fatigue, sleep
disturbances
• Psychological staleness:
irritability, restlessness,
excitability, loss of motivation and
vigor; lack of mental
concentration; feelings of
depression;
• Frequent colds
• Decrease in performance

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• Possible explanations for the overtraining syndrome include changes in the

function of the autonomic nervous system, altered endocrine responses,
suppressed immune function, and altered brain neurotransmitters.
• Overtraining syndrome is treated with a marked reduction in training
intensity, or complete rest, for weeks or months.
• For endurance athletes, it is important to ensure adequate calorie and
carbohydrate intake to meet energy needs.

Of Interest  Overtraining, chronic fatigue syndrome and fibromyalgia

• Chronic fatigue syndrome and fibromyalgia usually occur in nonathletes.
• There are many similarities in symptoms across the three syndromes. These
similarities can include:
• Chronic fatigue at rest and during exercise, psychological distress,
immune system dysfunction, hormonal dysfunction, and
neurotransmitter dysfunction.
• All three syndromes are difficult to diagnose, and their specific etiology
remains unknown.

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Rhabdomyolysis
Rhabdomyolysis is an acute disease, which can be fatal, caused by the
breakdown of skeletal muscle fibers.

Etiology
• Crush syndrome  Car accidents, Building collapse after earthquakes or
bombings
• Medications  Statins (drugs used to lower plasma cholesterol levels)
• Recreational Drugs  Cocaine, alcohol, heroin
• Infections  AIDS, Q fever…
• Strenuous Exercise. Also called Exertional Rhabdomyolisis. It can develop
after high-intensity exercise, particularly excessive eccentric exercise, and is
exacerbated by
• Exercising in the heat or at altitude,
• Dehydration during exercise
• The concomitant taking of some drugs:
• Statins
• Alcohol, heroin, or cocaine

Normally, Rhabdomyolisis is not dangerous and the symptoms are tolerable,

similar but more intense than those of the delayed-onset muscle soreness.

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Damaged muscle cells release into the bloodstream diverse intracellular

products, such as potassium ions, Myoglobin, and Enzymes (CK,
Transaminases, Lactate Dehydrogenase).
• Myoglobin (Molecular Mass = 17800 daltons) is filtrated by the
glomerulus and excreted by urine, giving it a dark color, similar to cola or
tea. If serum myoglobin concentration is very high (as in severe muscle
damage), it can precipitate into the renal tubules causing acute renal
failure and even death.

The most common signs and symptoms of rhabdomyolysis include

• Severe muscle pain in the entire body,
• Muscle weakness,
• Dark urine: cola- or tea-colored urine.
Diagnosis
• The patient`s medical history (anamnesis), including his/her signs and
symptons: severe muscle pain, dark-color urine…
• High serum levels of Creatinkinase (can also be observed in DOMS)
• Hyperkalemia  Potassium from broken muscle fibers enters the
bloodstream
• If acute renal failure: serum elevation of creatinine
Rhabdomyolysis becomes clinically relevant when the muscle damage is
severe, which can lead to Acute Renal Failure
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