Neuromuscular Fatigue
Muscle Physiology
420:289
Agenda
Introduction
 Central fatigue
 Peripheral fatigue
 Biochemistry of fatigue
 Recovery

Introduction  Fatigue

Common definition:
 Any
reduction in physical or mental
performance

Physiological definitions:
 The
gradual increase in effort needed to
maintain a constant outcome
 The failure to maintain the required or
expected outcome/task
Mechanisms  Difficult to Study
Many potential sites of fatigue
 Task specificity
 Central vs. peripheral factors
 Environment
 Depletion vs. accumulation
 Interactive nature of mechanisms
 Compartmentalization
 Training status

Potential Outcomes of Fatigue

Muscle force:
Isometric or dynamic
 Peak
force and RFD
reduced

Rate of relaxation:
 Reduced
Figure 15.6, McIntosh et al., 2005
Adopted from Garland et al. (1988)
Potential Outcomes of Fatigue

Muscle velocity and
power:
 Peak
and mean
reduced
McIntosh et al., 2005
Potential Outcomes of Fatigue

EMG
 Increases
with fatigue (submaximal load) as
CNS attempts to recruit more motor units
 Power frequency spectrum shifts to left

FT MUs fatigue resulting in greater stimulation of
ST MUs (lower threshold  lower frequency)
Brooks et al., 2000
Brooks et al., 2000
Gandevia, 2001
Potential Outcomes of Fatigue
Ratings of perceived exertion
 Rate of fatigue

 Fatigue

index  Wingate
Time to fatigue
Mechanisms of Fatigue

Fatigue can be classified in many ways:
 Psychological
vs. physiological
 Neuromuscular vs. metabolic
 Central vs. peripheral
Agenda
Introduction
 Central fatigue
 Peripheral fatigue
 Biochemistry of fatigue
 Recovery

Central Fatigue - Introduction
Central fatigue: A progressive reduction in
voluntary activation of muscle during
exercise
 Difficult to study however strong indirect
evidence

Central Fatigue - Introduction

Central fatigue may manifest itself in
several ways:
 Emotions
and other psychological factors
 Afferent input (pain, metabolites, ischemia,
muscle pressure/stretching)
 Intrinsic changes of the neuron
(hyperpolarization of RMP)
Bottom line: Central fatigue causes neural inhibition
 greater voluntary effort to drive any motor unit
Figure 1, Kalmer & Cafarelli, 2004
Evidence of Central Fatigue
Reduced motor unit firing rate and ½
relaxation time
 Suggests less central drive

Figure 12, Gandevia, 2001
Evidence of Central Fatigue






Concept of muscle wisdom
Decline in MU firing rate does not correlate well
with decline in force
As MU firing rate declines ½ relaxation time
increases (prolonged contractile mechanism)
Prolongation  steady force maintained with
lower MU firing rate
Increased efficiency?
Eventual fatigue is imminent
Evidence of Central Fatigue

Best evidence: Improvement in
performance with severe fatigue
 Sudden
encouragement
 Last “kick” at end of race
McIntosh et al., 2005
Gandevia, 2001
Gandevia, 2001
Agenda
Introduction
 Central fatigue
 Peripheral fatigue
 Biochemistry of fatigue
 Recovery

Peripheral Fatigue

1.
2.
3.
4.
Potential sites include (but not limited to):
Impulse conduction of efferent neurons
and terminals
Impulse conduction of muscle fibers
Excitation contraction coupling
Sliding of filaments
Efferent Neurons and Terminals



Impulse conduction
may fail at branch
points of motor axons
Unusual  Branch
point diameter < axon
diameter
Evidence: Krnjevic &
Miledi (1958)
Zhou & Shui, 2001
Krnjevic & Miledi (1958)
Rat diaphragm motor nerve
 Motor end plates of two fibers within same
motor unit observed
 Fatigue  One fiber did not demonstrate
motor end plate depolarization with
stimulation
 Conclusion: Branch point failure

Normal branch point propagation
Branch point failure
Efferent Neurons and Terminals
Note: “Dropping out” of muscle fibers in
single muscle fiber EMG studies is very
rare
 More research is needed

Efferent Neurons and Terminals
ACh release from axon terminals?
 ACh is synthesized and repackaged
quickly even during repetitive activity
 Safety margin: Very little ACh is required
to stimulate AP along sarcolemma

 At

least 100 vescicles released/impulse
Not considered a site of peripheral fatigue
Peripheral Fatigue

1.
2.
3.
4.
Potential sites include (but not limited to):
Impulse conduction of efferent neurons
and terminals
Impulse conduction of muscle fibers
Excitation contraction coupling
Sliding of filaments
Impulse Conduction Muscle Fibers
The ability of the sarcolemma to propagate
APs will eventually fail during repetitive
voluntary muscle actions
 Attenuation is modest
 Mechanism: Leaking of K+ from cell 
hyperpolarization of RMP

Figure 15.6, McIntosh et al., 2005
Adopted from Garland et al. (1988)
Peripheral Fatigue

1.
2.
3.
4.
Potential sites include (but not limited to):
Impulse conduction of efferent neurons
and terminals
Impulse conduction of muscle fibers
Excitation contraction coupling
Sliding of filaments
Excitation-Contraction Coupling
Potential sites of fatigue:
 Tubular system:

 T-tubules
 Sarcoplasmic
reticulum
ECC Fatigue  T-Tubules

Mechanism:
 Inability
of AP to be propagated down t-tubule
 Due to pooling of K+ in t-tubule (interstitial fluid)

Recall:
 Muscle activation causes:
 Increase of intracellular [Na+]
 Decrease of intracellular [K+]
 Na+/K+
pump attempts to restore resting [Na+/K+]
 Na+/K+ pump is facilitated by:


Increased intracellular [Na+}
Catecholamines
ECC Fatigue  T-Tubules
T-tubule membrane surface area is small
 Less absolute Na+/K+ pumps
 Pooling of K+ in t-tubules hyperpolarizes ttubule RMP
 Time constant for movement of K+ from ttubules = ~ 1s
 Does 1 s of rest alleviate fatigue?

 More
mechanisms!
ECC Fatigue  Sarcoplasmic
Reticulum

Several potential mechanisms:
 Impaired

Reduced uptake of Ca2+  prolonged relaxation?
 Impaired

RYR channel function
Reduced release of Ca2+  less crossbridges?
 General

SERCA function
rise in intracellular Ca2+
Increased uptake of Ca2+ by mitochondria 
reduced mitochondrial efficiency?
Peripheral Fatigue

1.
2.
3.
4.
Potential sites include (but not limited to):
Impulse conduction of efferent neurons
and terminals
Impulse conduction of muscle fibers
Excitation contraction coupling
Sliding of filaments
Sliding of Filaments

1.
2.
Troponin: Two potential mechanisms of
fatigue
Decreased responsiveness: Less force
at any given [Ca2+]
Decreased sensitivity: More [Ca2+]
needed for any given force
Agenda
Introduction
 Central fatigue
 Peripheral fatigue
 Biochemistry of fatigue
 Recovery

Biochemistry of Fatigue

Metabolic fatigue
 Depletion
 Accumulation

Metabolic depletion and accumulation is
related to central and peripheral fatigue
Metabolic Depletion
Phosphagens
 Glycogen
 Blood glucose

Phosphagen Depletion

Phosphagens include:
 ATP
 Creatine
phosphate
CP is most immediate source of
ATP due to creatine kinase
Rate of ATP: High
Capacity: Low
Phosphagen Depletion

Pattern of CP/ATP depletion
 CP
and ATP deplete rapidly
 CP continues to deplete  task failure
 ATP levels off and is preserved
Brooks, et al., 2000
Phosphagen Depletion

1.
2.
ATP depleted  why task failure?
Down regulation of “non essential” ATP
utilizing functions in order to maintain
“essential” functions
Free energy theory
Phosphagen Depletion

Bottom line:
 CP
depletion results in fatigue during high
intensity exercise
 CP supplementation delays onset of task
failure
Metabolic Depletion
Phosphagens
 Glycogen
 Blood glucose

Glycogen Depletion


Recall: Glycogen is storage mechanism for
CHO in muscle
Highly branched polyglucose molecule
Glycogen Depletion



Glycogen depletion is associated with fatigue
during prolonged submaximal exercise
Glycogen depletion is fiber type specific
depending on intensity of exercise
Bottom line:
 Glycogen
depletion impairs ability to generate ATP at
relatively fast rate  task failure at moderate
intensities
 Supercompensation?
Metabolic Depletion
Phosphagens
 Glycogen
 Blood glucose

Low Blood Glucose
High intensity exercise  increased blood
sugar due to liver glycogenolysis
 The rate of glycogenolysis does not match
the rate of glycolysis  lower blood
glucose
 Bottom line:

 Duration
of exercise depends glycogen stores
 CHO supplementation?
Brooks, et al., 2000
Biochemistry of Fatigue

Metabolic fatigue
 Depletion
 Accumulation
Metabolic Accumulation
Inorganic phosphate
 Lactate and H+

Pi Accumulation
ATP  ADP + Pi (HPO42-)
 Effects of intracellular accumulation

 Inhibition
of PFK
 Reduction of ATP free energy

ADP and Pi accumulation
 Inhibition
of Ca2+ binding with Tn-C
Lactate and H+ Accumulation

Recall
Two possible fates for pyruvate:
1. Lactic acid
2. Mitochondria
Lactate and H+ Accumulation
When LA production > LA clearance 
Accumulation
 At physiological pH  LA dissociates a
proton (H+)
 As [H+] increases, pH decreases

 pH
= -log of [H+]
H+
Lactate C3H5O3
www.lorenzsurgical.com/ CF_lactosorbSE_DE.shtml
Lactate and H+ Accumulation

Effects of intracellular H+ accumulation
 Inhibition of PFK
 Inhibition of Ca2+ binding of Tn-C
 Pain receptor stimulation  afferent
 Nausea and disorientation
 Inhibition of O2-Hg association
 Inhibition of FFA release
 Decreased force/crossbridge
 Reduced Ca2+ sensitivity
 Inhibition of SERCA function
inhibition
Lactate and H+ Accumulation

Lactate accumulation is beneficial:
 liver  glucose via
gluconeogenesis
 Lactate
http://cwx.prenhall.com/bookbind/pubbooks/mcmurrygob/medialib/media_portfolio/t
ext_images/FG23_10.JPG
Agenda
Introduction
 Central fatigue
 Peripheral fatigue
 Biochemistry of fatigue
 Recovery

Recovery - Intro

Recovery oxygen: Amt of O2 consumed in
excess of normal consumption at test
 EPOC:

Excess post-exercise oxygen consumption
Duration of recovery depends on:
 Intensity
of exercise
 Duration of exercise
 Training status
 Mode of exercise
Short Term Recovery

Two main
components:
 Fast
component
 Slow component
ST Recovery: Fast Component
Time: 2-3 minutes
 VO2 declines rapidly
 Related to intensity of exercise
 Not related to duration of exercise

ST Recovery: Fast Component

Elevated metabolic rate during fast
component has many functions:
 Resaturation
of myoglobin
 Restore blood O2
 Provide O2 for energy cost of ventilation
 Provide O2 for energy cost of cardiac activity
 Replenishment of ATP-PC stores
ATP-PC restoration dependent on blood flow
Short Term Recovery

Two main
components:
 Fast
component
 Slow component
ST Recovery: Slow Component
Time: ~ 1 hour
 Attenuated decline in VO2
 Related to intensity and duration of
exercise

ST Recovery: Slow Component

Elevated metabolic rate during slow
component has many functions:
 Reduce
core temperature
 Provide O2 for energy cost of ventilation
 Provide O2 for energy cost of cardiac activity
 Decrease catecholamine levels
 Replenishment of glycogen
 Removal of lactate
Glycogen Repletion


1.
2.
Full repletion of glycogen requires
several days
Glycogen depletion is dependent on:
Type of exercise (continuous vs.
intermittent)
Dietary CHO consumed during repletion
period
Glycogen Repletion

Glycogen repletion after continuous
exercise
2
hours: Insignificant repletion
 5 hours: Significant repletion
 10 hours: Greatest rate of repletion
 46 hours required for complete repletion with
high CHO intake
 CHO vs. PRO/Fat diet
High CHO diet
PRO/Fat diet
Glycogen Repletion

Glycogen repletion after intermittent
exercise
 30
min: Significant repletion
 2 hours: Greatest rate of repletion
 24 hours needed for complete repletion with
normal CHO intake
Glycogen Repletion
Reasons for differences b/w continuous and
intermittent exercise:
1. Total glycogen depleted
-Twice as much depleted with continuous
-Same amount synthesized in first 24 h
2. Availability of glycogen precursors
-Ex: Lactate, pyruvate, glucose
-Less precursors with continuous
3. Fiber type activation
-Glycogen resynthesis faster in Type II

Supercompensation

Glycogen repletion
levels can be greater
than pre-exercise
levels with CHO
loading
ST Recovery: Slow Component

Elevated metabolic rate during slow
component has many functions:
 Reduce
core temperature
 Provide O2 for energy cost of ventilation
 Provide O2 for energy cost of cardiac activity
 Decrease catecholamine levels
 Replenishment of glycogen
 Removal of lactate
ST Recovery: Lactate

Lactate is removed during the slow component
of short term recovery
 30

min - 1 h
Possible fates
 Urine/sweat
excretion (minimal)
 Lactate  glucose
 Lactate  protein
 Lactate  glycogen
 Lactate  pyruvate  Kreb’s cycle  CO2 + H2O