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Chapter 4. peripheral factors in
neuromuscular fatigue
PF. Gardiner, Advanced
neuromuscular exercise physiology
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Neuromuscular fatigue
• ↓ maximal force response in spite of continued
supramaximal stimulus
• ↑effort necessary to maintain a submaximal
contractile force
• During sustained submaximal muscle contraction
– ↑ excitation of the motor pool
– simultaneous ↓ in the maximal capacity of the
contractile system
• Neuromuscular fatigue: a condition that develops
gradually as exercise continues
Factors Affecting Performance
Sites of Fatigue
• Central fatigue
• Peripheral fatigue
– Neural factors
– Mechanical factors
– Energetics of
contraction
Changes in contractile properties
during fatigue
Jones DA et al, JP 2006
Changes in contractile properties
during fatigue
Jones DA et al, JP 2006
Changes in contractile properties
during fatigue
Jones DA et al, JP 2006
↑ neural signals when maintaining a
submaximal contractile force
Intramuscular factors: Interstitial K+
• MAJOR factor
• ↑interstitial 細胞間 potassium (K+),
↓membrane excitability
– critical interstitial potassium concentration at which
muscle tetanic force is affected similar to that in
exercising human muscles (resting: ~4 mM;
exercising: 10-13 mM)
• sodium-potassium ATPase (Na+/K+ ATPase)
– Training ↑ Na+/K+ ATPase, ↓accumulation of
interstitiaI K, longer time to fatigue
Na, K in nerve impulse
Interstitial K+ and muscle force
Interstitial K+ in
exercising human
muscles: 10-13 mM
Power output and interstitial K+ in
human muscles
Intramuscular factors
• ATP concentration only minor role
– ATP usually NOT depleted during exercise
– However, potential localized ATP depletion, especially in
triad region
– Na+/K+ ATPase, use ATP generated by glycolysis
– ↓ rate of ATP use by ↓crossbridge cycling, ↓ SR Ca2+ uptake
• ↑ calcium trapped in the cytoplasmic
compartment
– ↑ magnesium (Mg2+) ↓ calcium channel opening
– inorganic phosphate enter sarcoplasmic reticulum
and precipitate with Ca
– Minor factor : estimated <10% of maximum force
X: force, 
•: PCr, :ATP after 10s and 20 s. open: type I,
close type II human muscles
Exer Biochem c6-high intensity ex
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Fatigue mechanism – increased H+
• Human muscle pH dropped from 7.05 to ~6.5 after
exhaustive exercise
–
–
–
–
However, exhaustion in pH 6.8-6.9 in some situations
Force usually recover faster than pH
Ca2+ release from SR NOT inhibited even at pH 6.2
H+ has much less inhibitory effect in activation of the
contractile apparatus and Ca2+ release than previously
assumed
• Low pH could inhibit glycolytic enzyme activities
• However, alkalinizers DO increase performance in
HIE
Lactate metabolism
• Whenever glycolysis produce pyruvate, lactate also
produced
– Pyruvate synthesis rate >> pyruvate dehydrogenase activity
– Lactate dehydrogenase activity high in skeletal muscle
• Fate of lactate
– Leave muscle fiber via monocarboxylate transporter
– Enter adjacent fiber with lower intracellular [lac]
– Enter cells, used by heart, nonworking muscle (as fuel) or
liver and kidney (as sources for gluconeogenesis),
intercellular lactate shuttle
• monocarboxylate transporter act as a symport, transfer
lactate down gradient, accompanied by a H+
• Lactate is NOT responsible for muscle acidity, fatigue,
or soreness
Lactate synthesis REMOVE H+
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Major source of H+ during exercise
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Major mechanisms in muscle fatigue
Fatigue mechanisms
21
Structures other than muscle
Neuromuscular transmission failure
• failure of a nervous impulse to be translated
into sarcolemma
• Neurotransmitter depletion: acetylcholine
– ↓ in max force: stimulated by its motor nerve >
stimulated directly to muscle
– 3,4-diaminopyridine ↓ force difference between
indirect and direct stimulation
– 3,4-diaminopyridine↑acetylcholine release
Neuromuscular transmission failure
• Postsynaptic membrane failure
– Prolonged exposure to ACh  desensitize ACh receptor
• Failure of axon branches to pass on action potentials
– Action potential generated in axon is NOT propagated into
all of the branches extending to muscle fibers
Difference between direct and indirect
stimulation
Inhibition of motoneurons
• Inhibition of motoneurons: ↓motoneuronal
excitability, ↓ firing rates during fatigue at
maximal and submaximal force
• Afferent nerve (sensory nerve) signals
– Demonstrated under ischemia conditions
– Receptors for metabolic by-product concentrations?
Inhibition of motoneurons
Skinned muscle
• skinning the muscle fibers allows us to set the
intracellular concentrations of molecules
– no longer a semipermeable barrier or transporter
system that can become limiting