Metabolic basis of
Muscular Fatigue
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Muscular fatigue
Muscular fatigue
• Inability to maintain a
given exercise intensity
or force output
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Muscular fatigue
No one cause of fatigue Metabolic fatigue results from:
• Multifocal phenomenon • Depletion of key metabolites
• Central and peripheral which facilitate contraction
components • Accumulation of metabolites
which impair contraction
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Metabolite depletion - phosphagens
Phosphagen depletion
associated with fatigue during
short duration high-intensity
exercise
Copyright 1997 Associated Press. All rights reserved.
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Metabolite depletion - phosphagens
Immediate source of ATP
rephosphorylation is phosphocreatine (PCr)
• Creatine kinase functions so rapidly that
muscular ATP affected little until PCr
significantly depleted
• ATP and PCr concentrations in resting
muscle are low
• Utilisation must be matched by
restoration otherwise stores rapidly
deplete and fatigue occurs
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Metabolite depletion - phosphagens
During exercise at set work load PCr
decreases in two phases
Rapid initial decline
Slower secondary decline
• Slower due to glycolysis and KC
increasing ATP production which
rephosphorylates PCr
Both initial decline and extent of final
decrease related to relative exercise
Adapted from: Brooks GA & Fahey TD. (1985) Exercise Physiology:
intensity p705
6
Human Bioenergetics and its Applications. New York: MacMillan.
Metabolite depletion - phosphagens
ATP declines initially during
onset of exercise, but well
maintained during steady-
state exercise
ATP hydrolysis buffered by PCr
Adapted from: Brooks GA & Fahey TD. (1985) Exercise Physiology: Human Bioenergetics and its Applications.
New York: MacMillan. p705
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Metabolite depletion - phosphagens
Fatigue coincides with PCr
depletion
Once PCr stores depleted ATP
concentration falls
• Associated with fatigue during
short duration, high intensity
Adapted from: Sahlin K. (1986) Metabolic changes limiting muscle
exercise 8
performance. In: B Saltin (Ed) Biochemistry of Exercise VI.
Champaign: Human Kinetics. p334
Metabolite depletion - phosphagens
Formation of ATP from PCr ADP + PCr + H+ ATP + Cr
hydrolysis consumes H+
Important buffering effect
during high intensity exercise
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Metabolite depletion - glycogen
Glycogen depletion
associated with fatigue
during prolonged
submaximal exercise
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Metabolite depletion - glycogen
Slow-twitch fibres become glycogen depleted
first, followed by fast-twitch
• Same pattern occurs during high and low
intensity exercise due to Henneman’s size
principle
• Rate of depletion accelerated during high
intensity exercise
• Possible to fatigue due to glycogen depletion
from specific muscle fibres when glycogen
remains in other fibres
• Lactate shuttle offsets this effect
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Metabolite depletion - glycogen
Liver releases glucose to offset reduction
in muscle glycogen
When liver and muscle glycogen
depleted acetyl CoA formed from
-oxidation
glucose derived from gluconeogenesis
• This slows formation of acetyl CoA (and ATP) so
fatigue occurs
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Metabolite accumulation - lactate
During moderate-high intensity exercise lactic acid
accumulates within the active muscles and blood
• Lactic acid 99.5% dissociated at physiological pH
Lactic acid accumulation associated with fatigue
• Lactate ion involved in fatigue
• Mechanism not known
• H+ ion involved in fatigue
• Number of possible mechanisms
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Metabolite accumulation - lactate
H+ ion may contribute to fatigue via:
Rapid depletion of PCr stores
• H+ ion involved in CK reaction and will displace reaction
to favour PCr breakdown
• ADP + PCr + H+ ATP + Cr
Inhibition of PFK (widely accepted)
• H+ shown to inhibit PFK in vitro
• In vivo, increases in AMP, ADP and F 6-P overcome this
inhibition so that glycolytic rate is retained
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Metabolite accumulation - lactate
H+ ion may contribute to fatigue via:
Displacement of Ca2+ from binding with troponin C
• Failure to form cross-bridges and develop tension
Stimulation of pain receptors within muscle
• Negative feedback mechanism (protective effect)?
Inhibition of triacylglycerol lipase activity
• Reduced lipolysis will increase reliance on CHO as
fuel, leading to earlier glycogen depletion
Adapted from: Tortora GJ & Grabowski SR. (2000)
Principles of Anatomy and Physiology (9th Ed). New
York: Wiley. p279
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Metabolite accumulation - lactate
Recent evidence suggests that
intracellular acidosis may actually protect
against fatigue by enhancing the ability of
the T-tubule system to carry action
potentials to the sarcoplasmic reticulum
K+ accumulation in T-tubules during
muscle contraction reduces excitability of
T-tubules (due to inactivation of some
voltage gated channels)
• Reduces ability to carry electrical signals
to sarcoplasmic reticulum
Adapted from: Pedersen et al. Intracellular acidosis enhances the excitability of
• Reduced release of calcium from SR working muscle. Science 305:1144-1147, 2004.
results in fewer cross-bridges being
formed and loss of force
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Metabolite accumulation - calcium
Ca2+ released from sarcoplasmic
reticulum may enter mitochondria
Increased Ca2+ in mitochondrial
matrix would reduce electrical
gradient across inner membrane
• Would reduce H+ flow through ATP
synthase
• Reduced ATP production
From: Matthews, CK & van Holde KE (1990) Biochemistry. Redwood City:Benjamin Cummings p.526.
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