Metabolic basis of
Muscular Fatigue
Muscular fatigue
Muscular fatigue
Inability to maintain a given
exercise intensity or force output
Muscular fatigue
No one cause of fatigue
Multifocal phenomenon
Central and peripheral components
Metabolic fatigue results from:
Depletion of key metabolites which facilitate
contraction
Accumulation of metabolites which impair
contraction
Metabolite depletion - phosphagens
Phosphagen depletion
associated with fatigue during
short duration high-intensity
exercise
Copyright 1997 Associated Press. All rights
reserved.
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
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 intensity
Adapted from: Brooks GA & Fahey TD. (1985) Exercise
Physiology: Human Bioenergetics and its Applications. New York:
MacMillan. p705
Metabolite depletion - phosphagens
ATP declines initially during
onset of exercise, but well
maintained during steadystate exercise
ATP hydrolysis buffered by PCr
Adapted from: Brooks GA & Fahey TD. (1985) Exercise
Physiology: Human Bioenergetics and its Applications. New York:
MacMillan. p705
Metabolite depletion - phosphagens
Fatigue coincides with PCr
depletion
Once PCr stores depleted ATP
concentration falls
Associated with fatigue
during short duration, high
intensity exercise
Adapted from: Sahlin K. (1986) Metabolic changes limiting
muscle performance. In: B Saltin (Ed) Biochemistry of Exercise
VI. Champaign: Human Kinetics. p334
Metabolite depletion - phosphagens
Formation of ATP from PCr
hydrolysis consumes H+
Important buffering effect
during high intensity exercise
ADP + PCr + H+ ATP + Cr
Metabolite depletion - glycogen
Glycogen depletion
associated with fatigue
during prolonged
submaximal exercise
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
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
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
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
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
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
–
Reduced release of calcium from SR
results in fewer cross-bridges being
formed and loss of force
Adapted from: Pedersen et al. Intracellular acidosis enhances the excitability of
working muscle. Science 305:1144-1147, 2004.
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.
