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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 Hennemans 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.