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.