Metabolic basis Metabolic basis of Muscular of Muscular

FatigueFatigue

Muscular fatigueMuscular fatigue

Muscular fatigueMuscular fatigue

Inability to maintain a given Inability to maintain a given

exercise intensity or force exercise intensity or force

outputoutput

Muscular fatigueMuscular fatigue

No one cause of fatigueNo one cause of fatigue

Multifocal phenomenonMultifocal phenomenon

Central and peripheral componentsCentral and peripheral components

Metabolic fatigue results from:Metabolic fatigue results from:

Depletion of key metabolites which Depletion of key metabolites which

facilitate contractionfacilitate contraction

Accumulation of metabolites which impair Accumulation of metabolites which impair

contractioncontraction

Metabolite depletion - Metabolite depletion - phosphagensphosphagens

Phosphagen depletion Phosphagen depletion

associated with fatigue associated with fatigue

during short duration during short duration

high-intensity exercisehigh-intensity exercise

Copyright 1997 Associated Press. All rights reserved.

Metabolite depletion - Metabolite depletion - phosphagensphosphagens

Immediate source of ATP rephosphorylation is Immediate source of ATP rephosphorylation is

phosphocreatine (PCr)phosphocreatine (PCr)

Creatine kinase functions so rapidly that muscular ATP Creatine kinase functions so rapidly that muscular ATP

affected little until PCr significantly depletedaffected little until PCr significantly depleted

ATP and PCr concentrations in resting muscle are lowATP and PCr concentrations in resting muscle are low

Utilisation must be matched by restoration otherwise Utilisation must be matched by restoration otherwise

stores rapidly deplete and fatigue occursstores rapidly deplete and fatigue occurs

Metabolite depletion - Metabolite depletion - phosphagensphosphagens

During exercise at set work During exercise at set work

load PCr decreases in two load PCr decreases in two

phasesphases Rapid initial declineRapid initial decline

Slower secondary declineSlower secondary decline

Slower due to glycolysis and KC Slower due to glycolysis and KC

increasing ATP production which increasing ATP production which

rephosphorylates PCrrephosphorylates PCr

Both initial decline and extent of Both initial decline and extent of

final decrease related to relative final decrease related to relative

exercise intensityexercise intensity

Adapted from: Brooks GA & Fahey TD. (1985) Exercise Physiology: Human Bioenergetics and its Applications. New York:

MacMillan. p705

Metabolite depletion - Metabolite depletion - phosphagensphosphagens

ATP declines initially during ATP declines initially during

onset of exercise, but well onset of exercise, but well

maintained during steady-maintained during steady-

state exercisestate exercise

ATP hydrolysis buffered by ATP hydrolysis buffered by

PCrPCrAdapted from: Brooks GA & Fahey TD. (1985) Exercise

Physiology: Human Bioenergetics and its Applications. New York: MacMillan. p705

Metabolite depletion - Metabolite depletion - phosphagensphosphagens

Fatigue coincides with PCr Fatigue coincides with PCr

depletiondepletion

Once PCr stores depleted ATP Once PCr stores depleted ATP

concentration fallsconcentration falls

Associated with fatigue during Associated with fatigue during

short duration, high intensity short duration, high intensity

exerciseexercise

Adapted from: Sahlin K. (1986) Metabolic changes limiting muscle performance. In: B Saltin (Ed) Biochemistry of Exercise

VI. Champaign: Human Kinetics. p334

Metabolite depletion - Metabolite depletion - phosphagensphosphagens

Formation of ATP from PCr Formation of ATP from PCr

hydrolysis consumes Hhydrolysis consumes H++

Important buffering effect Important buffering effect

during high intensity exerciseduring high intensity exercise

ADP + PCr + H+ ATP + Cr

Metabolite depletion - glycogenMetabolite depletion - glycogen

Glycogen depletion Glycogen depletion

associated with fatigue associated with fatigue

during prolonged during prolonged

submaximal exercisesubmaximal exercise

Metabolite depletion - glycogenMetabolite depletion - glycogen

Slow-twitch fibres become glycogen depleted first, followed Slow-twitch fibres become glycogen depleted first, followed

by fast-twitchby fast-twitch

Same pattern occurs during high and low intensity exercise due Same pattern occurs during high and low intensity exercise due

to Henneman’s size principleto Henneman’s size principle

Rate of depletion accelerated during high intensity exerciseRate of depletion accelerated during high intensity exercise

Possible to fatigue due to glycogen depletion from specific Possible to fatigue due to glycogen depletion from specific

muscle fibres when glycogen remains in other fibresmuscle fibres when glycogen remains in other fibres

Lactate shuttle offsets this effectLactate shuttle offsets this effect

Metabolite depletion - glycogenMetabolite depletion - glycogen

Liver releases glucose to offset reduction in Liver releases glucose to offset reduction in

muscle glycogenmuscle glycogen

When liver and muscle glycogen depleted acetyl When liver and muscle glycogen depleted acetyl

CoA formed fromCoA formed from

-oxidation-oxidation

glucose derived from gluconeogenesisglucose derived from gluconeogenesis

This slows formation of acetyl CoA (and ATP) so fatigue This slows formation of acetyl CoA (and ATP) so fatigue

occursoccurs

Metabolite accumulation - Metabolite accumulation - lactatelactate

During moderate-high intensity During moderate-high intensity

exercise lactic acid accumulates exercise lactic acid accumulates

within the active muscles and bloodwithin the active muscles and blood

Lactic acid 99.5% dissociated at Lactic acid 99.5% dissociated at

physiological pHphysiological pH

Lactic acid accumulation associated Lactic acid accumulation associated

with fatiguewith fatigue

Lactate ion involved in fatigueLactate ion involved in fatigue

– Mechanism not knownMechanism not known

HH++ ion involved in fatigue ion involved in fatigue

– Number of possible mechanismsNumber of possible mechanisms

Metabolite accumulation - Metabolite accumulation - lactatelactate

HH++ ion may contribute to fatigue via: ion may contribute to fatigue via:

Rapid depletion of PCr storesRapid depletion of PCr stores

HH++ ion involved in CK reaction and will displace ion involved in CK reaction and will displace

reaction to favour PCr breakdownreaction to favour PCr breakdown

– ADP + PCr + H+ ATP + Cr

Inhibition of PFK (widely accepted)Inhibition of PFK (widely accepted)

HH++ shown to inhibit PFK in vitro shown to inhibit PFK in vitro

– In vivo, increases in AMP, ADP and F 6-P overcome this In vivo, increases in AMP, ADP and F 6-P overcome this

inhibition so that glycolytic rate is retainedinhibition so that glycolytic rate is retained

Metabolite accumulation - Metabolite accumulation - lactatelactate

HH++ ion may contribute to fatigue via: ion may contribute to fatigue via:

Displacement of CaDisplacement of Ca2+2+ from binding with from binding with

troponin Ctroponin C

Failure to form cross-bridges and develop Failure to form cross-bridges and develop

tensiontension

Stimulation of pain receptors within muscleStimulation of pain receptors within muscle

Negative feedback mechanism (protective Negative feedback mechanism (protective

effect)?effect)?

Inhibition of triacylglycerol lipase activityInhibition of triacylglycerol lipase activity

Reduced lipolysis will increase reliance on Reduced lipolysis will increase reliance on

CHO as fuel, leading to earlier glycogen CHO as fuel, leading to earlier glycogen

depletiondepletion

Adapted from: Tortora GJ & Grabowski SR. (2000) Principles of Anatomy and Physiology (9th Ed). New

York: Wiley. p279

Metabolite accumulation - Metabolite accumulation - lactatelactate

Recent evidence suggests that Recent evidence suggests that

intracellular acidosis may actually intracellular acidosis may actually

protect against fatigue by protect against fatigue by

enhancing the ability of the T-tubule enhancing the ability of the T-tubule

system to carry action potentials to system to carry action potentials to

the sarcoplasmic reticulumthe sarcoplasmic reticulum

K+ accumulation in T-tubules during K+ accumulation in T-tubules during

muscle contraction reduces muscle contraction reduces

excitability of T-tubules (due to excitability of T-tubules (due to

inactivation of some voltage gated inactivation of some voltage gated

channels)channels)

Reduces ability to carry electrical Reduces ability to carry electrical

signals to sarcoplasmic reticulumsignals to sarcoplasmic reticulum

– Reduced release of calcium from SR Reduced release of calcium from SR

results in fewer cross-bridges being results in fewer cross-bridges being

formed and loss of forceformed and loss of force

Adapted from: Pedersen et al. Intracellular acidosis enhances the excitability of working muscle. Science 305:1144-1147, 2004.

Metabolite accumulation - Metabolite accumulation - calciumcalcium

CaCa2+2+ released from released from

sarcoplasmic reticulum may sarcoplasmic reticulum may

enter mitochondriaenter mitochondria

Increased CaIncreased Ca2+2+ in mitochondrial in mitochondrial

matrix would reduce electrical matrix would reduce electrical

gradient across inner membranegradient across inner membrane

Would reduce HWould reduce H++ flow through flow through

ATP synthaseATP synthase

– Reduced ATP productionReduced ATP production From: Matthews, CK & van Holde KE (1990) Biochemistry. Redwood City:Benjamin Cummings p.526.