Metabolic basis of Muscular Fatigue

Muscular fatigueMuscular fatigueInability to maintain a given exercise intensity or force output

Muscular fatigueNo one cause of fatigueMultifocal phenomenonCentral and peripheral componentsMetabolic fatigue results from:Depletion of key metabolites which facilitate contractionAccumulation of metabolites which impair contraction

Metabolite depletion - phosphagensPhosphagen depletion associated with fatigue during short duration high-intensity exerciseCopyright 1997 Associated Press. All rights reserved.

Metabolite depletion - phosphagensImmediate source of ATP rephosphorylation is phosphocreatine (PCr)Creatine kinase functions so rapidly that muscular ATP affected little until PCr significantly depletedATP and PCr concentrations in resting muscle are lowUtilisation must be matched by restoration otherwise stores rapidly deplete and fatigue occurs

Metabolite depletion - phosphagensDuring exercise at set work load PCr decreases in two phasesRapid initial declineSlower secondary declineSlower due to glycolysis and KC increasing ATP production which rephosphorylates PCrBoth initial decline and extent of final decrease related to relative exercise intensityAdapted from: Brooks GA & Fahey TD. (1985) Exercise Physiology: Human Bioenergetics and its Applications. New York: MacMillan. p705

Metabolite depletion - phosphagensATP declines initially during onset of exercise, but well maintained during steady-state exerciseATP hydrolysis buffered by PCrAdapted from: Brooks GA & Fahey TD. (1985) Exercise Physiology: Human Bioenergetics and its Applications. New York: MacMillan. p705

Metabolite depletion - phosphagensFatigue coincides with PCr depletionOnce PCr stores depleted ATP concentration fallsAssociated 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 - phosphagensFormation of ATP from PCr hydrolysis consumes H+Important buffering effect during high intensity exercise

ADP + PCr + H+ ATP + Cr

Metabolite depletion - glycogenGlycogen depletion associated with fatigue during prolonged submaximal exercise

Metabolite depletion - glycogenSlow-twitch fibres become glycogen depleted first, followed by fast-twitchSame pattern occurs during high and low intensity exercise due to Hennemans size principleRate of depletion accelerated during high intensity exercisePossible to fatigue due to glycogen depletion from specific muscle fibres when glycogen remains in other fibresLactate shuttle offsets this effect

Metabolite depletion - glycogenLiver releases glucose to offset reduction in muscle glycogenWhen liver and muscle glycogen depleted acetyl CoA formed from-oxidationglucose derived from gluconeogenesisThis slows formation of acetyl CoA (and ATP) so fatigue occurs

Metabolite accumulation - lactateDuring moderate-high intensity exercise lactic acid accumulates within the active muscles and bloodLactic acid 99.5% dissociated at physiological pHLactic acid accumulation associated with fatigueLactate ion involved in fatigueMechanism not knownH+ ion involved in fatigueNumber of possible mechanisms

Metabolite accumulation - lactateH+ ion may contribute to fatigue via:Rapid depletion of PCr storesH+ ion involved in CK reaction and will displace reaction to favour PCr breakdownADP + PCr + H+ ATP + CrInhibition of PFK (widely accepted)H+ shown to inhibit PFK in vitroIn vivo, increases in AMP, ADP and F 6-P overcome this inhibition so that glycolytic rate is retained

Metabolite accumulation - lactateH+ ion may contribute to fatigue via:Displacement of Ca2+ from binding with troponin CFailure to form cross-bridges and develop tensionStimulation of pain receptors within muscleNegative feedback mechanism (protective effect)?Inhibition of triacylglycerol lipase activityReduced lipolysis will increase reliance on CHO as fuel, leading to earlier glycogen depletionAdapted from: Tortora GJ & Grabowski SR. (2000) Principles of Anatomy and Physiology (9th Ed). New York: Wiley. p279

Metabolite accumulation - lactateRecent 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 reticulumK+ 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 reticulumReduced release of calcium from SR results in fewer cross-bridges being formed and loss of force

Metabolite accumulation - calciumCa2+ released from sarcoplasmic reticulum may enter mitochondriaIncreased Ca2+ in mitochondrial matrix would reduce electrical gradient across inner membraneWould reduce H+ flow through ATP synthaseReduced ATP productionFrom: Matthews, CK & van Holde KE (1990) Biochemistry. Redwood City:Benjamin Cummings p.526.