1. Metabolic basis of Muscular Fatigue

2. Muscular fatigue Muscular fatigue Muscular fatigue Inability to maintain a given exercise intensity or force output Inability to maintain a given exercise intensity or force output

3. Muscular fatigue No one cause of fatigue No one cause of fatigue Multifocal phenomenon Multifocal phenomenon Central and peripheral components Central and peripheral components Metabolic fatigue results from: Metabolic fatigue results from: Depletion of key metabolites which facilitate contraction Depletion of key metabolites which facilitate contraction Accumulation of metabolites which impair contraction Accumulation of metabolites which impair contraction

4. Metabolite depletion - phosphagens Phosphagen depletion associated with fatigue during short duration high-intensity exercise Phosphagen depletion associated with fatigue during short duration high-intensity exercise Copyright 1997 Associated Press. All rights reserved.

5. Metabolite depletion - phosphagens Immediate source of ATP rephosphorylation is phosphocreatine (PCr) Immediate source of ATP rephosphorylation is phosphocreatine (PCr) Creatine kinase functions so rapidly that muscular ATP affected little until PCr significantly depleted Creatine kinase functions so rapidly that muscular ATP affected little until PCr significantly depleted ATP and PCr concentrations in resting muscle are low ATP and PCr concentrations in resting muscle are low Utilisation must be matched by restoration otherwise stores rapidly deplete and fatigue occurs Utilisation must be matched by restoration otherwise stores rapidly deplete and fatigue occurs

6. Metabolite depletion - phosphagens During exercise at set work load PCr decreases in two phases During exercise at set work load PCr decreases in two phases Rapid initial decline Rapid initial decline Slower secondary decline Slower secondary decline Slower due to glycolysis and KC increasing ATP production which rephosphorylates PCr 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 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

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

8. Metabolite depletion - phosphagens Fatigue coincides with PCr depletion Fatigue coincides with PCr depletion Once PCr stores depleted ATP concentration falls Once PCr stores depleted ATP concentration falls Associated with fatigue during short duration, high intensity exercise 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

9. Metabolite depletion - phosphagens Formation of ATP from PCr hydrolysis consumes H + Formation of ATP from PCr hydrolysis consumes H + Important buffering effect during high intensity exercise Important buffering effect during high intensity exercise ADP + PCr + H +  ATP + Cr

10. Metabolite depletion - glycogen Glycogen depletion associated with fatigue during prolonged submaximal exercise Glycogen depletion associated with fatigue during prolonged submaximal exercise

11. Metabolite depletion - glycogen Slow-twitch fibres become glycogen depleted first, followed by fast-twitch 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 Same pattern occurs during high and low intensity exercise due to Henneman’s size principle Rate of depletion accelerated during high intensity exercise 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 Possible to fatigue due to glycogen depletion from specific muscle fibres when glycogen remains in other fibres Lactate shuttle offsets this effect Lactate shuttle offsets this effect

12. Metabolite depletion - glycogen Liver releases glucose to offset reduction in muscle glycogen Liver releases glucose to offset reduction in muscle glycogen When liver and muscle glycogen depleted acetyl CoA formed from When liver and muscle glycogen depleted acetyl CoA formed from  -oxidation  -oxidation glucose derived from gluconeogenesis glucose derived from gluconeogenesis This slows formation of acetyl CoA (and ATP) so fatigue occurs This slows formation of acetyl CoA (and ATP) so fatigue occurs

13. Metabolite accumulation - lactate During moderate-high intensity exercise lactic acid accumulates within the active muscles and blood During moderate-high intensity exercise lactic acid accumulates within the active muscles and blood Lactic acid 99.5% dissociated at physiological pH Lactic acid 99.5% dissociated at physiological pH Lactic acid accumulation associated with fatigue Lactic acid accumulation associated with fatigue Lactate ion involved in fatigue Lactate ion involved in fatigue –Mechanism not known H + ion involved in fatigue H + ion involved in fatigue –Number of possible mechanisms

14. Metabolite accumulation - lactate H + ion may contribute to fatigue via: H + ion may contribute to fatigue via: Rapid depletion of PCr stores Rapid depletion of PCr stores H + ion involved in CK reaction and will displace reaction to favour PCr breakdown H + ion involved in CK reaction and will displace reaction to favour PCr breakdown – –ADP + PCr + H +  ATP + Cr Inhibition of PFK (widely accepted) Inhibition of PFK (widely accepted) H + shown to inhibit PFK in vitro 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

15. Metabolite accumulation - lactate H + ion may contribute to fatigue via: H + ion may contribute to fatigue via: Displacement of Ca 2+ from binding with troponin C Displacement of Ca 2+ from binding with troponin C Failure to form cross-bridges and develop tension Failure to form cross-bridges and develop tension Stimulation of pain receptors within muscle Stimulation of pain receptors within muscle Negative feedback mechanism (protective effect)? Negative feedback mechanism (protective effect)? Inhibition of triacylglycerol lipase activity Inhibition of triacylglycerol lipase activity Reduced lipolysis will increase reliance on CHO as fuel, leading to earlier glycogen depletion 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

16. 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 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) 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 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.

17. Metabolite accumulation - calcium Ca 2+ released from sarcoplasmic reticulum may enter mitochondria Ca 2+ released from sarcoplasmic reticulum may enter mitochondria Increased Ca 2+ in mitochondrial matrix would reduce electrical gradient across inner membrane Increased Ca 2+ in mitochondrial matrix would reduce electrical gradient across inner membrane Would reduce H + flow through ATP synthase Would reduce H + flow through ATP synthase –Reduced ATP production From: Matthews, CK & van Holde KE (1990) Biochemistry. Redwood City:Benjamin Cummings p.526.