1. Neuromuscular Fatigue
Muscle Physiology
420:289

2. Agenda Introduction Central fatigue Peripheral fatigue
Biochemistry of fatigue
Recovery

3. Introduction  Fatigue
Common definition:
Any reduction in physical or mental performance
Physiological definitions:
The gradual increase in effort needed to maintain a constant outcome
The failure to maintain the required or expected outcome/task

4. Mechanisms  Difficult to Study
Many potential sites of fatigue
Task specificity
Central vs. peripheral factors
Environment
Depletion vs. accumulation
Interactive nature of mechanisms
Compartmentalization
Training status

5. Potential Outcomes of Fatigue
Muscle force: Isometric or dynamic
Peak force and RFD reduced
Rate of relaxation:
Reduced
Figure 15.6, McIntosh et al., 2005
Adopted from Garland et al. (1988)

6. Potential Outcomes of Fatigue
Muscle velocity and power:
Peak and mean reduced
McIntosh et al., 2005

7. Potential Outcomes of Fatigue
EMG
Increases with fatigue (submaximal load) as CNS attempts to recruit more motor units
Power frequency spectrum shifts to left
FT MUs fatigue resulting in greater stimulation of ST MUs (lower threshold  lower frequency)

8. Brooks et al., 2000

9. Brooks et al., 2000

10. Gandevia, 2001

11. Potential Outcomes of Fatigue
Ratings of perceived exertion
Rate of fatigue
Fatigue index  Wingate
Time to fatigue

12. Mechanisms of Fatigue Fatigue can be classified in many ways:
Psychological vs. physiological
Neuromuscular vs. metabolic
Central vs. peripheral

13. Agenda Introduction Central fatigue Peripheral fatigue
Biochemistry of fatigue
Recovery

14. Central Fatigue - Introduction
Central fatigue: A progressive reduction in voluntary activation of muscle during exercise
Difficult to study however strong indirect evidence

15. Central Fatigue - Introduction
Central fatigue may manifest itself in several ways:
Emotions and other psychological factors
Afferent input (pain, metabolites, ischemia, muscle pressure/stretching)
Intrinsic changes of the neuron (hyperpolarization of RMP)

16. Bottom line: Central fatigue causes neural inhibition  greater voluntary effort to drive any motor unit
Figure 1, Kalmer & Cafarelli, 2004

17. Evidence of Central Fatigue
Reduced motor unit firing rate and ½ relaxation time
Suggests less central drive

18. Figure 12, Gandevia, 2001

19. Evidence of Central Fatigue
Concept of muscle wisdom
Decline in MU firing rate does not correlate well with decline in force
As MU firing rate declines ½ relaxation time increases (prolonged contractile mechanism)
Prolongation  steady force maintained with lower MU firing rate
Increased efficiency?
Eventual fatigue is imminent

20. Evidence of Central Fatigue
Best evidence: Improvement in performance with severe fatigue
Sudden encouragement
Last “kick” at end of race

21. McIntosh et al., 2005

22. Gandevia, 2001

23. Gandevia, 2001

24. Agenda Introduction Central fatigue Peripheral fatigue
Biochemistry of fatigue
Recovery

25. Peripheral Fatigue Potential sites include (but not limited to):
Impulse conduction of efferent neurons and terminals
Impulse conduction of muscle fibers
Excitation contraction coupling
Sliding of filaments

26. Efferent Neurons and Terminals
Impulse conduction may fail at branch points of motor axons
Unusual  Branch point diameter < axon diameter
Evidence: Krnjevic & Miledi (1958)
Zhou & Shui, 2001

27. Krnjevic & Miledi (1958) Rat diaphragm motor nerve
Motor end plates of two fibers within same motor unit observed
Fatigue  One fiber did not demonstrate motor end plate depolarization with stimulation
Conclusion: Branch point failure

28. Normal branch point propagation

29. Branch point failure

30. Efferent Neurons and Terminals
Note: “Dropping out” of muscle fibers in single muscle fiber EMG studies is very rare
More research is needed

31. Efferent Neurons and Terminals
ACh release from axon terminals?
ACh is synthesized and repackaged quickly even during repetitive activity
Safety margin: Very little ACh is required to stimulate AP along sarcolemma
At least 100 vescicles released/impulse
Not considered a site of peripheral fatigue

32. Peripheral Fatigue Potential sites include (but not limited to):
Impulse conduction of efferent neurons and terminals
Impulse conduction of muscle fibers
Excitation contraction coupling
Sliding of filaments

33. Impulse Conduction Muscle Fibers
The ability of the sarcolemma to propagate APs will eventually fail during repetitive voluntary muscle actions
Attenuation is modest
Mechanism: Leaking of K+ from cell  hyperpolarization of RMP

34. Figure 15.6, McIntosh et al., 2005
Adopted from Garland et al. (1988)

35. Peripheral Fatigue Potential sites include (but not limited to):
Impulse conduction of efferent neurons and terminals
Impulse conduction of muscle fibers
Excitation contraction coupling
Sliding of filaments

36. Excitation-Contraction Coupling
Potential sites of fatigue:
Tubular system:
T-tubules
Sarcoplasmic reticulum

37. ECC Fatigue  T-Tubules
Mechanism:
Inability of AP to be propagated down t-tubule
Due to pooling of K+ in t-tubule (interstitial fluid)
Recall:
Muscle activation causes:
Increase of intracellular [Na+]
Decrease of intracellular [K+]
Na+/K+ pump attempts to restore resting [Na+/K+]
Na+/K+ pump is facilitated by:
Increased intracellular [Na+}
Catecholamines

38. ECC Fatigue  T-Tubules
T-tubule membrane surface area is small
Less absolute Na+/K+ pumps
Pooling of K+ in t-tubules hyperpolarizes t-tubule RMP
Time constant for movement of K+ from t-tubules = ~ 1s
Does 1 s of rest alleviate fatigue?
More mechanisms!

39. ECC Fatigue  Sarcoplasmic Reticulum
Several potential mechanisms:
Impaired SERCA function
Reduced uptake of Ca2+  prolonged relaxation?
Impaired RYR channel function
Reduced release of Ca2+  less crossbridges?
General rise in intracellular Ca2+
Increased uptake of Ca2+ by mitochondria  reduced mitochondrial efficiency?

40. Peripheral Fatigue Potential sites include (but not limited to):
Impulse conduction of efferent neurons and terminals
Impulse conduction of muscle fibers
Excitation contraction coupling
Sliding of filaments

41. Sliding of Filaments Troponin: Two potential mechanisms of fatigue
Decreased responsiveness: Less force at any given [Ca2+]
Decreased sensitivity: More [Ca2+] needed for any given force

43. Agenda Introduction Central fatigue Peripheral fatigue
Biochemistry of fatigue
Recovery

44. Biochemistry of Fatigue
Metabolic fatigue
Depletion
Accumulation
Metabolic depletion and accumulation is related to central and peripheral fatigue

45. Metabolic Depletion
Phosphagens
Glycogen
Blood glucose

46. CP is most immediate source of ATP due to creatine kinase
Phosphagen Depletion
Phosphagens include:
ATP
Creatine phosphate
CP is most immediate source of ATP due to creatine kinase
Rate of ATP: High
Capacity: Low

47. Phosphagen Depletion Pattern of CP/ATP depletion
CP and ATP deplete rapidly
CP continues to deplete  task failure
ATP levels off and is preserved

48. Brooks, et al., 2000

49. Phosphagen Depletion ATP depleted  why task failure?
Down regulation of “non essential” ATP utilizing functions in order to maintain “essential” functions
Free energy theory

50. Phosphagen Depletion Bottom line:
CP depletion results in fatigue during high intensity exercise
CP supplementation delays onset of task failure

51. Metabolic Depletion
Phosphagens
Glycogen
Blood glucose

52. Glycogen Depletion
Recall: Glycogen is storage mechanism for CHO in muscle
Highly branched polyglucose molecule

53. Glycogen Depletion
Glycogen depletion is associated with fatigue during prolonged submaximal exercise
Glycogen depletion is fiber type specific depending on intensity of exercise
Bottom line:
Glycogen depletion impairs ability to generate ATP at relatively fast rate  task failure at moderate intensities
Supercompensation?

54. Metabolic Depletion
Phosphagens
Glycogen
Blood glucose

55. Low Blood Glucose
High intensity exercise  increased blood sugar due to liver glycogenolysis
The rate of glycogenolysis does not match the rate of glycolysis  lower blood glucose
Bottom line:
Duration of exercise depends glycogen stores
CHO supplementation?

56. Brooks, et al., 2000

57. Biochemistry of Fatigue
Metabolic fatigue
Depletion
Accumulation

58. Metabolic Accumulation
Inorganic phosphate
Lactate and H+

59. Pi Accumulation ATP  ADP + Pi (HPO42-)
Effects of intracellular accumulation
Inhibition of PFK
Reduction of ATP free energy
ADP and Pi accumulation
Inhibition of Ca2+ binding with Tn-C

60. Lactate and H+ Accumulation
Recall

61. Two possible fates for pyruvate:
Lactic acid
Mitochondria

62. Lactate and H+ Accumulation
When LA production > LA clearance  Accumulation
At physiological pH  LA dissociates a proton (H+)
As [H+] increases, pH decreases
pH = -log of [H+]

63. H+
Lactate C3H5O3
CF_lactosorbSE_DE.shtml

64. Lactate and H+ Accumulation
Effects of intracellular H+ accumulation
Inhibition of PFK
Inhibition of Ca2+ binding of Tn-C
Pain receptor stimulation  afferent inhibition
Nausea and disorientation
Inhibition of O2-Hg association
Inhibition of FFA release
Decreased force/crossbridge
Reduced Ca2+ sensitivity
Inhibition of SERCA function

65. Lactate and H+ Accumulation
Lactate accumulation is beneficial:
Lactate  liver  glucose via gluconeogenesis

67. Agenda Introduction Central fatigue Peripheral fatigue
Biochemistry of fatigue
Recovery

68. Recovery - Intro
Recovery oxygen: Amt of O2 consumed in excess of normal consumption at test
EPOC: Excess post-exercise oxygen consumption
Duration of recovery depends on:
Intensity of exercise
Duration of exercise
Training status
Mode of exercise

69. Short Term Recovery
Two main components:
Fast component
Slow component

70. ST Recovery: Fast Component
Time: 2-3 minutes
VO2 declines rapidly
Related to intensity of exercise
Not related to duration of exercise

71. ST Recovery: Fast Component
Elevated metabolic rate during fast component has many functions:
Resaturation of myoglobin
Restore blood O2
Provide O2 for energy cost of ventilation
Provide O2 for energy cost of cardiac activity
Replenishment of ATP-PC stores

74. ATP-PC restoration dependent on blood flow

75. Short Term Recovery
Two main components:
Fast component
Slow component

76. ST Recovery: Slow Component
Time: ~ 1 hour
Attenuated decline in VO2
Related to intensity and duration of exercise

77. ST Recovery: Slow Component
Elevated metabolic rate during slow component has many functions:
Reduce core temperature
Provide O2 for energy cost of ventilation
Provide O2 for energy cost of cardiac activity
Decrease catecholamine levels
Replenishment of glycogen
Removal of lactate

78. Glycogen Repletion Full repletion of glycogen requires several days
Glycogen depletion is dependent on:
Type of exercise (continuous vs. intermittent)
Dietary CHO consumed during repletion period

79. Glycogen Repletion Glycogen repletion after continuous exercise
2 hours: Insignificant repletion
5 hours: Significant repletion
10 hours: Greatest rate of repletion
46 hours required for complete repletion with high CHO intake
CHO vs. PRO/Fat diet

80. High CHO diet
PRO/Fat diet

82. Glycogen Repletion Glycogen repletion after intermittent exercise
30 min: Significant repletion
2 hours: Greatest rate of repletion
24 hours needed for complete repletion with normal CHO intake

85. Glycogen Repletion
Reasons for differences b/w continuous and intermittent exercise:
1. Total glycogen depleted
-Twice as much depleted with continuous
-Same amount synthesized in first 24 h
2. Availability of glycogen precursors
-Ex: Lactate, pyruvate, glucose
-Less precursors with continuous
3. Fiber type activation
-Glycogen resynthesis faster in Type II

86. Supercompensation
Glycogen repletion levels can be greater than pre-exercise levels with CHO loading

87. ST Recovery: Slow Component
Elevated metabolic rate during slow component has many functions:
Reduce core temperature
Provide O2 for energy cost of ventilation
Provide O2 for energy cost of cardiac activity
Decrease catecholamine levels
Replenishment of glycogen
Removal of lactate

88. ST Recovery: Lactate
Lactate is removed during the slow component of short term recovery
30 min - 1 h
Possible fates
Urine/sweat excretion (minimal)
Lactate  glucose
Lactate  protein
Lactate  glycogen
Lactate  pyruvate  Kreb’s cycle  CO2 + H2O