Neuromuscular Fatigue Muscle Physiology 420:289

Agenda Introduction Central fatigue Peripheral fatigue Biochemistry of fatigue Recovery

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

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

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)

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

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)

Brooks et al., 2000

Brooks et al., 2000

Gandevia, 2001

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

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

Agenda Introduction Central fatigue Peripheral fatigue Biochemistry of fatigue Recovery

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

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)

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

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

Figure 12, Gandevia, 2001

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

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

McIntosh et al., 2005

Gandevia, 2001

Gandevia, 2001

Agenda Introduction Central fatigue Peripheral fatigue Biochemistry of fatigue Recovery

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

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

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

Normal branch point propagation

Branch point failure

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

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

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

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

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

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

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

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

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!

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?

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

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

Agenda Introduction Central fatigue Peripheral fatigue Biochemistry of fatigue Recovery

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

Metabolic Depletion Phosphagens Glycogen Blood glucose

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

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

Brooks, et al., 2000

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

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

Metabolic Depletion Phosphagens Glycogen Blood glucose

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

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?

Metabolic Depletion Phosphagens Glycogen Blood glucose

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?

Brooks, et al., 2000

Biochemistry of Fatigue Metabolic fatigue Depletion Accumulation

Metabolic Accumulation Inorganic phosphate Lactate and H+

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

Lactate and H+ Accumulation Recall

Two possible fates for pyruvate: Lactic acid Mitochondria

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+]

H+ Lactate C3H5O3 www.lorenzsurgical.com/ CF_lactosorbSE_DE.shtml

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

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

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Agenda Introduction Central fatigue Peripheral fatigue Biochemistry of fatigue Recovery

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

Short Term Recovery Two main components: Fast component Slow component

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

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

ATP-PC restoration dependent on blood flow

Short Term Recovery Two main components: Fast component Slow component

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

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

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

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

High CHO diet PRO/Fat diet

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

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

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

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

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