Neuromuscular Fatigue

Muscle Physiology

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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. physiologicalNeuromuscular vs. metabolicCentral 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 factorsAfferent input (pain, metabolites, ischemia,

muscle pressure/stretching) Intrinsic changes of the neuron

(hyperpolarization of RMP)

Figure 1, Kalmer & Cafarelli, 2004

Bottom line: Central fatigue causes neural inhibition greater voluntary effort to drive any motor unit

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 fatigueSudden encouragementLast “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):

1. Impulse conduction of efferent neurons and terminals

2. Impulse conduction of muscle fibers

3. Excitation contraction coupling

4. 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 sarcolemmaAt least 100 vescicles released/impulse

Not considered a site of peripheral fatigue

Peripheral Fatigue

Potential sites include (but not limited to):

1. Impulse conduction of efferent neurons and terminals

2. Impulse conduction of muscle fibers

3. Excitation contraction coupling

4. 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):

1. Impulse conduction of efferent neurons and terminals

2. Impulse conduction of muscle fibers

3. Excitation contraction coupling

4. Sliding of filaments

Excitation-Contraction Coupling

Potential sites of fatigue: Tubular system:

T-tubulesSarcoplasmic 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):

1. Impulse conduction of efferent neurons and terminals

2. Impulse conduction of muscle fibers

3. Excitation contraction coupling

4. Sliding of filaments

Sliding of Filaments

Troponin: Two potential mechanisms of fatigue

1. Decreased responsiveness: Less force at any given [Ca2+]

2. Decreased sensitivity: More [Ca2+] needed for any given force

Agenda

Introduction Central fatigue Peripheral fatigue Biochemistry of fatigue Recovery

Biochemistry of Fatigue

Metabolic fatigueDepletionAccumulation

Metabolic depletion and accumulation is related to central and peripheral fatigue

Metabolic Depletion

Phosphagens Glycogen Blood glucose

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 depletionCP and ATP deplete rapidlyCP continues to deplete task failureATP levels off and is preserved

Brooks, et al., 2000

Phosphagen Depletion

ATP depleted why task failure?

1. Down regulation of “non essential” ATP utilizing functions in order to maintain “essential” functions

2. Free energy theory

Phosphagen Depletion

Bottom line:CP depletion results in fatigue during high

intensity exerciseCP 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 storesCHO supplementation?

Brooks, et al., 2000

Biochemistry of Fatigue

Metabolic fatigueDepletionAccumulation

Metabolic Accumulation

Inorganic phosphate Lactate and H+

Pi Accumulation

ATP ADP + Pi (HPO42-)

Effects of intracellular accumulation Inhibition of PFKReduction 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:

1. Lactic acid

2. Mitochondria

Lactate and H+ Accumulation

When LA production > LA clearance Accumulation

At physiological pH LA dissociates a proton (H+)

As [H+] increases, pH decreasespH = -log of [H+]

www.lorenzsurgical.com/ CF_lactosorbSE_DE.shtml

H+

Lactate C3H5O3

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 myoglobinRestore 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 temperatureProvide O2 for energy cost of ventilationProvide O2 for energy cost of cardiac activityDecrease catecholamine levelsReplenishment of glycogenRemoval of lactate

Glycogen Repletion

Full repletion of glycogen requires several days

Glycogen depletion is dependent on:

1. Type of exercise (continuous vs. intermittent)

2. Dietary CHO consumed during repletion period

Glycogen Repletion

Glycogen repletion after continuous exercise2 hours: Insignificant repletion5 hours: Significant repletion10 hours: Greatest rate of repletion46 hours required for complete repletion with

high CHO intakeCHO vs. PRO/Fat diet

High CHO diet

PRO/Fat diet

Glycogen Repletion

Glycogen repletion after intermittent exercise30 min: Significant repletion2 hours: Greatest rate of repletion24 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 temperatureProvide O2 for energy cost of ventilationProvide O2 for energy cost of cardiac activityDecrease catecholamine levelsReplenishment of glycogenRemoval 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