Skeletal Muscle Fatigue

Fatigue definition

• Failure to maintain the required or expected force

  • Appropriate for isometric contractions

• Failure to maintain force, power or velocity

  • For dynamic contractions

Submaximal fatigue

• Increase effort needed to maintain submaximal task

• Some fibres are fatigued and less able to generate force

• Must recruit additional motor units to achieve the same task (run a steady pace)

Skeletal Muscle Fatigue

• Ability of muscle to meet energy needs is a major determinants of exercise duration

• Fatigue isn't result of depleted stores

• Metabolic byproducts are key factors for fatigue

• Can occur between the CNS or PNS

• ATP is always present at sufficient levels

Ability to meet energy needs determines exercise duration, not from depleted energy stores

Motor Nerves and Motor Units

• Alpha-motor neuron efferent innervate skeletal muscle cells from the spinal cord (CNS)

• Cell bodies of alpha-motor neurons are localized to ventral (anterior) horn

• 1 motor neuron can innervate many fibres

• 1 fibre is innervated by only 1 alpha motor neuron

Cause of Fatigue in General

• Metabolic byproducts

• Can be central or peripheral

• Brief periods of tetany, O2 levels are sufficient but force decays rapidly to a level that can be maintained for a long period

• Cause of rapid failure of fast motor units, causative factors are unknown

• Fatigue parallels depleted muscle glycogen stores and CrP; and accumulation of inorganic phosphate and lactic acid

• It is possible to fatigue without tiring the muscle itself

Central vs Peripheral Fatigue

• Location

  • In the CNS (motor cortex, descending pathways and spinal motor neurons, anything within CNS)

  • In muscle/motor units (NMJ, sarcolemma, T-tubules, SR Ca2+ availability, contractile proteins, anything outside CNS)

• Cause

  • CNS: Reduced excitatory drive, NT imbalance

  • Peripheral: metabolic byproducts, ion imbalances

• Measurement

  • Central: interpolated twitch technique

  • Peripheral: Tetanic stimulation of muscles

Central Fatigue

• Motor areas in CNS has excitatory and inhibitory inputs on spinal motor neurons to produce a force output

• Neural Factors

  • Reduced excitatory drive from motor cortex

  • Less presynaptic inhibition, less control over muscle spindle input = reduced smoothness of muscles

  • Neural factors: serotonin, dopamine, norepinephrine, GABA important for exercise

  • Exercise induced changes in the NT can lead to CNS fatigue

Neurotransmitters and Central fatigue

• NT regulates the balances between excitatory drive and inhibitory control in CNS

  • GABAergic interneurons shape motor output, inhibiting or gating sensory motor transmission

  • GABA is an inhibitory NT

• Inihibitory interneurons from direct posynaptic connections with motor or pre motor neurons (GAD1)

• Small subset of GABAeric (GAD2) interneurons form axo-axonic contacts with sensory afferent terminals

  • Regulate sensory-motor drive though presynaptic inhibition

• GAD2 releases GABA onto sensory presynaptic terminals, this causes less NT release from 1 alpha afferents filtering sensory input and allows for smooth motor output

• Without GAD2, there is an excessive excitatory drive to motor neurons causing oscillatory movements

Measuring Central Fatigue by Interpolated Twitch technique

• Quantifies central fatigue by comparing voluntary muscle activation to max possible activation during MVC using electrical stimuli

• Electrical stimuli superimposed a max voluntary isometric contraction and is compared with a resting twitch

• If force increases to equilvalent of the during interpolated twitch, the muscle was capable of generating extra force

• Poor force in MVC is due to reduce motor drive from CNS

• When there is central fatigue there is a difference in force production, when electrical stimuli is applied the force increases to the same amount for both contractions.

  • By having the same force with the electrical stimuli both with max force output and reduced force output proves that there is no peripheral fatigue present as all motor units were able to contract

Twitch Interpolation Technique Athletes vs Sedentary

• Many subjects cannot fully activate their muscles voluntarily, athletes are better are recruiting whole motor unit pools

• Athletes improved this by enhancing neural drive and coordination, learns to recruit more and fire faster, reduce antagonist co-contraction, and overcoming CNS limits

• Leads to greater strength and efficiency by better controlling brain-muscle connection

Peripheral Fatigue

• In an entire muscle, tetanic fatigue occurs in 2 phases

  • Rapid decline from fatigue of type 2 fibres, unknown factor

  • Type 1 fibres are fatigue resistant

  • Difference is oxidative and glycolytic metabolism is related to fatigability

• Fatigue parallel metabolic byproduct in

  • Depletion of glycogen, CrP

  • Increase in inorganic phosphate and lactic acid

  • Decrease in pH

• Decrease pH alters Calcium binding to TnC, altering actin-myosin interactions

• Increase inorganic phosphate causes it to go to SR and bind to Calcium, sequestering it

K+ accumulation in T-Tubules

• In sustained contraction, high concentration of extracellular potassium occurs as K+ efflux out of cell through Kv channels into the T-tubes

• Because K+ leaves the cell, [K+] outside increase, making the exit of K+ through Kv dfficult

• Because density of Na+/K+ ATPase is low in t-tubes it cannot prevent K+ induce depol

• The RMP is less negative causes sodium channels to be in deactivated state and cannot generates AP's

• Muscle cell is struck partially depolarized

• Sustained depolar of T-tubule membrane blocks local AP which decrease release of Ca2+ from SR = decreased contractility

 Sr/Ca2+ and Fatigue

Impaired Ca2+ release from SR is a cause of fatigue, several possible mechanism

• AP cause Na+ influx, repolarize by K+ efflux

• High ECF [K+] reduce voltage channel activation and AP amplitude = reduce RyR1 activity from lower depolarization and weaker AP, decreases voltage signal to DHPR-RYR1 and hinders optimal coupling neeed for optimal calcium release = weaker contraction

• ATP in rested muscle is bodned to Mg2+, use of ATP increase free MG2+ = decrease RyR1 activity

• Lots of inorganic phosphate sequester Ca2+ in the SR, prevent from being easily released = reduce signal for contraction

• Cl ion inhibit cells by hyperpolarization by usually flowing into the cell, but cause of high K+, it interferes the Cl- channels.

  • RMP is more positive than EC; so now by opening chloride channels it causes Cl- to exit the cell (think about +/- charge attraction)

  • Cl- leaving cell depolarizes and makes cell hyperexcitable

Cy3G/PGC-1alpha Reduce fatigue

• Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

1. Cyanidin-3-glucoside, natural compound (grapes, raspberries, cherries), plays a significant role in enhancing exercise performance ad reduce fatigue by upregulating PGC-1alpha

2. Exposure to cold temp, body initiates mechanism to increase heat production = activate sympathetic system = release of NE. Potent inducer of PGC-1alpha expression (adipose and skeletal muscle)

3. PGC-1alpha is a transcriptional coactivator, it enhances ability to express specific genes. Master regulator of metabolic processes

1. Increased mitochondrial content

   1. Cells develop more mitochondria

1. Increased Lactate Metabolism

   1. Promote shift from lactate production and accumulation toward efficient utilization and clearance

2. Increase Lactate uptake

   1. Increased MCT1 (monocarboxylate transporter 1)

   2. PGC-1alpha boost expression of MCT1, responsible for moving lactate across cell membrane, higher MCT1 = more uptake lactate by cells for utilization

3. Increase LDH B

   1. Enzyme catalyze conversion of lactate back to pyruvate

Skeletal muscle differentiation

Pre-skeletal muscle fibres and differentiate into muscle fibres before innervated, some NMJs are formed after birth

• Type 1 motor neurons innervate fibers to become slow oxidative MU

• Type 2 motor neurons become fast Mus

Lengthening During Growth

• Adds sarcomeres in series

• Its reversible with immobilization

• Increase in shortening capacity

• Increases velocity

Hypertrophy

• Sarcomeres are added in parallel of myofibril

• Increase strength and diameter

• Increase force

 Hyperplasia

• Formation of new muscle fibres from satellite cells

• Increase total number of fibres

• Satellite cells is a crucial progenitor cell for muscle fiber formation

Muscle Atrophy

• Disuse will inhibit protein synthesis and stimulate protein degradation

• Muscle requires load to maintain size

• Sarcopenia: age-related loss of mass/strength/function

Reduction in muscle tension

• Titin signaling is disrupted and triggers activation of MuRF

• Senses that muscle isn't being used

• Starts process of atrophy

Caspase 3

• Activated when PI3K is dephosphorylated

• The enzyme is activated and targets proteins for Ubiquitin-proteasomal degradation

• Activates BAX which signals Apoptosis

Apoptosis

• Ensures that damage or unused muscle cell nuclei are removed and reduce capacity for protein synthesis

• Contribute to net loss of muscle mass and function during atrophy

Testosterone has anabolic/myotrophic activity

• Anabolic steroids Increase muscle mass

• Abuse can lead to serious hormone disturbances

• Impaired testosterone production

Feedback look for in normal man for Intratesticular testosterone

1. Luteinizing hormone acts of pituitary gland, act on Leydig cell to produce testosterone

2. Leydig cell produces testosterone, found in testicular tissue

3. High T in testicle leads to production of sperm

4. Low T in peripheral circulation, diluted about 100 fold than in testes

Disruption with Administration of testosterone

1. Injection of drugs to increase T, increase circulating concentration in periphery

2. Exogenous androgens have excessive negative feedback on hypothalamus and pituitary gland, down regulation of LH release, Leydig cells cannot produce T

3. Low T concentration in testicles, impairs the production of sperm