Peripheral Mechanisms of Fatigue

Peripheral Mechanisms and Contributors to Exercise-Induced Fatigue

Intracellular Mediators of Muscle Fatigue (COSA, 2010)

  • Factors Surrounding the Green Circle:
    • Insufficient blood flow (circulatory and pulmonary function).
    • Insufficient oxygen supply.
    • Hormonal dysregulation.
    • Changes in acid-base balance.
    • Impaired excitation-contraction coupling.
    • Sarcoplasmic reticulum dysfunction (calcium release and reuptake).
    • Decreased glucose availability and uptake (glycolytic function).
    • Microvascular insufficiency.
  • Within the Green Circle (Muscle Fiber Cell):
    • Attenuated cross-bridge function (impaired formation, attachment, decreased power stroke).
    • Increased inorganic phosphates and ADP levels (mucked up ATP:ADP ratio).
    • Increased hydrogen ions (affecting metabolic environment).
    • Impaired calcium flux (release and reuptake by the sarcoplasmic reticulum).

Energetic Processes and ATP Production

  • Hypothesis: Peripheral fatigue involves the failure of energetic processes to produce ATP at a sufficient rate to maintain performance.
  • Supplementation studies (creatine, carbohydrate) support this.
  • Factors influencing peripheral fatigue:
    • Depletion of muscle glycogen.
    • Intracellular acidosis (accumulation of hydrogen ions).
    • Hypoxic conditions: Strong muscle contractions compress blood vessels, temporarily occluding blood flow.
      • Sustained isometric contractions (e.g., climbers hand grip in forearm muscles).
      • Wrestling or grappling sports (whole body contractions occluding blood flow).
    • Reduced blood flow.
  • ATP is never completely depleted.
  • Muscle fatigue correlates with signs of energy deficiency.
    • ATP usage exceeds ATP generation.
    • Part of the nucleotide pool is deaminated into inosine monophosphate (IMP).
    • IMP can be:
      • Reaminated to AMP, then ideally back to ADP and ATP.
      • Further degraded into hypoxanthine, xanthine, and urate.
    • Increased degradation products of ATP:
      • In blood: hypoxanthine and NH3NH_3.
      • In muscles: IMP and NH3NH_3.

Salin et al. Study

  • Athletes performing a cycling task at 70-75% of VO2VO_2 max for around 90 minutes.
  • MVC (Maximal Voluntary Contraction) decreases across the task, with partial restoration during a 30-minute recovery.
  • PCR (phosphocreatine) Concentrations:
    • Rapid and significant reduction in PCR as exercise commences.
    • Rapid recovery of PCR early in the recovery phase.
  • Figure 1: Power and capacity of energy-yielding processes in human skeletal muscle.
    • PCR and glycolytic systems produce the most ATP for a given time, but are shorter in duration.
    • Oxidative systems (carbohydrates or free fatty acids) produce ATP at a slower rate but in large amounts over long periods.

Phosphocreatine and Peripheral Fatigue

  • Maximal force production is related to PCR concentrations during contraction and recovery.
  • Decline in PCR is associated with increased inorganic phosphates, potentially affecting calcium handling and reducing force production.
  • Relationship between PCR reduction and isometric force generating capacity.

Muscle Glycogen

  • Hocken et al. (2021): Study on 10 male weightlifters performing:
    • Four sets of five at 75% one RM back squats and deadlifts.
    • Four sets of twelve at 65% one RM split squats.
    • Showed a 38% reduction in glycogen after exercise.
  • Type I Fibers:
    • Large decrease in intermyofibular glycogen.
    • No or minor changes in intramyofibrillar or sub sarcolemma glycogen.
  • Type II Fibers:
    • Large decreases across all sub sarcolemma regions.
    • Some type II fibers showed almost complete depletion of glycogen stores.
  • Figures showing frequency and diameter of glycogen particles pre- and post-exercise, measured via transmission electron microscopy.
  • Shift to the left (reduction) is more significant for Type II fibers compared to Type I fibers.

High-Intensity Intermittent Exercise Study (2022)

  • 18 moderately to well-trained male participants.
  • Three periods of 10 x 45 seconds cycling at 105% of their watt max, coupled with 5 x 6 seconds maximal sprints.
  • Muscle biopsy, blood sample, and repeat sprint ability test pre-exercise and after each exercise period.
  • After exercise bout one: Type II fiber-specific enhanced utilization of intra- and intramyofibrillar glycogen.
  • Accelerated Type II single-fiber intra glycogen depletion.
  • With exercise bouts two and three, reduced utilization of Type II fiber intra- and intramyofibrillar glycogen.
  • In high-intensity exercise, there is preferential usage of Type II fibers, which store a lot of glycogen. This is used early on, but partial or full depletion occurs from these fibers as exercise progresses.

Glycogen and Muscle Performance

  • Reductions in muscle glycogen are associated with:
    • Reductions in maximal force generating capacity.
    • Reductions in power output.
    • Reductions in strength endurance.

Ottumblatt (2011) Study

  • Glycogen levels and sarcoplasmic calcium release were measured before, immediately after, and 4 and 22 hours after one hour of exhausting cross-country race (or simulation).
  • Compared a group fed carbohydrates after the exercise bowel versus a group only allowed to drink water.
  • Carbohydrate-fed group recovered muscle glycogen stores rapidly over 4 hours and near full repletion after 24 hours.
  • The group restricted from carbohydrate intake for 18 hours showed no repletion of muscle glycogen stores until 22 hours after.
  • Same trend happened with sarcoplasmic calcium release.
  • Without carbohydrate intake after exercise/competition, sarcoplasmic reticulum function was impacted.
  • Reductions in muscle glycogen reduce calcium release rate from the sarcoplasmic reticulum.
  • This reduces cross-bridge cycling rate, hence reduces force output, and increases fatigue.

Glycogen Repletion and Fatigue

  • Subsequent bout of fatigue occurs more quickly when glycogen is not consumed during recovery.
  • Mouse model study (2013): Stimulated fast-twitch fibers to decrease glycogen to ~30%.
  • PanelAPanel A: Better maintenance of force and calcium function when glycogen was supplied during the 60-minute recovery period.
  • PanelBPanel B: Fatigue bout two shows much shorter time to fatigue if no glycogen replenishment occurred (this is also better/worse than normal/control respectively).

Possible Implications of Reduced Glycogen on Fatigue

  • Levels of analysis (sarcoplasmic reticulum, mechanically skinned fibre, intact fibre, whole muscle, whole body) show consistent evidence.
  • Mechanically skinned fibres: altered action potential function or generation, decreasing force production.
  • Overall: impaired sarcoplasmic reticulum calcium release, more intracellular free calcium, problems with force production.

Peripheral Fatigue and Calcium Handling

  1. Impaired SR calcium channel release of calcium.
  2. Hydrogen ion-induced decrease in the maximal effect of calcium on muscle force (lower pH).
  3. Decreased calcium sensitivity (less effect)

Possible Factors Related to Calcium Release During Fatiguing Exercise

  • Probably not related to action potential failure or inadequate voltage sensor activation.
  • More related to changes in calcium release from the sarcoplasmic reticulum itself or delayed recovery of calcium back into the sarcoplasmic reticulum.
  • Ryanodine receptors play an important role in regulating calcium release from the SR.
    • Sense ATP depletion and reduce calcium release, resulting in decreased cross spread cycling rate and sarcoplasmic reticulum calcium uptake.
    • Results in decreased power output and forced generation capacity.
    • Prevents complete exhaustion of all cellular ATP, that is important from a survival perspective.

Stress Responses in Skeletal Muscle During Excitation-Contraction Coupling

  • Depolarisation of the T-tubule membrane activates Cav1.1, triggering SR calcium release through the ryanodine receptor, leading to sarcomere contraction.
  • Intracellular signaling pathways activated in skeletal muscle by pathological stress affect ryanodine receptor function and alter excitation-contraction coupling.
  • Stress-induced ryanodine receptor dysfunction can result in sarcoplasmic reticulum calcium leak.
  • Activates numerous calcium-dependent cellular damage mechanisms (pathological conditions or conditions with high muscle fibre damage).
  • Healthy muscle: calcium release occurs in a coordinated fashion during contraction, and calcium is low at rest.
  • Stressed muscle: PKA-mediated phosphorylation of the ryanodine receptor alters calcium handling during contraction and relaxation, leading to sarcoplasmic reticulum calcium leak in the resting muscle.
  • Calcium leak influences nuclear and mitochondrial function and leads to a decrease in sarcoplasmic reticulum load, so less will be available at the next cycle.

High-Intensity Exercise and Lactic Acid Accumulation

  • Increases fatigue and stimulates lactic acid accumulation.
  • Increase in circulating or produced hydrogen ions, which lowers the pH (more acidic).
  • Lower pH:
    • Decreases the number of high-force cross-bridge attachments in type II fibres.
    • Decreases the force produced per cross-sectional area in type I and type II fibres.
  • Increase in hydrogen ions and inorganic phosphates decreases myofibrilar calcium sensitivity in type I and type II fibres.