Chapter 4. peripheral factors in neuromuscular fatigue PF. Gardiner, Advanced neuromuscular exercise physiology

Neuromuscular fatigue ↓ maximal force response in spite of continued supramaximal stimulus ↑effort necessary to maintain a submaximal contractile force During sustained submaximal muscle contraction ↑ excitation of the motor pool simultaneous ↓ in the maximal capacity of the contractile system Neuromuscular fatigue: a condition that develops gradually as exercise continues

Factors Affecting Performance

Sites of Fatigue Central fatigue Peripheral fatigue Neural factors Mechanical factors Energetics of contraction

Changes in contractile properties during fatigue Jones DA et al, JP 2006

Changes in contractile properties during fatigue Jones DA et al, JP 2006

Changes in contractile properties during fatigue Jones DA et al, JP 2006

↑ neural signals when maintaining a submaximal contractile force

Intramuscular factors: Interstitial K+ MAJOR factor ↑interstitial 細胞間 potassium (K+), ↓membrane excitability critical interstitial potassium concentration at which muscle tetanic force is affected similar to that in exercising human muscles (resting: ~4 mM; exercising: 10-13 mM) sodium-potassium ATPase (Na+/K+ ATPase) Training ↑ Na+/K+ ATPase, ↓accumulation of interstitiaI K, longer time to fatigue

Na, K in nerve impulse

Interstitial K+ and muscle force Interstitial K+ in exercising human muscles: 10-13 mM

Power output and interstitial K+ in human muscles

Intramuscular factors ATP concentration only minor role ATP usually NOT depleted during exercise However, potential localized ATP depletion, especially in triad region Na+/K+ ATPase, use ATP generated by glycolysis ↓ rate of ATP use by ↓crossbridge cycling, ↓ SR Ca2+ uptake ↑ calcium trapped in the cytoplasmic compartment ↑ magnesium (Mg2+) ↓ calcium channel opening inorganic phosphate enter sarcoplasmic reticulum and precipitate with Ca Minor factor : estimated <10% of maximum force

Exer Biochem c6-high intensity ex X: force, : PCr, :ATP after 10s and 20 s. open: type I, close type II human muscles Exer Biochem c6-high intensity ex

Fatigue mechanism – increased H+ Human muscle pH dropped from 7.05 to ~6.5 after exhaustive exercise However, exhaustion in pH 6.8-6.9 in some situations Force usually recover faster than pH Ca2+ release from SR NOT inhibited even at pH 6.2 H+ has much less inhibitory effect in activation of the contractile apparatus and Ca2+ release than previously assumed Low pH could inhibit glycolytic enzyme activities However, alkalinizers DO increase performance in HIE

Lactate metabolism Whenever glycolysis produce pyruvate, lactate also produced Pyruvate synthesis rate >> pyruvate dehydrogenase activity Lactate dehydrogenase activity high in skeletal muscle Fate of lactate Leave muscle fiber via monocarboxylate transporter Enter adjacent fiber with lower intracellular [lac] Enter cells, used by heart, nonworking muscle (as fuel) or liver and kidney (as sources for gluconeogenesis), intercellular lactate shuttle monocarboxylate transporter act as a symport, transfer lactate down gradient, accompanied by a H+ Lactate is NOT responsible for muscle acidity, fatigue, or soreness

Lactate synthesis REMOVE H+

Major source of H+ during exercise

Major mechanisms in muscle fatigue

Fatigue mechanisms

Structures other than muscle Neuromuscular transmission failure failure of a nervous impulse to be translated into sarcolemma Neurotransmitter depletion: acetylcholine ↓ in max force: stimulated by its motor nerve > stimulated directly to muscle 3,4-diaminopyridine ↓ force difference between indirect and direct stimulation 3,4-diaminopyridine↑acetylcholine release

Neuromuscular transmission failure Postsynaptic membrane failure Prolonged exposure to ACh  desensitize ACh receptor Failure of axon branches to pass on action potentials Action potential generated in axon is NOT propagated into all of the branches extending to muscle fibers

Difference between direct and indirect stimulation

Inhibition of motoneurons Inhibition of motoneurons: ↓motoneuronal excitability, ↓ firing rates during fatigue at maximal and submaximal force Afferent nerve (sensory nerve) signals Demonstrated under ischemia conditions Receptors for metabolic by-product concentrations?

Inhibition of motoneurons

Skinned muscle skinning the muscle fibers allows us to set the intracellular concentrations of molecules no longer a semipermeable barrier or transporter system that can become limiting