Fatigue, defined as the failure to maintain the required or expected power output, is a complex problem, since multiple factors are clearly involved, with the relative importance of each dependent on the fiber type composition of the contracting muscles(s), and the intensity, type, and duration of the contractile activity. The primary sites of fatigue appear to be within the muscle cell itself and for the most part do not involve the central nervous system or the neuromuscular junction. The major hypotheses of fatigue center on disturbances in the surface membrane, E-C coupling, or metabolic events. The cell sites most frequently linked to the etiology of skeletal muscle fatigue are shown in Figure 1. Skeletal muscles are composed of at least four distinct fiber types (3 fast twitch and 1 slow twitch), with the slow type I and fast type IIa fibers containing the highest mitochondrial content and fatigue resistance. Despite fiber type differences in the degree of fatigability, the contractile properties undergo characteristic changes with the development of fatigue that can be observed in whole muscles, single motor units, and single fibers. The Po declines, and the contraction and relaxation times are prolonged. Additionally, there is a decrease in the peak rate of tension development and decline and a reduced Vo. Changes in Vo are more resistant to fatigue than Po and are not observed until Po has declined by at least 10% of its initial prefatigued value. However, the reduced peak power by which fatigue is defined results from both a reduction in Vo and Po. In the absence of muscle fiber damage, the prolonged relaxation time associated with fatigue causes the force-frequency curve to shift to the left, such that peak tensions are obtained at lower frequencies of stimulation. In a mechanism not clearly understood, the central nervous system senses this condition and reduces the alpha-motor nerve activation frequency as fatigue develops. In some cases, selective LFF develops that displaces the force-frequency curve to the right. Although not proven, it appears likely that this condition is associated with and likely caused by muscle injury, such that the SR releases less Ca2+ at low frequencies of activation. Alternatively, LFF could result from a reduced membrane excitability, such that the sarcolemma action potential frequency is considerably less than the stimulation frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

Cellular mechanisms of muscle fatigue

Classical biochemistry is founded on several assumptions valid in dilute aqueous solutions that are often extended without question to the interior milieu of intact cells. In the first section of this chapter, we present these assumptions and briefly examine the ways in which the cell interior may depart from the conditions of an ideal solution. In the second section, we summarize experimental evidence regarding the physical properties of the cell cytoplasm and their effect on the diffusion and binding of macromolecules and vesicles. While many details remain to be worked out, it is clear that the aqueous phase of the cytoplasm is crowded rather than dilute, and that the diffusion and partitioning of macromolecules and vesicles in cytoplasm is highly restricted by steric hindrance as well as by unexpected binding interactions. Furthermore, the enzymes of several metabolic pathways are now known to be organized into structural and functional units with specific localizations in the solid phase, and as much as half the cellular protein content may also be in the solid phase.

http://cmgm.stanford.edu/biochem/biosci214/papers/Luby-Phelps.pdf

Cytoarchitecture and physical properties of cytoplasm: volume, viscosity, diffusion, intracellular surface area.

Janmey, Paul A. The Cytoskeleton and Cell Signaling: Component Localization and Mechanical Coupling. Physiol. Rev. 78: 763–781, 1998. — The three-dimensional intracellular network formed by the fil...

The Cytoskeleton and Cell Signaling: Component Localization and Mechanical Coupling

New insights into an old protein: the functional diversity of mammalian glyceraldehyde-3-phosphate dehydrogenase.

Implications of macromolecular crowding for protein assembly.

Glycolytic enzyme interactions with tubulin and microtubules.

The diverse physical associations of the glycolytic enzymes with structural components of the cell suggest that the glycolytic enzymes are not entirely soluble in the cell. The relatively low affinities of the associations are likely responsible for the apparently transient interactions. The binding phenomenon is suggested to regulate metabolism through changes in enzymatic activity and facilitates localized enrichment of the enzymes.

Association of glycolytic enzymes with the cytoskeleton.

A Glycolytic Enzyme Binding Domain on Tubulin

https://www.cell.com/biophysj/pdf/S0006-3495(06)72328-1.pdf

Harvey R. Knull

Papers

Glycolytic enzyme interactions with tubulin and microtubules.

Association of glycolytic enzymes with the cytoskeleton.

A Glycolytic Enzyme Binding Domain on Tubulin

Glycolytic enzyme interactions with yeast and skeletal muscle F-actin.

Heteromerous interactions among glycolytic enzymes and of glycolytic enzymes with F-actin: effects of poly(ethylene glycol)