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Cellular, Molecular, and Metabolic Basis of Muscle Fatigue

Robert H. Fitts

10.1002/cphy.cp120126

Source: Supplement 29: Handbook of Physiology, Exercise: Regulation and Integration of Multiple Systems

Originally published: 1996

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Definition and Current Theories of Fatigue
2 Muscle Fiber‐Type Composition
3 Mechanical Properties
3.1 The Isometric Contractile Properties
3.2 The Maximal Shortening Speed and Peak Power
3.3 The Force‐Frequency Relationship
4 Excitation‐Contraction Coupling
4.1 Sarcolemma and T‐Tubular Membranes
4.2 T‐Tubular–Sarcoplasmic Reticulum Junction and Calcium Release
5 Lactic Acid, Intracellular pH And Fatigue
5.1 Muscle Lactate
5.2 Hydrogen Ion and Muscle Fatigue
6 Inorganic Phosphate and Muscle Fatigue
6.1 Total Phosphate and the Diprotonated Form
6.2 Mechanisms of Phosphate Action
7 High‐Energy Phosphates and the Free Energy of ATP Hydrolysis
7.1 ATP and Muscle Fatigue
8 Blood Glucose and Muscle Glycogen
8.1 Hypoglycemia and Performance
8.2 Carbohydrate Metabolism and Muscle Fatigue
9 Ultrastructural Changes and Muscle Fatigue
9.1 Muscle Damage and Exercise Intensity
9.2 Organelle Susceptibility to Damage
10 Summary and Conclusions
Figure 1. Figure 1.

The major potential sites of fatigue as originally described by Bigland‐Ritchie 26 are shown. The neural components are: 1, excitatory input to higher motor centers; 2, excitatory drive to lower motoneurons; 3, motoneuron excitability; and 4, neuromuscular transmission. The peripheral factors within the muscle cell include: 5, sarcolemma excitability; 6, excitation‐contraction coupling to include T‐tubular and SR Ca2+ release and reuptake events; 7, contractile mechanisms; and 8, metabolic energy supply and metabolic accumulation.
Figure 2. Figure 2.

A block diagram of the actomyosin ATP hydrolysis reaction during contraction in skeletal muscle, where A is actin and M is heavy meromyosin or myosin S1.

The scheme is adapted from the current models of ATP hydrolysis (see 210). The shaded blocks represent the cross‐bridge state and products of the reaction thought to increase with muscle fatigue
Figure 3. Figure 3.

A summary of the known changes in the isometric twitch and tetanus, and isotonic contractions with fatigue. +dP/ dt and ‐dP/dt represent the peak rate of tension development and decline, respectively. CT, isometric twitch contraction time; 1/2 RT, twitch one‐half relaxation time; Vo, maximal velocity of unloaded shortening.
Figure 4. Figure 4.

Slowing of relaxation during fatiguing stimulation of a single fiber isolated from the mouse flexor brevis muscle. A typical fatigue curve is shown in the upper part. Each tetanus appears as a vertical line. The lower part displays the relaxation of the tetani indicated above the fatigue curve (a–d). The tension bar refers to the upper part only.

Reprinted with permission from Westerblad, H., and J. Lannergren. J. Physiol. 434: 323–336, 1991 280
Figure 5. Figure 5.

A schematic representation of E‐C coupling showing a representative sarcolemma action potential (AP) at rest (#1) and following fatigue (#2). It is unknown how fatigue affects the AP in the depths of the T‐tubule (#3), hence the displayed record is theoretical and not an actual measured AP. The question mark (?) indicates that the composition of the extracellular fluid in the depths of the T‐tubule in a fatigued muscle is currently unknown. The dotted line across each AP represents the resting and zero overshoot potentials.
Figure 6. Figure 6.

A schematic drawing of the T‐tubular SR junction showing the T‐tubular dihydropyridine receptor or charge sensor (site 1), the calcium release channel (site 2), and the lumen of the SR (site 3). Disturbances in E‐C coupling could result from fatigue‐induced alterations in any or all of the three sites. See text for possible factors affecting each site.

The figure was modified from that presented previously [233
Figure 7. Figure 7.

Application of 10 mM caffeine in control (A) and during two successive fatigue runs (B and C). Bars below tension records in the top panels indicate caffeine exposure during fatiguing stimulations; caffeine was applied after 22 fatiguing tetani (B) and when tetanic tension was depressed to 0.36 Po by 187 tetani (C). Fluorescence ratio (representative of the intracellular free Ca2+) and tension records from tetani elicited before application of caffeine (a) and in the presence of caffeine (b) are shown in the two lower panels. Dashed lines represent resting ratio in control; stimulation periods are displayed below tension records. Note that the tetanic ratio increase induced by caffeine in late fatigue was accompanied by a substantially enhanced tension production, whereas tension was not markedly affected by the increased ratios in the other two states.

Reprinted with permission from Westerblad, H., and D. G. Allen. J. Gen. Physiol. 98: 615–635, 1991 276 by copyright permission of the Rockefeller University Press
Figure 8. Figure 8.

Schematic representation of mechanisms by which increases in H+, inorganic phosphate (Pi), and ADP could contribute to fatigue during high‐intensity exercise. An upward or downward arrow indicates an increased or decreased response for the indicated variable, respectively [an exception is the arrows indicating the cross‐bridge and troponin C (TNC) reactions]. A negative sign indicates inhibition at the site indicated. AM, actomyosin cross‐bridge.
Figure 9. Figure 9.

Various sources of energy during prolonged exercise at 79% Vo2max. Note that blood glucose becomes the predominant source of carbohydrate energy during the latter stages of exercise and thus it is important to maintain blood glucose concentration by eating carbohydrates.

Reprinted with permission from Coyle, E. F. Carbohydrate metabolism and fatigue. In: Muscle Fatigue: Biochemical and Physiological Aspects, edited by G. Atlan, L. Beliveau, and P. Bouissou. Paris: Masson Pub., 1991, p. 153–164 70
Figure 10. Figure 10.

Schematic representation of important blood and tissue changes with prolonged exercise. The shaded boxes indicate substances known to decline during prolonged exercise. Depletion of muscle glycogen, dehydration, and hypoglycemia have all been linked to fatigue in prolonged exercise. Sites 1–3 represent carnitine palmitoyltransferase‐mediated FFA uptake into mitochondria, concentrations of tricarboxylic acid cycle intermediates, and the production rate of NADH, respectively. Disturbances in all three sites have been linked to fatigue during endurance exercise (see text).


Figure 1.

The major potential sites of fatigue as originally described by Bigland‐Ritchie 26 are shown. The neural components are: 1, excitatory input to higher motor centers; 2, excitatory drive to lower motoneurons; 3, motoneuron excitability; and 4, neuromuscular transmission. The peripheral factors within the muscle cell include: 5, sarcolemma excitability; 6, excitation‐contraction coupling to include T‐tubular and SR Ca2+ release and reuptake events; 7, contractile mechanisms; and 8, metabolic energy supply and metabolic accumulation.



Figure 2.

A block diagram of the actomyosin ATP hydrolysis reaction during contraction in skeletal muscle, where A is actin and M is heavy meromyosin or myosin S1.

The scheme is adapted from the current models of ATP hydrolysis (see 210). The shaded blocks represent the cross‐bridge state and products of the reaction thought to increase with muscle fatigue


Figure 3.

A summary of the known changes in the isometric twitch and tetanus, and isotonic contractions with fatigue. +dP/ dt and ‐dP/dt represent the peak rate of tension development and decline, respectively. CT, isometric twitch contraction time; 1/2 RT, twitch one‐half relaxation time; Vo, maximal velocity of unloaded shortening.



Figure 4.

Slowing of relaxation during fatiguing stimulation of a single fiber isolated from the mouse flexor brevis muscle. A typical fatigue curve is shown in the upper part. Each tetanus appears as a vertical line. The lower part displays the relaxation of the tetani indicated above the fatigue curve (a–d). The tension bar refers to the upper part only.

Reprinted with permission from Westerblad, H., and J. Lannergren. J. Physiol. 434: 323–336, 1991 280


Figure 5.

A schematic representation of E‐C coupling showing a representative sarcolemma action potential (AP) at rest (#1) and following fatigue (#2). It is unknown how fatigue affects the AP in the depths of the T‐tubule (#3), hence the displayed record is theoretical and not an actual measured AP. The question mark (?) indicates that the composition of the extracellular fluid in the depths of the T‐tubule in a fatigued muscle is currently unknown. The dotted line across each AP represents the resting and zero overshoot potentials.



Figure 6.

A schematic drawing of the T‐tubular SR junction showing the T‐tubular dihydropyridine receptor or charge sensor (site 1), the calcium release channel (site 2), and the lumen of the SR (site 3). Disturbances in E‐C coupling could result from fatigue‐induced alterations in any or all of the three sites. See text for possible factors affecting each site.

The figure was modified from that presented previously [233


Figure 7.

Application of 10 mM caffeine in control (A) and during two successive fatigue runs (B and C). Bars below tension records in the top panels indicate caffeine exposure during fatiguing stimulations; caffeine was applied after 22 fatiguing tetani (B) and when tetanic tension was depressed to 0.36 Po by 187 tetani (C). Fluorescence ratio (representative of the intracellular free Ca2+) and tension records from tetani elicited before application of caffeine (a) and in the presence of caffeine (b) are shown in the two lower panels. Dashed lines represent resting ratio in control; stimulation periods are displayed below tension records. Note that the tetanic ratio increase induced by caffeine in late fatigue was accompanied by a substantially enhanced tension production, whereas tension was not markedly affected by the increased ratios in the other two states.

Reprinted with permission from Westerblad, H., and D. G. Allen. J. Gen. Physiol. 98: 615–635, 1991 276 by copyright permission of the Rockefeller University Press


Figure 8.

Schematic representation of mechanisms by which increases in H+, inorganic phosphate (Pi), and ADP could contribute to fatigue during high‐intensity exercise. An upward or downward arrow indicates an increased or decreased response for the indicated variable, respectively [an exception is the arrows indicating the cross‐bridge and troponin C (TNC) reactions]. A negative sign indicates inhibition at the site indicated. AM, actomyosin cross‐bridge.



Figure 9.

Various sources of energy during prolonged exercise at 79% Vo2max. Note that blood glucose becomes the predominant source of carbohydrate energy during the latter stages of exercise and thus it is important to maintain blood glucose concentration by eating carbohydrates.

Reprinted with permission from Coyle, E. F. Carbohydrate metabolism and fatigue. In: Muscle Fatigue: Biochemical and Physiological Aspects, edited by G. Atlan, L. Beliveau, and P. Bouissou. Paris: Masson Pub., 1991, p. 153–164 70


Figure 10.

Schematic representation of important blood and tissue changes with prolonged exercise. The shaded boxes indicate substances known to decline during prolonged exercise. Depletion of muscle glycogen, dehydration, and hypoglycemia have all been linked to fatigue in prolonged exercise. Sites 1–3 represent carnitine palmitoyltransferase‐mediated FFA uptake into mitochondria, concentrations of tricarboxylic acid cycle intermediates, and the production rate of NADH, respectively. Disturbances in all three sites have been linked to fatigue during endurance exercise (see text).

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Article Title: Cellular, Molecular, and Metabolic Basis of Muscle Fatigue
 

How to Cite

Robert H. Fitts. Cellular, Molecular, and Metabolic Basis of Muscle Fatigue. Compr Physiol 2011, Supplement 29: Handbook of Physiology, Exercise: Regulation and Integration of Multiple Systems: 1151-1183. First published in print 1996. doi: 10.1002/cphy.cp120126