Force records during fatigue produced by repeated short tetani in an isolated mouse flexor digitorum brevis (FDB) fiber; each tetanus appears as a vertical line. In the top panel, the phases of fatigue (see sect. vii) have been indicated. The bottom panel shows records from the same fiber fatigued in the presence of cyanide to inhibit mitochondrial oxidative phosphorylation. Stimulation protocol: 350-ms, 70-Hz tetani repeated every 4 s for 2 min, and the interval was decreased by ∼20% every 2 min (interval changes indicated by open triangles). Temperature was 25°C. [From Lännergren and Westerblad (268).]
Force record from a fast-twitch lumbrical muscle fiber of Xenopus stimulated at 70 Hz for 30 s. Recovery followed with 500-ms, 70-Hz tetani given at 2-s intervals. Note very rapid recovery after 2 s. [From Lännergren and Westerblad (265).]
Tetanic [Ca2+]i and force records at various phases of fatigue obtained in a fast-twitch (A) and a slow-twitch (B) mouse fiber. Numbers above [Ca2+]i records indicate order of tetani. The fast-twitch FDB fiber in A shows the normal pattern of easily fatigued fibers: an early increase in tetanic [Ca2+]i accompanied by ∼10% decrease in force (phase 1; tetanus 1–10), followed by a relatively stable period (phase 2; tetanus 10–60), and finally a rapid decrease of tetanic [Ca2+]i and force (phase 3; tetanus 60–88). Stimulation protocol: 350-ms, 70-Hz tetani given at 2.5-s intervals. The fatigue-resistant soleus fiber in B shows little changes in tetanic [Ca2+]i and force during a markedly more demanding fatiguing stimulation protocol [a total of 1,000 tetani (500 ms, 70 Hz) given at 2-s intervals]. [A from Dahlstedt et al. (107); B from Bruton et al. (67).]
The major reactive oxygen species in muscle. Numbers in brackets indicate approximate lifetimes of various species (39, 196). GPX, glutathione peroxidase; GR, glutathione reductase. Other abbreviations are as in text.
Amount of Ca2+ released by single action potential (AP) stimuli versus sarcoplasmic reticulum (SR) Ca2+ content in a skinned fiber from rat extensor digitorum longus (EDL) muscle. The SR was progressively depleted of all its releasable Ca2+ in two sequences, first starting with the endogenous Ca2+ content and then a second time after reloading the SR to its maximal level. Ca2+ reuptake was blocked by an SR Ca2+ pump blocker during AP-induced release. The amount of Ca2+ released by an AP is virtually unchanged when the SR is loaded well above its endogenous content, but is decreased at lower content levels. Ca2+ is expressed in micromoles per liter fiber volume. [From Posterino and Lamb (360).]
Schematic showing mechanisms underlying a more marked force depression at low stimulation frequencies. Red arrows show what happens with a decrease in tetanic [Ca2+]i, and blue arrows with a decrease in myofibrillar Ca2+ sensitivity (indicated by dashed line). Note that the effect on force of both these changes is markedly larger when they originate from the steep part of the force-[Ca2+]i relationship, i.e., at low stimulation frequencies.
Examples of decreased force production at low-frequency stimulation observed 30 min after fatigue induced by repeated tetani in a fast-twitch mouse (A) and rat (B) FDB fiber. Note two different mechanisms: the force decrease at 50 Hz in the mouse FDB fiber can be explained by a decreased [Ca2+]i (A), and the force decrease at 30 Hz in the rat FDB fiber was not accompanied by any decrease in [Ca2+]i (B). The fact that force at 100 Hz was similar before and after fatigue shows that maximal Ca2+-activated force was little affected, and hence, the force decrease at low frequencies was due to a decrease in myofibrillar Ca2+ sensitivity. [A from Westerblad et al. (474); B from J. D. Bruton and H. Westerblad, unpublished observations.]
Schematic diagram illustrating the major mechanisms that contribute to muscle fatigue. Heading in each box identifies subcellular function, and the subsequent list indicates cellular changes occurring during fatigue that influence the subcellular function. SM, surface membrane; TT, t tubule; SR, sarcoplasmic reticulum; AP, action potential.
Schematic to illustrate different mechanisms leading to exhaustion. Dashed line shows how the maximum force (or power) declines during repeated tetani. Solid red line indicates a submaximal force required for a particular activity. Exhaustion (failure to produce the required force) occurs at the intersection of the two lines. Increases and decreases in the required force (arrow 1) will cause earlier and later onset of exhaustion, respectively. Increases and decreases in the maximum force that the muscle can produce (arrow 2) will also change the time to exhaustion. Finally, changes in the intrinsic fatiguability of the muscle (arrow 3) will also change the time to exhaustion.
Cover: Paracrine hormones, released from the vascular endothelium in response to shear stress, impact on the subintimal space and vascular smooth muscle cell function. Artwork by Paul Ricketts. See Green, Daniel J., Maria T. E. Hopman, Jaume Padilla, M. Harold Laughlin, and Dick H. J. Thijssen. Physiol Rev 97: 495–527, 2017.