Skeletal muscle fatigue

As you should know, muscles get tired. But how do they get tired? Well, read on to find out!

Central Fatigue

Central fatigue occurs when the CNS becomes less active and thus sends fewer signals to the muscles. This may occur either because the "drive" of the motor neurons declines, or because muscle receptors (such as proprioceptors) are inhibiting the motor neurons. As we are focusing more on skeletal muscle rather than on neurons, I'm not going to talk any more about central fatigue.

Peripheral Fatigue

Peripheral fatigue has to do with the muscles itself. Fatigue can affect both the action potential and cell metabolism.

The effect of fatigue on the action potential only occurs at very high frequencies of stimulation. Fatigue can cause an increase in the resting membrane potential (which sounds like it would make the cell more excitable, but if you go over your notes for electrophysiology, you'll see why this is not the case), reduce the magnitude of the action potential, reduce intracellular K⁺, and increase intracellular Na⁺. This results in a decreased activation of dihydropyridine receptors, which in turn makes the muscle less excitable.

The effect of fatigue on metabolism occurs during high-intensity exercise. As mentioned here, aerobic metabolism is relatively time-consuming. During high-intensity exercise, the cell won't have time to go through the whole citric acid cycle and so forth, so anaerobic metabolism begins to take over. This produces lactate (lactic acid), and it has long been thought that lactate causes fatigue. In fact, that is not totally true. Here I will present to you some possible causes of fatigue, as well as what we know about them:

Products of Lactic Acid Production

As the rate of glycolysis increases over the first 20 seconds or so, so too does the production of lactic acid. Lactic acid can dissociate into H⁺ and lactate, so both of these things also increase with the rate of glycolysis. Now for the million-dollar question: do these metabolites cause muscle fatigue?

H⁺ ions actually have very little effect on fatigue. Studies have been done in which a muscle has been contracted at pH 7.4 and at pH 6.9. While there was a small decrease in force produced at the lower pH, this decrease was not very large. Low pH has been found to cause some slowing of force relaxation, but no effect on cross-bridge force production, release of Ca²⁺ from the sarcoplasmic reticulum, or fatigue resistance of the muscle cells. However, low pH may increase central fatigue, reducing the stimulation provided to the muscles.

Lactate also has very little effect on fatigue. Lactate has been added to skinned fibres (i.e. muscle cells with the membrane removed). It has been found to have very little effect on contraction.

Products of Creatine Phosphate Hydrolysis

As mentioned here, creatine phosphate (also known as phosphocreatine, or PCr), can be broken down to form ATP and creatine via creatine kinase. ATP is further broken down to form ADP and Pi (phosphate). Hence, breakdown of creatine phosphate causes an increase in phosphate levels.

Using the skinned fibre technique, exposure to phopshate has been found to cause a decrease in tension. Hence, increased phosphate may be a major contributor to fatigue, reducing cross-bridge force production, Ca²⁺ release from the SR and its later reuptake, and Ca²⁺ sensitivity. One mechanism in which Pi may achieve these effects is by its binding to Ca²⁺ in the lumen of the SR. This reduces the concentration of free Ca²⁺ and therefore the concentration gradient driving the exit of Ca²⁺ from the SR.

Long-lasting peripheral fatigue

Aside from acute fatigue, which results from high stimulation over a short amount of time, muscles can also be affected by a longer-lasting fatigue. Long-lasting peripheral fatigue results following prolonged, less intense exercise, and can last for hours to days. Interestingly enough, it can only be found at low stimulation frequencies. Long-lasting peripheral fatigue is definitely not due to metabolic factors (such as Pi etc.) as they return to normal levels long before the force does. I'll discuss potential causes for long-lasting fatigue in a bit, but let's first talk about a couple of ways in which long-lasting fatigue can be explained.

Firstly, long-lasting peripheral fatigue may involve a decrease in Ca²⁺ release from the SR. This decrease, in turn, may involve the DHPRs in the T-tubules and their coupling with the RyRs.

Secondly, fatigue can be explained by the sigmoidal shape of the force-Ca²⁺ curve. This is a curve that shows the amount of force generated for different amounts of Ca²⁺. Just like the haemoglobin dissociation curve, it is sigmoidal: that is, it has a steep part and a plateau part. The plateau part occurs at high levels of Ca²⁺, as would be released from a high frequency of stimulation. A small drop in Ca²⁺ at this stage would not cause much change in force, as it is still in the plateau part. On the other hand, lower frequencies are represented by the steeper part of the curve, so a change in Ca²⁺ would cause a significant drop in force.

Now it's time to look at the causes of long-lasting peripheral fatigue! Specifically, these are the causes of the loss of Ca²⁺ release during long-lasting fatigue.

High Ca2+ levels

While moderately high Ca²⁺ can increase force, very high levels of Ca²⁺ can cause an inhibition in further Ca²⁺ release. Skinned fibres exposed to very high levels of Ca²⁺ have a strong response, but following this, the fibres are unexcitable. It is possible that this occurs due to the activation of Ca²⁺-activated proteases, such as calpain. Calpain inhibitors, such as leupeptin, can protect from this damage, but only partially.

Reactive Oxygen Species (ROS)

Reactive oxygen species include stuff like superoxide and hydrogen peroxide. They are products of metabolism, so their levels may increase during strenuous exercise. At low levels, ROS can actually enhance force production by acting as intracellular second messengers; however, at high levels, they can inhibit force production by damaging or altering other intracellular proteins. High ROS can inhibit voltage-dependent Ca²⁺ release, decrease Ca²⁺ uptake by the SR and decrease Ca²⁺ sensitivity. High ROS shifts the force-Ca²⁺ relationship to the right, so higher levels of Ca²⁺ are needed in order to generate the same amount of force.

Antioxidants may be able to prevent ROS damage from happening. In fact, treatment with N-acetylcysteine has been found to inhibit fatigue development in humans. Another antioxidant, tiron, has been found to reduce the development of muscle fatigue (though in what species, I have no idea :P).