In this article we're going to take an in-depth look at the physiological reasons why a muscle fatigues. Why is this important? Because, if we understand what causes a muscle to fail we can understand whether or not training to failure is actually an effective training 'technique'. We can also gain a perspective on how intensely we should, in fact, be training. Maybe we can even gain a small glimpse into such things as ideal training volume and frequency. So, like other articles on the 'Physiology Related Articles' page, this stuff can be pretty dull (for some) but it can also be very useful.
Our focus here will be on the muscular and neural fatigue that occurs when training in the strength training rep range (1-20). Fatigue may occur in the higher rep ranges for reasons other than those that will be dealt with in this article.
As was covered in the The Neuromuscular System Part II: What A Weight Trainer Needs To Know About Muscle article, lactic acid build-up in the muscle cell (due to repeated muscular contractions) causes a reduced intracellular pH that affects force development. This occurs largely because lactic acid accumulation leads to increased intracellular hydrogen ion (H+) concentrations (most of the lactic acid dissociates into H+ and lactate) - and H+ is thought to be a competitive inhibitor of Ca++ binding to troponin. When this happens, fewer actin molecules are 'exposed' to the myosin heads for cross-bridging. Of course, this leads to a weaker contraction. Note that this appears to affect Type II fibers more than Type I. As was also mentioned, lactic acid (actually the H+ produced from lactic acid) also interferes with ATP formation (inteferes with the glycolysis process). This means that less ATP will be around to actually 'fuel' contractions - potentially leading to further weakening.
For you biochemistry buffs, increased H+ interferes with glycolysis by decreasing the transformation of 'phosphorylase b' to the active 'a' form, and also inhibits phosphofructokinase (PFK).
All this would be a strong factor in work that utilizes the anaerobic glycolysis mechanism of energy production - especially work in the 8 - 15 rep range. So that 'burn' you get when doing higher reps and pushing close to failure may actually be part of the reason that you're failing and not just a side effect.
Declining intramuscular ATP is thought to be a major cause of fatigue during high intensity exercise. However, numerous studies have demonstrated that ATP concentrations fall to no less than ~70% of pre-exercise levels during high-intensity exercise. This would seem to imply that ATP shortage is not a major cause of muscle fatigue.
The rebuttal to this argument lies in the speculation that 70-80% of the sarcoplasmic ATP is restricted to the mitochondria and is, in fact, unavailable for cross-bridging. This would mean that while sufficient ATP is actually inside the cell, it is not located where it could be used to 'fuel' muscle contraction. So high intensity exercise may cease due to ATP depletion in the specific areas of cross-bridging, but total sarcoplasmic ATP concentrations may still remain relatively high (at ~70%). This is the 'ATP compartmentalization' hypothesis of muscle fiber fatigue.
There are, of course, worthy arguments against this hypothesis, though. So, let's just say the jury's still out on whether declining ATP levels, themselves, are significant contributors to muscular fatigue during 'normal' conditions. I make the qualification of 'normal' conditions because low intramuscular ATP and/or glycogen levels at the onset of exercise will result in a loss of strength due to low or declining ATP concentrations. In this case there just isn't enough 'gas in the tank' to begin with. This condition can be brought on by overtraining (too much volume or too frequent training) or by insufficient carbohydrates in the diet or impairment of their utilization (such as in insulin resistance).
As was explained in the The Neuromuscular System Part II: What A Weight Trainer Needs To Know About Muscle article, creatine phosphate (CP) is used to replenish intramuscular ATP levels during contraction. CP concentrations quickly decrease within the first few seconds of exercise and eventually decreasing to 5-10% of the pre-exercise concentration within 30 seconds. When this happens there is insufficient CP levels to adequately support ATP replenishment. Does this, in fact, cause muscular fatigue? One would intuitively think so, but there are reasons to question this. It has been established that CP levels, during the initial seconds of exercise, deplete more rapidly than the decline in muscle force occurs. And, because intracellular ATP concentrations rarely fall more than 30% during high intensity exercise, it seems that fatigue caused by CP depletion does not occur. If one believes the ATP compartmentalization theory, though (which I do), then this becomes easily explained and fatigue due to CP depletion seems very likely.
As an aside: Creatine supplementation has been speculated to result in more rapid CP resynthesis between sets and, therefore, increase endurance across multiple sets. It is also well known to produce strength gains in low-rep maximum sets - I consider this as evidence for the ATP compartmentalization theory.
It was explained in the article The Neuromuscular System Part III: What A Weight Trainer Needs To Know About The Nervous System that, during muscle contraction, calcium ions (Ca++) are released from the sarcoplasmic reticulum by way of the T System and then returned to that organelle by way of the Ca-Pump. What would happen then, if all this didn't go as smoothly as anticipated?
Studies on isolated muscle fibers have, indeed, linked reduced sarcoplasmic Ca++ concentrations to fatigue. Specifically, repetitive 'tetanic' contractions of isolated muscles caused a gradual decline of force that was closely associated with a decline in sarcoplasmic Ca++ concentrations (Westerblad & Allen, 1991). After only 10-20 such contractions, sarcoplasmic calcium concentrations became insufficient for forceful contraction (Westerblad et al., 1991). The reason for this is simply because decreased Ca++ release for binding to troponin reduces the number of actin/myosin cross-bridges that can be formed.
Forceful contraction could be reestablished with extremely high doses of caffeine (which stimulates greater Ca++ release from the sarcoplasmic reticulum), but this required caffeine doses at physiologically dangerous levels. This does show, however, that the problem appears not to be with the Ca++ concentrations in the sarcoplasmic reticulum, or their release channels, but probably as a consequence of impaired T-tubule signaling. During repeated contractions of a muscle fiber, K+ begins 'pooling' in the T-tubules. This results from an inability of the Na+/K+ ATPase Pump to maintain the proper Na+/K+ balance on the sarcolemma (at the T-tubules). This disturbance of the membrane potential in the T-tubules inhibits the conduction of the action potential to the sarcoplasmic reticulum and Ca++ is not optimally released - and, thus, forceful contraction is not achieved.
In addition, lactic acid build-up factors in here also. Increased intracellular H+ concentrations (caused by lactic acid accumulation) slows the uptake of Ca++ by the sarcoplasmic reticulum. This occurs because H+ interferes with the operation of the Ca++/ATPase Pump. This reduces muscle contraction force by interfering with intracellular and sarcoplasmic reticulum Ca++ concentrations.
Incidently, the Ca-Pump is, itself, a major ATP consumer. During isometric contractions (when it's relative ATP consumption is greatest) it is estimated to consume ~30% of the total ATP produced in the muscle cell. This could, theoretically, contribute to declining ATP stores available for cross-bridge formation.
As ATP is broken down to provide energy for muscular contraction inorganic phosphate (Pi) accumulates in the cell. On the one hand this is 'good' because phosphate (Pi) is known to be an important stimulator of glycolysis (the breakdown of glucose to produce ATP) and glycogenolysis (the breakdown of glycogen to produce ATP) - thus stimulating the production of more ATP by these pathways. But the increased Pi levels also inhibit further cross-bridges from being formed between actin and myosin filaments. When ATP is used to fuel contraction Pi must be released from the myosin head. Elevated intracellular Pi concentrations impairs this process, resulting in reduced tension development - meaning that as Pi builds up, muscular force production goes down. This may be another contributing factor to muscle fatigue.
It is a well-established fact that as a maximum muscular contraction continues, the frequency of motor units firing decreases. In fact, one study showed that by the end of a 30 second maximum voluntary contraction the firing frequency decreased by 80%. Eventually the frequency of twitching of the high threshold fibers becomes insufficient to sustain the effort.
Neurons transmit impulses down the length of their axons by way of Sodium/Potassium transport and the Sodium/Potassium ATPase Pump. The signal is carried across the membrane of the muscle cell in the same manner. The process also relies heavily on calcium concentrations and enzymes that are involved in the synthesis and breakdown of acetylcholine and numerous other substances. The frequency of motor unit firing decreases, therefore, as the cycling of these substances cannot keep pace with the firing frequency required to maintain the necessary force production.
There is evidence that fatigue during fast and powerful activities (such as some forms of weight training) occurs first at the neuromuscular junction. Precisely, the motor neurons cannot manufacture and release acetylcholine (ACh) fast enough to maintain transmission of the action potential from the motor neurons to the muscles.
The theory that peripheral signaling fatigue is a primary contributing factor to muscular fatigue/failure has gained much support in recent years.
In order for a muscle fiber to 'twitch' the central nervous system (CNS) must send a nerve impulse to the controlling motor unit. The innervating nerve cannot maintain its capacity to transmit this signal, with optimum frequency, speed and power for extended periods of time. Eventually concentrations of substrates such as sodium, potassium, calcium, neurotransmitters, enzymes, etc. decreases to the point where muscle contraction becomes markedly slower and weaker. If high discharge rates are continued the nerve cell will assume a state of inhibition to protect itself from further stimuli. The force of contraction, therefore, is directly related to the frequency, speed and power of the electrical 'signal' sent by the CNS.
Interestingly, though far from understood, is the fact that a trainee's motivation and emotional state can profoundly affect the discharge characteristics of the central nervous system.
Clearly, the central nervous system can play a pivotal role in the perception and reality of fatigue.
It is currently believed that, although muscle fatigue can be traced to fewer attached cross-bridges, the major portion of the force decline is attributable to reduced force output of the individual cross-bridges. If this is true, it would point to accumulation of Pi and H+ as the likely dominant mechanisms of causing fatigue. However, failure of the sarcoplasmic reticulum to release sufficient Ca++ due to signaling problems from the T-tubules is also a probable contributor - if the reps or set volume is high enough. And, also depending on the number of reps performed and the weight used, the nervous system's inability to maximally recruit and fire muscle fibers (both peripherally and centrally) may factor heavily.
All of this is under the assumption that the lifter can muster a sufficient level of effort to train intensely enough to bring these factors into prominence (i.e. the central nervous system is not in a state of inhibition and the lifter's 'psyche' is sufficient).
So, after all that, you may have a different perspective on what's actually going on when your muscles hit failure. As with all of the articles in this physiology section of the site, the information presented here will be used to examine how a muscle should actually be trained ...from the perspective of what is actually going on in your body.
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Marsden CD, Meadows JC and Merton PA: Isolated single motor units in human muscle and their rate of discharge during maximal voluntary effort. Journal of Physiology (London), 1971; 217: 12-13.