Fatigued muscle produces less force and has a reduced velocity of shortening
Muscle fatigue is defined as the inability to maintain a desired power output—resulting from muscle contraction against a load—with a decline in both force and velocity of shortening. A decline in maximal force production with fatigue results from a reduction in the number of active cross-bridges as well as in the force produced per cross-bridge. N9-6 As fatigue develops, the production of force usually declines earlier and to a greater extent than shortening velocity. Other characteristics of fatigued skeletal muscle are lower rates of both force production and relaxation, owing to impaired release and reuptake of Ca2+from the sarcoplasmic reticulum (SR). As a result, fast movements become difficult or impossible, and athletic performance suffers accordingly. Nevertheless, fatigue may serve an important protective role in allowing contractions at reduced rates and lower forces while preventing extreme changes in cell composition that could cause damage. Muscle fatigue is reversible with rest, which contrasts with muscle damage or weakness, in which even muscles that are well rested are compromised in their ability to develop force. For example, muscle damage induced by eccentric contractions (see p. 1207) can easily be mistaken for fatigue, except the recovery period can last for days.
Factors contributing to fatigue include motivation, physical fitness, nutritional status, and the types of motor units (i.e., fibers) recruited as governed by the intensity and duration of activity. Fatigue during prolonged activity of moderate intensity involving relatively low frequencies of motor-unit activation (see p. 1212) is caused by different factors than fatigue during bursts of high intensity involving high frequencies of motor-unit activation (see p. 1212). Moreover, fatigue can result from events occurring in the central nervous system (CNS; central fatigue) as well as from changes within the muscle (peripheral fatigue).
Changes in the CNS produce central fatigue
Central fatigue reflects changes in the CNS and may involve altered input from muscle sensory nerve fibers, reduced excitatory input to motor control centers of the brain and spinal cord, and altered excitability of α and γ motor neurons (see Fig. 15-30). The contributions of these factors vary with the individual and with the nature of the activity. For example, central fatigue is likely to play only a minor role in limiting performance of highly trained athletes who have learned to pace themselves according to the task and are mentally conditioned to discomfort and stress. In contrast, central fatigue is likely of greater importance in novice athletes and during repetitive (i.e., boring) tasks. The identification of specific sites involved in central fatigue is difficult because of the complexity of the CNS. Nevertheless, external sensory input, such as shouting and cheering, can often increase muscle force production and physical performance, which indicates that pathways proximal to corticospinal outputs can oppose central fatigue.
Impaired excitability and impaired Ca2+ release can produce peripheral fatigue
Under normal conditions, transmission block at the neuromuscular junction does not cause muscle fatigue, even though the release of neurotransmitter can decline. Thus, peripheral fatigue reflects a spectrum of events at the level of the muscle fiber, including impairments in the initiation and propagation of muscle action potentials, the release and handling of intracellular Ca2+ for cross-bridge activation, depletion of substrates for energy metabolism, and the accumulation of metabolic byproducts. The nature of fatigue and the time required for recovery vary with the recruitment pattern of motor units and the metabolic properties of their constitutive muscle fibers (see Fig. 60-2).
With continuous firing of action potentials during intense exercise, Na+ entry and K+ exit exceed the ability of the Na-K pump (see pp. 115–117) to restore and maintain normal resting ion concentration gradients. As a result, [K+]o and [Na+]i increase, so that the resting membrane potential of muscle fibers is more positive by 10 to 20 mV. This depolarization inactivates voltage-gated Na+ channels, which makes it more difficult to initiate and propagate action potentials. Within the T tubule, such depolarization impairs the ability of L-type Ca2+ channels to activate Ca2+-release channels in the SR (see Fig. 9-3). Fatigue resulting from impaired membrane excitability is particularly apparent at high frequencies of stimulation during recruitment of type II motor units—high-frequency fatigue. On cessation of contractile activity, ionic and ATP homeostasis recovers within 30 minutes; thus, the recovery from high-frequency fatigue occurs relatively quickly.
In prolonged moderate-intensity exercise, the release of Ca2+ from the SR falls, which apparently reflects changes in the Ca2+-release channel or its associated proteins along with inhibition of the SERCA pump (sarcoplasmic and endoplasmic reticulum Ca-ATPase; see p. 118) and thus diminished SR Ca2+ stores; this decrease in Ca2+ release leads to a depression in the amplitude of the [Ca2+]i transient that accompanies the muscle twitch. A diminution of Ca2+ release is apparent at all stimulation frequencies. However, the effect on force development is most apparent at low stimulation frequencies. Indeed, during unfused tetani (see Fig. 9-10C), [Ca2+]i does not continuously remain at high enough levels to saturate troponin C (see p. 233). As a result, cross-bridge formation is highly sensitive to the amount of Ca2+ released from the SR with each stimulus. In contrast, with high frequencies of stimulation that produce fused tetani (see Fig. 9-10D), [Ca2+]i is at such high levels that Ca2+ continuously saturates troponin C and thereby maximizes cross-bridge interactions, which masks the effects of impaired Ca2+ release with each stimulus. Fatigue resulting from impaired Ca2+ release is thus particularly apparent at low frequencies of stimulation during recruitment of type I motor units—low-frequency fatigue. Recovery requires several hours.
Fatigue can result from ATP depletion, lactic acid accumulation, and glycogen depletion
As outlined in Chapter 9, muscle fibers require ATP for contraction (see pp. 234–236), relaxation (see p. 237), and the activity of the membrane pumps that maintain ionic homeostasis. Therefore, the cells must maintain [ATP]i to avoid fatigue.
Intense stimulation of muscle fibers (particularly type IIx) requires high rates of ATP utilization, with PCr initially buffering [ATP]i (see pp. 1208–1209). As fatigue develops and [PCr]i diminishes, [ATP]i can fall from 5 mM to <2 mM, particularly at sites of cross-bridge interaction and in the vicinity of membrane pumps, so that respective ATPase activities are impaired. Simultaneously, Pi, ADP, Mg2+, lactate, and H+accumulate in the sarcoplasm. Impairment of SERCA (see p. 118) at the SR prolongs the Ca2+ transient while reducing the electrochemical driving force for Ca2+ release from the SR. Independently, the fall in [ATP]i and increase in [Mg2+] can also inhibit Ca2+ release via the ryanodine receptor (see p. 230).
Lactic Acid Accumulation
Intense activity also activates glycolysis (see pp. 1174–1176)—again, particularly in type IIx fibers)—which results in a high rate of lactic acid production and thus reduces pHi to as low as 6.2 (see Equation 60-4). This fall in pHi inhibits myosin ATPase activity, and thereby reduces the velocity of shortening. The fall in pHi also inhibits cross-bridge interaction, the binding of Ca2+ to troponin, the Na-K pump, as well as phosphofructokinase (the rate-limiting step of muscle glycolysis; see p. 1176). The combined effects of low pHi and high Pi interact to impair the peak force production of muscle fibers more than either agent alone. The mechanisms are reductions in the number of cross-bridges and in the force per cross-bridge by impairment of the transition from weak to strong binding states between actin and myosin (see p. 235). In addition, both H+ and Pi reduce Ca2+ sensitivity of contractile proteins, so that higher free [Ca2+]i is required for a given level of force production.
During prolonged exercise of moderate intensity (~50% of maximal aerobic power), and with well-maintained O2 delivery, the eventual decrease in glycogen stores in oxidative (type I and IIa) muscle fibers decreases power output. Long-distance runners describe this phenomenon as “hitting the wall.” Muscle glycogen stores are critical because the combination of blood-borne delivery of substrates and the availability of intramuscular fatty acids is inadequate to accommodate the energy requirements. N60-6 In long-distance running, endurance depends on the absolute amount of glycogen stored in the leg muscles before exercise. To postpone hitting the wall, the athlete must either begin the event with an elevated level of muscle glycogen or race more slowly. Because glycogen storage is primarily a function of diet, carbohydrate loading can increase resting muscle glycogen stores and postpone the onset of fatigue. Low-carbohydrate diets have the opposite effect. Although physical training has little effect on the capacity for glycolysis, it can promote glycogen storage, particularly if combined with a carbohydrate-rich diet. Aerobic training can spare muscle glycogen by adaptations such as mitochondrial proliferation (see pp. 1220–1222) that shift the mix of oxidized fuels toward fatty acids. Indeed, well-trained athletes can maintain moderate-intensity exercise for hours.
Mechanism of Fatigue During Prolonged Exercise
Contributed by Steven Segal
The onset of fatigue under conditions of prolonged exercise of moderate intensity may be attributable to the leakage of intermediates (e.g., α-ketoglutarate) from the citric acid cycle (see Fig. 58-11), which impairs aerobic energy production. Until the concentrations of these intermediates fall below critical levels, glycogen breakdown can restore these intermediates through anaplerotic additions and thereby serve to maintain power output.
During exercise at relatively high intensities (>65% of maximal aerobic power), fatigue develops in the order of tens of minutes. One explanation for this decrement in performance is that type IIx muscle fibers fatigue when their glycogen supplies become exhausted, which results in a decline in whole-muscle power output.