Skeletal muscle fatigue – regulation of excitation–contraction coupling to avoid metabolic catastrophe

Abstract

Summary ATP provides the energy in our muscles to generate force, through its use by myosin ATPases, and helps to terminate contraction by pumping Ca 2+ back into the sarcoplasmic reticulum, achieved by Ca 2+ ATPase. The capacity to use ATP through these mechanisms is sufficiently high enough so that muscles could quickly deplete ATP. However, this potentially catastrophic depletion is avoided. It has been proposed that ATP is preserved not only by the control of metabolic pathways providing ATP but also by the regulation of the processes that use ATP. Considering that contraction (i.e. myosin ATPase activity) is triggered by release of Ca 2+ , the use of ATP can be attenuated by decreasing Ca 2+ release within each cell. A lower level of Ca 2+ release can be accomplished by control of membrane potential and by direct regulation of the ryanodine receptor (RyR, the Ca 2+ release channel in the terminal cisternae). These highly redundant control mechanisms provide an effective means by which ATP can be preserved at the cellular level, avoiding metabolic catastrophe. This Commentary will review some of the known mechanisms by which this regulation of Ca 2+ release and contractile response is achieved, demonstrating that skeletal muscle fatigue is a consequence of attenuation of contractile activation; a process that allows avoidance of metabolic catastrophe.Key words: Endurance, Membrane excitability, Skeletal muscle contraction Introduction Typically, when exercise scientists think of control of skeletal muscle contraction, they consider motor unit recruitment and rate coding, the primary means by which the brain regulates the magnitude of muscle contraction. However, the magnitude of skeletal muscle contraction can also be regulated at the cellular level. This level of control is necessary to avoid cellular metabolic catastrophe, i.e. the situation in which ATP depletion reaches a level that is damaging to the fiber.ATP is the common final source for energy in the cell, and its concentration [along with the concentrations of ADP and inorganic phosphate (Pi)] affects the magnitude of energy that is made available from its hydrolysis. At rest, skeletal muscle has a low metabolic rate, not unlike many other passive tissues, and the intracellular concentration of ATP is in the 5-7 mM range (Hochachka and Matheson, 1992). However, during muscle activity, there are three major ATPases that require ATP for their function (Box 1); during exercise, skeletal muscle can increase its rate of ATP use by more than 100 times (Hochachka and McClelland, 1997), a rate that is much faster than can be replenished by aerobic metabolism. This latter point is clear from the fact that the muscle power output can greatly exceed the level that can be supported by aerobic metabolism (MacIntosh et al., 2000). To accommodate this additional energy requirement, ATP is provided by non-aerobic means (through phosphocreatine hydrolysis and glycolysis resulting in lactate formation), but this alternative source of ATP has limited capacity (Monod ...

The assessment of neuromuscular fatigue during 120 min of simulated soccer exercise

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Targeting the sarcomere to correct muscle function

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