Membrane Excitability, Weakness, and Fatigue

Abstract

A failure in membrane excitability, defined as an inability of the sarcolemma and T-tubule to translate the neural discharge command into repetitive action potentials, represents an inviting cause of mechanical disfunction in both health and disease. A failure at this level would precipitate a disturbance in signal transmission between the T-tubule and the calcium release channels of the sarcoplasmic reticulum, resulting in reduced release of Ca2+, lower cytosolic free Ca2+levels, and depressed myofibrillar activation and force generation. The ability of the sarcolemma and T-tubules to conduct repetitive action potentials is intimately dependent on active transport of Na+and K+following an action potential. The active transport of these cations is mediated by the Na+-K+-ATPase, an integral membrane protein that uses the energy from the hydrolysis of 1 ATP to transport 3Na+out of the cell and 2K+into the cell. A failure to recruit sufficient Na+-K+-ATPase activity during contractile activity could result in a rundown of the transmembrane gradients for Na+and K+, leading to a loss of membrane excitability. The Na+-K+-ATPase activity depends on the amount and isoform composition of the protein, substrate availability, and acute regulatory factors. Each of these factors is examined as a potential cause of altered activation of the Na+-K+-ATPase activity and loss of membrane excitability in fatigue. Regular exercise represents a potent stimulus for upregulating Na+-K+-ATPase levels and for increasing the ability for cation transport across the sarcolemma and T-tubule membrane. As such, training may be a valuable tool in the management of fatigue in health and disease. Key words: muscle, Na+-K+-ATPase, isoforms, action potentials