Membrane excitability and excitation–contraction uncoupling in muscle fatigue

Abstract

High-frequency tetanic stimulation is associated with an increase in extracellular and T-tubular K⁺ and changes of Na⁺ and Cl⁻ concentrations, membrane depolarization as well as inactivation of voltage-gated Na⁺ channels. These alterations are expected to lead to fiber inexcitability, which is largely prevented by mechanisms intrinsic or extrinsic to muscle fibers. They act by adapting electrical membrane properties or by accelerating the reconstitution of ionic homeostasis. The high Cl⁻ conductance of muscle fibers supports the K⁺ conductance in fast and complete repolarization and creates a mechanism for the fast reuptake of K⁺, thereby reducing the T-tubular K⁺ accumulation. Excitability is increased by a Ca²⁺ and proteinkinase C dependent inhibition of the Cl⁻ conductance which is efficient especially in the T-tubular system. Several mediators activate the Na⁺/K⁺-ATPase and thus enhance the restoration of ionic homeostasis. Examples are purines (ATP, ADP), calcitonin-gene related peptide and adrenaline. It is also necessary to adapt the strength of the sarcoplasmic Ca²⁺ concentration to the requirements of tetanic contractions. An overwhelming Ca²⁺ signal leads to enzymatically driven excitation–contraction uncoupling. This process is most likely driven by the Ca²⁺ dependent protease μ-calpain and might lead to the long-lasting fatigue observed after excessive physical activity.

Introduction

The actuation of muscle fiber contraction is a complex process involving several distinct steps. It is initiated by the interplay of various brain regions and propagates over the spinal cord to primary motor neurons, which elicit an action potential at the neuromuscular junction. From there, an action potential wave has to spread along the sarcolemma to excite the complete surface of the muscle fiber. At openings of the transverse tubular system the excitation wave propagates deep into the fiber where electrical excitation is subsequently transduced into contraction by a process called excitation–contraction coupling. This is mainly mediated by Ca²⁺ release from the sarcoplasmic reticulum (SR). At all stages of this complex process, beginning from the motivation to perform limb or body movement, across the initiation and coordination of stimulation of motor neurons, downstream to the muscle fiber itself and its subcellular domains, failure might occur which could be objectively expressed as weakness and might be perceived as fatigue [1]. Activation of a muscle fiber goes along with a sequence of distinct alterations in the physical state of cells followed by their recovery. Repetitive activation, as during exercise, can result in the prolonged persistence of an activated state with incomplete recovery between stimuli. If the rate of stimulation is higher than the rate of recovery, the accumulation of remainders can constitute a striking homeostatic challenge. An accumulation like the tetanic increase of sarcoplasmic Ca²⁺ concentration might be desirable or detrimental, since it increases force but might also trigger excitation–contraction (EC) uncoupling [2]. Myogenic fatigue ultimately develops if the rate of muscle stimulation is higher than the rate of complete recovery. Homeostatic impairments occur at least on four different levels with different time scales: (i) electrical dis- and recharge of the membrane during the action potential, (ii) changes of Na⁺, K⁺ and Cl⁻ concentrations, (iii) Ca²⁺ transients, and (iv) metabolic changes. The action potential represents a rapid discharge of the membrane capacity and its somewhat slower recharge. Since depolarizing currents are mediated by different charge carriers (Na⁺) than repolarizing currents (K⁺ and Cl⁻), every action potential is associated with changes of ion concentrations [3]. The complete restoration of ionic homeostasis is slower than the action potential itself and is not complete within the refractory period. Therefore, fast repetitive stimulation can represent a profound challenge to ionic homeostasis. It compromises excitability and needs mechanisms that upregulate K⁺ uptake and Na⁺ extrusion or an adaptive reduction of electrical membrane stability in order to avoid excitation failure. On a similar time-scale changes of free Ca²⁺ concentration occur. Ca²⁺ serves as a messenger that activates the contractile machinery but in addition has different signaling functions. The signal Ca²⁺ transmits (initiation of contraction or cell-signaling) depends on its spatial and temporal occurrence. A strong rise of the EC-coupling signal might be overwhelming and disrupt the microdomains of spatially and temporally organized information processing units within muscle fibers [2].

The contribution of reduced excitability to the development of muscle fatigue depends on the type, intensity and duration of exercise. Especially short bouts of high-intense muscle activity might lead to a decline of fiber excitability. More typical modes of exercise are affected by metabolic or other causes of fatigue. In such cases excitability is essentially maintained by several regulatory mechanisms within muscles. The preservation of excitability has to be traded off against the risk of Ca²⁺ overload which disturbs the physiological signaling to the contractile machinery and other Ca²⁺-dependent signal proteins by the activation of proteases that uncouple the excitation–contraction interface [2]. Here we concentrate on electrical excitation of muscle fibers and excitation–contraction coupling in relation to the development of muscular fatigue during exercise. The paper is based on the comprehensive reviews by Ament et al. [1] and Allen et al. [3]. If not quoted otherwise, statements are reasoned by these reviews.