scholarly journals Role of physiological ClC-1 Cl− ion channel regulation for the excitability and function of working skeletal muscle

2016 ◽  
Vol 147 (4) ◽  
pp. 291-308 ◽  
Author(s):  
Thomas Holm Pedersen ◽  
Anders Riisager ◽  
Frank Vincenzo de Paoli ◽  
Tsung-Yu Chen ◽  
Ole Bækgaard Nielsen
Keyword(s):  
Skeletal Muscle ◽  
Muscle Activity ◽  
Muscle Fibers ◽  
Membrane Conductance ◽  
Membrane Properties ◽  
Equilibrium Potential ◽  
Myotonia Congenita ◽  
Clcn1 Gene ◽  
Wide Range ◽  
Muscle Excitability

Electrical membrane properties of skeletal muscle fibers have been thoroughly studied over the last five to six decades. This has shown that muscle fibers from a wide range of species, including fish, amphibians, reptiles, birds, and mammals, are all characterized by high resting membrane permeability for Cl− ions. Thus, in resting human muscle, ClC-1 Cl− ion channels account for ∼80% of the membrane conductance, and because active Cl− transport is limited in muscle fibers, the equilibrium potential for Cl− lies close to the resting membrane potential. These conditions—high membrane conductance and passive distribution—enable ClC-1 to conduct membrane current that inhibits muscle excitability. This depressing effect of ClC-1 current on muscle excitability has mostly been associated with skeletal muscle hyperexcitability in myotonia congenita, which arises from loss-of-function mutations in the CLCN1 gene. However, given that ClC-1 must be drastically inhibited (∼80%) before myotonia develops, more recent studies have explored whether acute and more subtle ClC-1 regulation contributes to controlling the excitability of working muscle. Methods were developed to measure ClC-1 function with subsecond temporal resolution in action potential firing muscle fibers. These and other techniques have revealed that ClC-1 function is controlled by multiple cellular signals during muscle activity. Thus, onset of muscle activity triggers ClC-1 inhibition via protein kinase C, intracellular acidosis, and lactate ions. This inhibition is important for preserving excitability of working muscle in the face of activity-induced elevation of extracellular K+ and accumulating inactivation of voltage-gated sodium channels. Furthermore, during prolonged activity, a marked ClC-1 activation can develop that compromises muscle excitability. Data from ClC-1 expression systems suggest that this ClC-1 activation may arise from loss of regulation by adenosine nucleotides and/or oxidation. The present review summarizes the current knowledge of the physiological factors that control ClC-1 function in active muscle.

Dynamics and Consequences of Potassium Shifts in Skeletal Muscle and Heart During Exercise

2000 ◽  
Vol 80 (4) ◽  
pp. 1411-1481 ◽  
Author(s):  
Ole M. Sejersted ◽  
Gisela Sjøgaard
Keyword(s):  
Skeletal Muscle ◽  
Force Production ◽  
Membrane Conductance ◽  
Cell Swelling ◽  
Modifying Factors ◽  
Fast Twitch Muscle ◽  
T Tubules ◽  
Exercise Induced ◽  
Fast Twitch ◽  
Muscle Excitability

Since it became clear that K+shifts with exercise are extensive and can cause more than a doubling of the extracellular [K+] ([K+]s) as reviewed here, it has been suggested that these shifts may cause fatigue through the effect on muscle excitability and action potentials (AP). The cause of the K+shifts is a transient or long-lasting mismatch between outward repolarizing K+currents and K+influx carried by the Na+-K+pump. Several factors modify the effect of raised [K+]sduring exercise on membrane potential ( Em) and force production. 1) Membrane conductance to K+is variable and controlled by various K+channels. Low relative K+conductance will reduce the contribution of [K+]sto the Em. In addition, high Cl−conductance may stabilize the Emduring brief periods of large K+shifts. 2) The Na+-K+pump contributes with a hyperpolarizing current. 3) Cell swelling accompanies muscle contractions especially in fast-twitch muscle, although little in the heart. This will contribute considerably to the lowering of intracellular [K+] ([K+]c) and will attenuate the exercise-induced rise of intracellular [Na+] ([Na+]c). 4) The rise of [Na+]cis sufficient to activate the Na+-K+pump to completely compensate increased K+release in the heart, yet not in skeletal muscle. In skeletal muscle there is strong evidence for control of pump activity not only through hormones, but through a hitherto unidentified mechanism. 5) Ionic shifts within the skeletal muscle t tubules and in the heart in extracellular clefts may markedly affect excitation-contraction coupling. 6) Age and state of training together with nutritional state modify muscle K+content and the abundance of Na+-K+pumps. We conclude that despite modifying factors coming into play during muscle activity, the K+shifts with high-intensity exercise may contribute substantially to fatigue in skeletal muscle, whereas in the heart, except during ischemia, the K+balance is controlled much more effectively.

scholarly journals Muscle Activity and Muscle Agrin Regulate the Organization of Cytoskeletal Proteins and Attached Acetylcholine Receptor (Achr) Aggregates in Skeletal Muscle Fibers

2001 ◽  
Vol 153 (7) ◽  
pp. 1453-1464 ◽  
Author(s):  
Gabriela Bezakova ◽  
Terje Lømo
Keyword(s):  
Skeletal Muscle ◽  
Acetylcholine Receptor ◽  
Muscle Activity ◽  
Muscle Fibers ◽  
Cytoskeletal Proteins ◽  
Transverse Orientation ◽  
Single Application ◽  
Skeletal Muscle Fibers ◽  
Denervated Muscles ◽  
Electrical Muscle

In innervated skeletal muscle fibers, dystrophin and β-dystroglycan form rib-like structures (costameres) that appear as predominantly transverse stripes over Z and M lines. Here, we show that the orientation of these stripes becomes longitudinal in denervated muscles and transverse again in denervated electrically stimulated muscles. Skeletal muscle fibers express nonneural (muscle) agrin whose function is not well understood. In this work, a single application of ≥10 nM purified recombinant muscle agrin into denervated muscles preserved the transverse orientation of costameric proteins that is typical for innervated muscles, as did a single application of ≥1 μM neural agrin. At lower concentration, neural agrin induced acetylcholine receptor aggregates, which colocalized with longitudinally oriented β-dystroglycan, dystrophin, utrophin, syntrophin, rapsyn, and β2-laminin in denervated unstimulated fibers and with the same but transversely oriented proteins in innervated or denervated stimulated fibers. The results indicate that costameres are plastic structures whose organization depends on electrical muscle activity and/or muscle agrin.

scholarly journals Effects of sulfhydryl inhibitors on nonlinear membrane currents in frog skeletal muscle fibers.

1993 ◽  
Vol 101 (3) ◽  
pp. 425-451 ◽  
Author(s):  
A Gonzalez ◽  
P Bolaños ◽  
C Caputo
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fibers ◽  
Membrane Conductance ◽  
Membrane Currents ◽  
Potential Range ◽  
Charge Movement ◽  
Frog Skeletal Muscle ◽  
Skeletal Muscle Fibers ◽  
Sh Reagents ◽  
Nonlinear Membrane

The effect of sulhydryl reagents on nonlinear membrane currents of frog skeletal muscle fibers has been studied using the triple Vaseline gap voltage-clamp technique. These compounds, which are known to interfere with depolarization contraction coupling, also appear to diminish intramembranous charge movement recorded with fibers polarized to -100 mV (charge 1). This effect, however, is accompanied by changes in the fiber membrane conductance and in most cases by the appearance of an inwardly directed current in the potential range between -60 and +20 mV. This current is reduced by both cadmium and nifedipine and does not occur in Ca-free solution, suggesting that it is carried by calcium ions flowing through regular calcium channels that are more easily activated in the presence of SH reagent. These changes in the membrane electrical active and passive properties decrease the quality and reliability of the P/n pulse subtracting procedure normally used for charge movement measurements. These effects can be substantially reduced by cadmium ions (0.1 mM), which has no effect on charge movement. When SH reagents are applied in the presence of cadmium, no effects are observed, indicating that this cation may protect the membrane from the reagent effects. The effects of -SH reagents can be observed by applying them in the absence of cadmium, followed by addition of the cation. Under these conditions the conductance changes are reversed and the effects of the SH reagents on charge movement can be measured with a higher degree of confidence. Maximum charge is reduced by 32% in the presence of 1.5 mM PCMB and by 31% in the presence of 2 mM PHMPS. These effects do not occur in the presence of DTT and in some cases they may be reversed by this agent. Charge 2, recorded in depolarized muscle fibers, is also reduced by these agents.

scholarly journals An analysis of the relationships between subthreshold electrical properties and excitability in skeletal muscle

2011 ◽  
Vol 138 (1) ◽  
pp. 73-93 ◽  
Author(s):  
Thomas H. Pedersen ◽  
Christopher L.-H. Huang ◽  
James A. Fraser
Keyword(s):  
Skeletal Muscle ◽  
Electrical Properties ◽  
Muscle Activity ◽  
Neuromuscular Transmission ◽  
Muscle Fibers ◽  
Low Frequency ◽  
Mammalian Muscle ◽  
Fast Twitch ◽  
T System

Skeletal muscle activation requires action potential (AP) initiation followed by its sarcolemmal propagation and tubular excitation to trigger Ca2+ release and contraction. Recent studies demonstrate that ion channels underlying the resting membrane conductance (GM) of fast-twitch mammalian muscle fibers are highly regulated during muscle activity. Thus, onset of activity reduces GM, whereas prolonged activity can markedly elevate GM. Although these observations implicate GM regulation in control of muscle excitability, classical theoretical studies in un-myelinated axons predict little influence of GM on membrane excitability. However, surface membrane morphologies differ markedly between un-myelinated axons and muscle fibers, predominantly because of the tubular (t)-system of muscle fibers. This study develops a linear circuit model of mammalian muscle fiber and uses this to assess the role of subthreshold electrical properties, including GM changes during muscle activity, for AP initiation, AP propagation, and t-system excitation. Experimental observations of frequency-dependent length constant and membrane-phase properties in fast-twitch rat fibers could only be replicated by models that included t-system luminal resistances. Having quantified these resistances, the resulting models showed enhanced conduction velocity of passive current flow also implicating elevated AP propagation velocity. Furthermore, the resistances filter passive currents such that higher frequency current components would determine sarcolemma AP conduction velocity, whereas lower frequency components excite t-system APs. Because GM modulation affects only the low-frequency membrane impedance, the GM changes in active muscle would predominantly affect neuromuscular transmission and low-frequency t-system excitation while exerting little influence on the high-frequency process of sarcolemmal AP propagation. This physiological role of GM regulation was increased by high Cl− permeability, as in muscle endplate regions, and by increased extracellular [K+], as observed in working muscle. Thus, reduced GM at the onset of exercise would enhance t-system excitation and neuromuscular transmission, whereas elevated GM after sustained activity would inhibit these processes and thereby accentuate muscle fatigue.

Potassium activation and K spikes in muscle fibers of the mealworm larva (Tenebrio molitor)

1962 ◽  
Vol 203 (3) ◽  
pp. 588-594 ◽  
Author(s):  
Peter Belton ◽  
Harry Grundfest
Keyword(s):  
Muscle Fiber ◽  
Muscle Fibers ◽  
Membrane Conductance ◽  
Tenebrio Molitor ◽  
Resting Potential ◽  
Terminal Portion ◽  
Graded Responses ◽  
High K ◽  
Wide Range ◽  
Electrical Stimuli

Muscle fibers of larval mealworms ( Tenebrio molitor) can be set to a wide range of resting potentials (ca. –40 to –90 mv), while remaining responsive to electrical stimuli. The initial resting potential is maintained long after K+0 is increased to levels well above the normal value (ca. 40 mEq/liter). However, spikes or graded responses are markedly affected by the level of K+0. For levels between 40 and 150 mEq/liter the terminal portion of the responses may become prolonged depolarizations, and for K+0 above about 200 mEq/liter positive overshoots occur. These changes follow the Nernst relation for K+0 > 20 mEq/liter. Thus, the membrane of the muscle fiber at rest is not a K electrode, but changes to the latter state during a response, indicating occurrence of K activation. The "K spikes" which develop in high K+0 lack an early depolarizing component, which is comparable to that subsumed under the Na activation and inactivation processes of the Hodgkin-Huxley theory. The K spikes may last for many seconds and are associated with increased membrane conductance throughout this time. The K spikes are probably terminated by a process of depolarizing K inactivation.

scholarly journals Effect of Peptide PV on the Ionic Permeability of Lipid Bilayer Membranes

1974 ◽  
Vol 63 (4) ◽  
pp. 492-508 ◽  
Author(s):  
H. P. Ting-Beall ◽  
M. T. Tosteson ◽  
B. F. Gisin ◽  
D. C. Tosteson
Keyword(s):  
Lipid Bilayers ◽  
Membrane Conductance ◽  
Equilibrium Potential ◽  
Lipid Bilayer Membranes ◽  
Bilayer Membranes ◽  
Membrane Surfaces ◽  
Zero Current ◽  
Wide Range ◽  
Current Flows ◽  
Calculated Equilibrium

This paper reports the effects of peptide PV (primary structure: cyclo-(D-val-L-pro-L-val-D-pro)δ) on the electrical properties of sheep red cell lipid bilayers. The membrane conductance (Gm) induced by PV in either Na+ or K+ medium is proportional to the concentration of PV in the aqueous phase. The PV concentration required to produce a comparable increase in Gm in K+ medium is about 104 times greater than for its analogue, valinomycin (val). Although the selectivity sequence for PV and val is similar, K+ ≳ Rb+ > Cs+ > NH4+ > TI+ > Na+ > Li+; the ratio of GGm in K+ to that in Na+ is about 10 for PV compared to > 103 for val. When equal concentrations of PV are added to both sides of a bilayer, the membrane current approaches a maximum value independent of voltage when the membrane potential exceeds 100 mV. When PV is added to only one side of a bilayer separating identical salt solutions of either Na+ or K+ salts, rectification occurs such that the positive current flows more easily away rather than toward the side containing the carrier. Under these conditions, a large, stable, zero-current potential (VVm) is also observed, with the side containing PV being negative. The magnitude of this VVm is about 90 mV and relatively independent of PV concentration when the latter is larger than 2 Times; 10–5 M. From a model which assumes that Vm equals the equilibrium potential for the PV-cation complexes (MS+) and that the reaction between PV and cations is at equilibrium on the two membrane surfaces, we compute the permeability of the membrane to free PV to be about 10–5 cm s–1, which is about 10–7 times the permeability of similar membranes to free val. This interpretation is supported by the fact that the observed values of Vm are in agreement with the calculated equilibrium potential for MS+ over a wide range of ratios of concentrations of total PV in the two bathing solutions, if the unstirred layers are taken into account in computing the MS+ concentrations at the membrane surfaces.

scholarly journals Length-dependent electromechanical coupling in single muscle fibers.

1976 ◽  
Vol 68 (6) ◽  
pp. 653-669 ◽  
Author(s):  
A M Gordon ◽  
E B Ridgway
Keyword(s):  
Membrane Potential ◽  
Calcium Release ◽  
Muscle Fibers ◽  
Membrane Properties ◽  
Constant Current ◽  
Equilibrium Potential ◽  
Muscle Membrane ◽  
Single Muscle ◽  
Fiber Membrane ◽  
Length Dependence

In single muscle fibers from the giant barnacle, a small decrease in muscle length decreases both the calcium activation and the peak isometric tension produced by a constant current stimulus. The effect is most pronounced if the length change immediately precedes the stimulation. In some cases, the decrease in tension with shortening can be accounted for almost entirely by a decrease in calcium release rather than changes in mechanical factors such as filament geometry. During the constant current stimulation the muscle membrane becomes more depolarized at longer muscle lengths than at the shorter muscle lengths. Under voltage clamp conditions, when the membrane potential is kept constant during stimulation, there is little length dependence of calcium release. Thus, the effect of length on calcium release is mediated through a change in membrane properties, rather than an effect on a subsequent step in excitation-contraction coupling. Stretch causes the unstimulated fiber membrane to depolarize by about l mV while release causes the fiber membrane to hyperpolarize by about the same amount. The process causing this change in potential has an equilibrium potential nearly 10 mV hyperpolarized from the resting level. This change in resting membrane potential with length may account for the length dependence of calcium release.

scholarly journals Delayed rectification in the transverse tubules: origin of the late after-potential in frog skeletal muscle.

1977 ◽  
Vol 70 (1) ◽  
pp. 1-21 ◽  
Author(s):  
G E Kirsch ◽  
R A Nichols ◽  
S Nakajima
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fibers ◽  
Tetanic Stimulation ◽  
Potassium Accumulation ◽  
Transverse Tubular System ◽  
System A ◽  
Delayed Rectification ◽  
Wide Range ◽  
Time Courses ◽  
T System

Tetanic stimulation of skeletal muscle fibers elicits a train of spikes followed by a long-lasting depolarization called the late after-potential (LAP). We have conducted experiments to determine the origin of the LAP. Isolated single muscle fibers were treated with a high potassium solution (5 mM or 10 mM K) followed by a sudden reduction of potassium concentration to 2.5 mM. This procedure produced a slow repolarization (K repolarization), which reflects a diffusional outflow of potassium from inside the lumen of the transverse tubular system (T system). Tetanic stimulation was then applied to the same fiber and the LAP was recorded. The time courses of K repolarization and LAP decay were compared and found to be roughly the same. This approximate equality held under various conditions that changed the time courses of both events over a wide range. Both K repolarization and the LAP became slower as fiber radius increased. These results suggest that LAP decay and K repolarization represent the same process. Thus, we conclude that the LAP is caused by potassium accumulation in the T system. A consequence of this conclusion is that delayed rectification channels exist in the T system. A rough estimation suggests that the density of delayed rectification channels is less in the T system than in the surface membrane.

Hyperinnervation of Skeletal Muscle Fibers: Dependence on Muscle Activity

Science ◽  
1973 ◽  
Vol 181 (4099) ◽  
pp. 559-561 ◽  
Author(s):  
J. K. S. Jansen ◽  
T. Lomo ◽  
K. Nicolaysen ◽  
R. H. Westgaard
Keyword(s):  
Skeletal Muscle ◽  
Muscle Activity ◽  
Muscle Fibers ◽  
Skeletal Muscle Fibers

Stretch-induced activation of Ca2+-activated K+ channels in mouse skeletal muscle fibers

2000 ◽  
Vol 278 (3) ◽  
pp. C473-C479 ◽  
Author(s):  
Nora Mallouk ◽  
Bruno Allard
Keyword(s):  
Skeletal Muscle ◽  
Muscle Fibers ◽  
Channel Activity ◽  
Patch Clamp Technique ◽  
Mouse Skeletal Muscle ◽  
Membrane Stretch ◽  
Skeletal Muscle Fibers ◽  
Intracellular Ca ◽  
Potential Mode ◽  
Muscle Excitability

High-conductance Ca2+-activated K+(KCa) channels were studied in mouse skeletal muscle fibers using the patch-clamp technique. In inside-out patches, application of negative pressure to the patch induced a dose-dependent and reversible activation of KCa channels. Stretch-induced increase in channel activity was found to be of the same magnitude in the presence and in the absence of Ca2+ in the pipette. The dose-response relationships between KCa channel activity and intracellular Ca2+ and between KCa channel activity and membrane potential revealed that voltage and Ca2+ sensitivity were not altered by membrane stretch. In cell-attached patches, in the presence of high external Ca2+ concentration, stretch-induced activation was also observed. We conclude that membrane stretch is a potential mode of regulation of skeletal muscle KCa channel activity and could be involved in the regulation of muscle excitability during contraction-relaxation cycles.

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