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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.

Background: Epidural analgesia (EA) is effective in patients undergoing minimal invasive repair of pectus excavatum (MIRPE) but is associated with major complications such as epidural hematomas. It is recommended to assess coagulation status in patients receiving anticoagulant therapy prior to EA, although no consensus exists in patients without a history of bleeding tendency or anticoagulant therapy. Thus, the aim of this paper was to assess 1) the prevalence of abnormal routine coagulation parameters, i.e., international normalized ratio (INR) and platelet count, and 2) the safety of EA in patients undergoing MIRPE.Methods: In this retrospective study, we identified 1,973 patients undergoing MIRPE at our center between 2001 and 2019. Complications related to EA were registered for all patients. Information on coagulation parameters was present in 929 patients. Patients with spontaneously elevated INR ≥1.5 were referred for assessment of coagulation factor VII in order to assess the cause of the elevated INR.Results: Of 929 patients with coagulation information available, 18 patients had spontaneously elevated INR ≥1.5 (1.9%). In patients with INR ≥1.5, 12 patients underwent further assessment of factor VII, with all patients having a slightly reduced factor VII close to the lower reference range. The majority of the 1,973 patients undergoing MIRPE received EA (99.6%) with very low complication rates (0.2%) and no incidence of epidural hematomas.Conclusion: In patients undergoing MIRPE, coagulation screening prior to EA should not be mandatory as it revealed no clinically relevant consequences. EA is safe with very low complication rates. [ABSTRACT FROM AUTHOR]

Action potential (AP) excitation requires a transient dominance of depolarizing membrane currents over the repolarizing membrane currents that stabilize the resting membrane potential. Such stabilizing currents, in turn, depend on passive membrane conductance ([G.sub.m]), which in skeletal muscle fibers covers membrane conductances for [K.sup.+] ([G.sub.k]) and CI- ([G.sub.cl]). Myotonic disorders and studies with metabolically poisoned muscle have revealed capacities of [G.sub.k] and Gcx to inversely interfere with muscle excitability. However, whether regulation of [G.sub.k] and [G.sub.cl] occur in AP-firing muscle under normal physiological conditions is unknown. This study establishes a technique that allows the determination of [G.sub.cl] and [G.sub.k] with a temporal resolution of seconds in AP-firing muscle fibers. With this approach, we have identified and quantified a biphasic regulation of [G.sub.m] in active fast-twitch extensor digitorum longus fibers of the rat. Thus, at the onset of AP firing, a reduction in [G.sub.cl] of ~70% caused [G.sub.m] to decline by ~55% in a manner that is well described by a single exponential function characterized by a time constant of ~200 Aps (phase 1). When stimulation was continued beyond ~1,800 APs, synchronized elevations in [G.sub.k] (~14-fold) and [G.sub.cl] (~3-fold) caused [G.sub.m] to rise si[G.sub.m]oidally to ~400% of its level before AP firing (phase 2). Phase 2 was often associated with a failure to excite APs. When AP firing was ceased during phase 2, [G.sub.m] recovered to its level before AP firing in ~1 min. Experiments with glibenclamide (KAvv channel inhibitor) and 9-anthracene carboxylic acid (C1C-1 C1channel inhibitor) revealed that the decreased [G.sub.m] during phase 1 reflected C1C-1 channel inhibition, whereas the massively elevated [G.sub.m] during phase 2 reflected synchronized openings of C1C-1 and KATe channels. In conclusion, [G.sub.cl] and C-no are acutely regulated in AP-firing fast-twitch muscle fibers. Such regulation may contribute to the physiological control of excitability in active muscle.

In several pathological and experimental conditions, the passive membrane conductance of muscle fibers ([G.sub.m]) and their excitability are inversely related. Despite this capacity of [G.sub.m] to determine muscle excitability, its regulation in active muscle fibers is largely unexplored. In this issue, our previous study (Pedersen et al. 2009. J. Gen. Physiol. doi:10.1085/jgp.200910291) established a technique with which biphasic regulation of [G.sub.m] in action potential (AP)-firing fast-twitch fibers of rat extensor digitorum longus muscles was identified and characterized with temporal resolution of seconds. This showed that AP firing initially reduced [G.sub.m] via C1C-1 channel inhibition but after ~1,800 APs, [G.sub.m] rose substantially, causing AP excitation failure. This late increase of [G.sub.m] reflected activation of C1C-1 and KATe channels. The present study has explored regulation of [G.sub.m] in AP-firing slow-twitch fibers of soleus muscle and compared it to [G.sub.m] dynamics in fast-twitch fibers. It further explored aspects of the cellular signaling that conveyed regulation of [G.sub.m] in AP-firing fibers. Thus, in both fiber types, AP firing first triggered protein kinase C (PKC)-dependent C1C-1 channel inhibition that reduced [G.sub.m] by ~50%. Experiments with dantrolene showed that AP-triggered SR [Ca.sup.2+] release activated this PKC-mediated C1C-1 channel inhibition that was associated with reduced rheobase current and improved function of depolarized muscles, indicating that the reduced [G.sub.m] enhanced muscle fiber excitability. In fast-twitch fibers, the late rise in [G.sub.m] was accelerated by glucose-free conditions, whereas it was postponed when intermittent resting periods were introduced during AP firing. Remarkably, elevation of [G.sub.m] was never encountered in AP-firing slow-twitch fibers, even after 15,000 APs. These observations implicate metabolic depression in the elevation of [G.sub.m] in AP-firing fast-twitch fibers. It is concluded that regulation of [G.sub.m] is a general phenomenon in AP-firing muscle, and that differences in [G.sub.m] regulation may contribute to the different phenotypes of fast- and slow-twitch muscle.

Generation of the action potentials (AP) necessary to activate skeletal muscle fibers requires that inward membrane currents exceed outward currents and thereby depolarize the fibers to the voltage threshold for AP generation. Excitability therefore depends on both excitatory Na+ currents and inhibitory [K.sup.+] and [Cl.sup.-] currents. During intensive exercise, active muscle loses K+ and extracellular [K.sup.+] ([[[K.sup.+]].sub.o]) increases. Since high [[[K.sup.+]].sub.o] leads to depolarization and ensuing inactivation of voltage-gated [Na.sup.+] channels and loss of excitability in isolated muscles, exercise-induced loss of K+ is likely to reduce muscle excitability and thereby contribute to muscle fatigue in vivo. Intensive exercise, however, also leads to muscle acidification, which recently was shown to recover excitability in isolated [K.sup.+]-depressed muscles of the rat. Here we show that in rat soleus muscles at 11 mM [K.sup.+], the almost complete recovery of compound action potentials and force with muscle acidification (C[O.sub..2 changed from 5 to 24%) was associated with reduced chloride conductance (1731 [plus or minus] 151 to 938 [plus or minus] 64 [micro]S/c[m.sup.2], P < 0.01 but not with changes in potassium conductance (405 [plus or minus] 20 to 455 [plus or minus] 30 [micro]S/c[m.sup.2], P < 0.16). Furthermore, acidification reduced the rheobase current by 26% at 4 mM [K.sup.+] and increased the number of excitable fibers at elevated [[[K.sup.+]].sub.o]. At 11 mM [K.sup.+] and normal pH, a recovery of excitability and force similar to the observations with muscle acidification could be induced by reducing extracellular [Cl.sup.-] or by blocking the major muscle [Cl.sup.-] channel, ClC-1, with 30 [micro]M 9-AC. It is concluded that recovery of excitability in K+-depressed muscles induced by muscle acidification is related to reduction in the inhibitory [Cl.sup.-+] currents, possibly through inhibition of ClC-1 channels, and acidosis thereby reduces the Na+ current needed to generate and propagate an AP. Thus short term regulation of [Cl.sup.-] channels is important for maintenance of excitability in working muscle. KEY WORDS: lactic acid * muscle fatigue * action potentials * [Na.sup.+] channels * [Cl.sup.1] channels