ClC-1 Inhibition as a Mechanism for Accelerating Skeletal Muscle Recovery After Neuromuscular Block in Rats.

Neuromuscular blocking agents are used commonly to induce skeletal muscle relaxation during surgery. While muscle relaxation facilitates surgical procedures and tracheal intubation, adequate recovery of muscle function after surgery is required to support pulmonary function, and even mild residual neuromuscular block increases the risk of severe postoperative pulmonary complications. While recovery of muscle function after surgery involving neuromuscular blocking agents can be monitored and, in addition, be accelerated by use of current antagonists (reversal agents), there is a clear clinical need for a safe drug to antagonize all types of neuromuscular blocking agents.

The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise.

Role of recovery of acetylcholine release in compromised neuromuscular junction function.

Everyday physical activities, such as walking, are enabled by repeated skeletal muscle contractions and require a well-functioning neuromuscular transmission. In myasthenic disorders, activities of daily living are debilitated by a compromised neuromuscular transmission leading to muscle weakness and fatiguability in patients. To enable physical activity, acetylcholine (ACh) is released repeatedly from the motor nerve, however, the role of the nerve terminals' capacity to sustain ACh release to support repetitive contractions under compromised neuromuscular transmission remains unclear.

Force potentiation during eccentric contractions in rat skeletal muscle.

Postactivation potentiation refers to an acute enhancement of contractile properties following muscle activity. Previously, the effects of prior muscle activation on eccentric force at tetanic activation frequencies have only been sparsely reported. This paper aimed to study acute activity-induced effects on eccentric force of slow and fast-twitch muscles and characterize them in relation to postactivation potentiation.

Alterations in fast-twitch muscle membrane conductance regulation do not explain decreased muscle function of SOD1 rats.

Introduction/aims: Both neuromuscular junction (NMJ) dysfunction and altered electrophysiological properties of muscle fibers have been reported in amyotrophic lateral sclerosis (ALS) patients. ALS-related preclinical studies typically use rodent SOD1 overexpression models, but translation to the human disease has been challenged. The present work explored NMJ function and cellular electrophysiological properties of muscles fibers in SOD1 overexpression rats.

Fatiguing stimulation increases curvature of the force-velocity relationship in isolated fast-twitch and slow-twitch rat muscles.

In skeletal muscles, the ability to generate power is reduced during fatigue. In isolated muscles, maximal power can be calculated from the force-velocity relationship. This relationship is well described by the Hill equation, which contains three parameters: (1) maximal isometric force, (2) maximum contraction velocity and (3) curvature.

Contractile benefits of doublet-initiated low-frequency stimulation in rat extensor digitorum longus muscle exposed to high extracellular [K] or fatiguing contractions.

During dynamic contractions, high-frequency muscle activation is needed to achieve optimal power. This must be balanced against an increased excitation-induced accumulation of extracellular K, which can reduce excitability and ultimately may prevent adequate responses to high-frequency activation. Mean activation frequencies in vivo are often low (subtetanic), but activation patterns contain bursts of high (supratetanic) frequencies known as doublets, which enhance dynamic contraction in rested muscles at normal extracellular K concentration ([K]).

Early effects of eccentric contractions on muscle glucose uptake.

Muscle-damaging eccentric exercise impairs muscle glucose uptake several hours to days after exercise. Little, however, is known about the acute effects of eccentric exercise on contraction- and insulin-induced glucose uptake. This study compares glucose uptake rates in the first hours following eccentric, concentric, and isometric contractions with and without insulin present.

Cold exposure causes cell death by depolarization-mediated Ca overload in a chill-susceptible insect.

Cold tolerance of insects is arguably among the most important traits defining their geographical distribution. Even so, very little is known regarding the causes of cold injury in this species-rich group. In many insects it has been observed that cold injury coincides with a cellular depolarization caused by hypothermia and hyperkalemia that develop during chronic cold exposure.

The ins and outs of acid-base transport in skeletal muscle.

Aalkjær and Nielsen discuss new data revealing the basis of acid–base transport in t-tubules of skeletal muscle.

The anti-convulsants lacosamide, lamotrigine, and rufinamide reduce myotonia in isolated human and rat skeletal muscle.

Introduction: In myotonia congenita, loss of ClC-1 Cl channel function results in skeletal muscle hyperexcitability and myotonia. Anti-myotonic treatment has typically targeted the voltage-gated sodium channel in skeletal muscle (Nav1.4).

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

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.

Protein kinase C-dependent regulation of ClC-1 channels in active human muscle and its effect on fast and slow gating.

Key Points: Regulation of ion channel function during repeated firing of action potentials is commonly observed in excitable cells. Recently it was shown that muscle activity is associated with rapid, protein kinase C (PKC)-dependent ClC-1 Cl(-) channel inhibition in rodent muscle. While this PKC-dependent ClC-1 inhibition during muscle activity was shown to be important for the maintenance of contractile endurance in rat muscle it is unknown whether a similar regulation exists in human muscle.

Skeletal muscle dysfunction in the db/db mouse model of type 2 diabetes.

Introduction: In this study we examined the mechanisms of motor dysfunction in type 2 diabetes.

Methods: Contractile force was measured in isolated nerve-muscle preparations of db/db mice using various protocols for electrical stimulation. Sarcoplasmic reticulum Ca(2+) adenosine triphosphatase protein (SERCA) was quantified by comparing Ca(2+) -dependent and non-specific phosphorylation.

Cardiac Dysfunction in a Porcine Model of Pediatric Malnutrition.

Background: Half a million children die annually of severe acute malnutrition and cardiac dysfunction may contribute to the mortality. However, cardiac function remains poorly examined in cases of severe acute malnutrition.

Objective: To determine malnutrition-induced echocardiographic disturbances and longitudinal changes in plasma pro-atrial natriuretic peptide and cardiac troponin-T in a pediatric porcine model.

Determination of cable parameters in skeletal muscle fibres during repetitive firing of action potentials.

Recent studies in rat muscle fibres show that repetitive firing of action potentials causes changes in fibre resting membrane conductance (Gm) that reflect regulation of ClC-1 Cl(-) and KATP K(+) ion channels. Methodologically, these findings were obtained by inserting two microelectrodes at close proximity in the same fibres enabling measurements of fibre input resistance (Rin) in between action potential trains. Since the fibre length constant (λ) could not be determined, however, the calculation of Gm relied on the assumptions that the specific cytosolic resistivity (Ri) and muscle fibre volume remained constant during the repeated action potential firing.

Why do insects enter and recover from chill coma? Low temperature and high extracellular potassium compromise muscle function in Locusta migratoria.

When exposed to low temperatures, many insect species enter a reversible comatose state (chill coma), which is driven by a failure of neuromuscular function. Chill coma and chill coma recovery have been associated with a loss and recovery of ion homeostasis (particularly extracellular [K(+)], [K(+)]o) and accordingly onset of chill coma has been hypothesized to result from depolarization of membrane potential caused by loss of ion homeostasis. Here, we examined whether onset of chill coma is associated with a disturbance in ion balance by examining the correlation between disruption of ion homeostasis and onset of chill coma in locusts exposed to cold at varying rates of cooling.

Extracellular magnesium and calcium reduce myotonia in isolated ClC-1 chloride channel-inhibited human muscle.

Introduction: Experimental myotonia induced in rat muscle by ClC-1 chloride channel-inhibited has been shown to be related inversely to extracellular concentrations of Mg(2+) and Ca(2+) ([Mg(2+) ]o and [Ca(2+) ]o) within physiological ranges. Because this implicates a role for [Mg(2+)]o and [Ca(2+)]o in the variability of symptoms among myotonia congenita patients, we searched for similar effects of [Mg(2+)]o and [Ca(2+)]o on myotonia in human muscle.

Methods: Bundles of muscle fibers were isolated from abdominal rectus in patients undergoing abdominal surgery.

Effects of high-frequency stimulation and doublets on dynamic contractions in rat soleus muscle exposed to normal and high extracellular [K(+)].

The development of maximal velocity and power in muscle depends on the ability to transmit action potentials (AP) at very high frequencies up to about 400 Hz. However, for every AP there is a small loss of K(+) to the interstitium, which during intense exercise, may build up to a point where excitability is reduced, thus limiting the intensity of further exercise. It is still unknown how the muscle responds to high-frequency stimulation when exposed to high [K(+)].

Neuro-muscular function in the wobbler murine model of primary motor neuronopathy.

The wobbler mouse represents a model for neurodegenerative disease affecting motor neurons. This study explored the importance of fiber type specific changes for the contractile dysfunction of soleus and extensor digitorum longus (EDL) muscles from wobbler mice using a specific inhibitor of force generation by the type II myosin protein. Generally, wobbler condition was associated with ~50% reductions in muscle mass and contractile capacity in both muscles.

Intrarater reproducibility and validity of Nintendo Wii balance testing in community-dwelling older adults.

The aims of the current study were to examine the intrarater intersession reproducibility of the Nintendo Wii agility and stillness tests and explore the concurrent validity in relation to gold-standard force-plate analysis. Within-day intersession reproducibility was examined in 30 older adults (age 71.8 ± 5.

Extracellular magnesium and calcium reduce myotonia in ClC-1 inhibited rat muscle.

Loss-of-function mutations in the ClC-1 Cl(-) channel trigger skeletal muscle hyperexcitability in myotonia congenita. For reasons that remain unclear, the severity of the myotonic symptoms can vary markedly even among patients with identical ClC-1 mutations, and may become exacerbated during pregnancy and with diuretic treatment. Since both these conditions are associated with hypomagnesemia and hypocalcemia, we explored whether extracellular Mg(2+) and Ca(2+) ([Mg(2+)]o and [Ca(2+)]o) can affect myotonia.

Efficacy of Nintendo Wii training on mechanical leg muscle function and postural balance in community-dwelling older adults: a randomized controlled trial.

Background: Older adults show increased risk of falling and major risk factors include impaired lower extremity muscle strength and postural balance. However, the potential positive effect of biofeedback-based Nintendo Wii training on muscle strength and postural balance in older adults is unknown.

Methods: This randomized controlled trial examined postural balance and muscle strength in community-dwelling older adults (75±6 years) pre- and post-10 weeks of biofeedback-based Nintendo Wii training (WII, n = 28) or daily use of ethylene vinyl acetate copolymer insoles (controls [CON], n = 30).

Relationship between membrane Cl- conductance and contractile endurance in isolated rat muscles.

Resting skeletal muscle fibres have a large membrane Cl(-) conductance (G(Cl)) that dampens their excitability. Recently, however, muscle activity was shown to induce PKC-mediated reduction in G(Cl) in rat muscles of 40-90%. To examine the physiological significance of this PKC-mediated G(Cl) reduction for the function of muscles, this study explored effects of G(Cl) reductions on contractile endurance in isolated rat muscles.