Terje Lømo

• University of Oslo

Correction for “NFAT is a nerve activity sensor in skeletal muscle and controls activity-dependent myosin switching,” by Karl J. A. McCullagh, Elisa Calabria, Giorgia Pallafacchina, Stefano Ciciliot, Antonio L. Serrano, Carla Argentini, John M. Kalhovde, Terje Lømo, and Stefano Schiaffino, which was first published July 9, 2004; 10.1073/pnas.030803...

In 1985, at a meeting in Abano, I presented results showing that direct stimulation of skeletal muscles with appropriate stimulus patterns prevents the effects of denervation on non-junctional properties of muscle fibers. Hence, it appeared unnecessary to postulate that unknown nerve-derived trophic factors control such properties, as posited by th...

In 1985, at a meeting in Abano, I presented results showing that direct stimulation of skeletal muscles with appropriate stimulus patterns prevents the effects of denervation on non-junctional properties of muscle fibers. Hence, it appeared unnecessary to postulate that unknown nerve-derived trophic factors control such properties, as posited by th...

Adapted from: Lømo T, Westgaard RH, Hennig R, Gundersen K. The response of denervated muscle to long-term electrical stimulation, In: Carraro U, Angelini C, eds. Proceedings of the First Abano Terme Meeting on Rehabilitation, 1985 August 28-30, Abano Terme, Padova, Italy, An International Symposium, Satellite Meeting of the XIII World Congress of N...

Andersen et al. (1971) proposed that excitatory activity in the entorhinal cortex propagates topographically to the dentate gyrus, and on through a "trisynaptic circuit" lying within transverse hippocampal "slices" or "lamellae." In this way, a relatively simple structure might mediate complex functions in a manner analogous to the way independent...

The functional organization of the perforant path input to the dentate gyrus of the exposed hippocampus was studied in adult rabbits anesthetized with urethane and chloralose. Electrical stimulation of perforant path fibers caused excitation of granule cells along narrow, nearly transverse strips (lamellae) of tissue. Stimulation of granule cell ax...

Adult skeletal muscle accepts ectopic innervation by foreign motor axons only after section of its own nerve, suggesting that the formation of new neuromuscular junctions is promoted by muscle denervation. With the aim to identify new proteins involved in neuromuscular junction formation we performed an mRNA differential display on innervated versu...

Tonic firing behavior in soleus muscle of unrestrained rats aged 7 to >or=100 days was studied by chronic single-motor-unit and gross-electromyographic (EMG) recordings. Median motor-unit firing frequency at 10 days was 19-26 Hz and did not change appreciably after this time, whereas interval-to-interval firing variability was reduced with age. Two...

Skeletal muscle fibers contain hundreds to thousands of nuclei which lie immediately under the plasmalemma and are spaced out along the fiber, except for a small cluster of specialized nuclei at the neuromuscular junction. How the nuclei attain their positions along the fiber is not understood. Here we show that the nuclei are preferentially locali...

Application of electrical pulses after DNA injection into muscle increases expression of the encoded genes, and is shown to improve antigen-specific immune responses when used for DNA vaccination. In addition, electroporation causes tissue injury and inflammatory reactions. Together with immune stimulatory motifs in the injected DNA these factors m...

Myosin heavy chain (MyHC) expression was examined in regenerating fast extensor digitorum longus (EDL) and slow soleus (SOL) muscles of adult rats. Myotoxic bupivacaine was injected into SOL and EDL and the muscles were either denervated or neuromuscularly blocked by tetrodotoxin (TTX) on the sciatic nerve. Three to 10 or 30 days later, denervated...

Motor neurons to the slowly contracting extensor soleus muscle in behaving rats begin to fire tonically in the 2nd week after birth. In the adult, tonic firing becomes predominant and appears to arise from plateau potentials under monoaminergic control. In the present work, motor neurons to slowly contracting extensor soleus and rapidly contracting...

Calcineurin (Cn) signaling has been implicated in nerve activity-dependent fiber type specification in skeletal muscle, but the downstream effector pathway has not been established. We have investigated the role of the transcription factor nuclear factor of activated T cells (NFAT), a major target of Cn, by using an in vivo transfection approach in...

This chapter focuses on the ways motor neurons dictate skeletal muscle fibers and the ways muscle fibers adapt to these dictates. The response of muscle fibers on motor neurons to serve nerve–muscle integration is also addressed in the chapter. The chapter focuses on nerve–muscle interactions in adults. Motor neurons control the membrane and the co...

Neuromuscular junctions (NMJs) on fast and slow muscle fibers display different transmitter release characteristics that appear well adapted to the different patterns of nerve impulses that they transmit in vivo. Here, we ask whether the release properties of such NMJs, termed fast and slow, can be transformed by chronic nerve stimulation. In young...

This review focuses on mechanisms that determine the position, number, size, and distribution of neuromuscular junctions (NMJs) on skeletal muscle fibers. Most of the data reviewed derive from studies of ectopic NMJ formation on soleus (SOL) muscle fibers in adult rats, which recapitulates essential aspects of NMJ formation in normal development. T...

This paper describes circumstances around the discovery of long-term potentiation (LTP). In 1966, I had just begun independent work for the degree of Dr medicinae (PhD) in Per Andersen's laboratory in Oslo after an eighteen-month apprenticeship with him. Studying the effects of activating the perforant path to dentate granule cells in the hippocamp...

We report that functional subtypes of spinal motoneurons and skeletal muscle fibers can be selectively transduced using replication-defective adenoviral (ADV) or adeno-associated (AAV) viral vectors. After intramuscular injection in adult rodents, ADV vectors transduced both fast-twitch and slow-twitch skeletal muscle fibers. Intramuscular injectio...

We have examined protein kinase A (PKA) subunit expression in adult rat skeletal muscles. Northern blots identified PKA catalytic alpha and regulatory (R) I alpha and RII alpha subunits as the major subunits expressed in slowly contracting soleus (SOL) and rapidly contracting extensor digitorum longus (EDL) muscles. In addition, the steady-state RN...

Voltage-gated sodium channels (VGSCs) are highly concentrated at the neuromuscular junction (NMJ) in mammalian skeletal muscle. Here we test the hypothesis that local upregulation of mRNA contributes to this accumulation. We designed radiolabeled antisense RNA probes, specific for the "adult" Na(V)1.4 and "fetal" Na(V)1.5 isoforms of VGSC in mammal...

Nerve activity can induce long-lasting, transcription-dependent changes in skeletal muscle fibers and thus affect muscle growth and fiber-type specificity. Calcineurin signaling has been implicated in the transcriptional regulation of slow muscle fiber genes in culture, but the functional role of calcineurin in vivo has not been unambiguously demon...

At mammalian neuromuscular junctions (NMJs), innervation induces and maintains the metabolic stability of acetylcholine receptors (AChRs). To explore whether neural agrin may cause similar receptor stabilization, we injected neural agrin cDNA of increasing transfection efficiencies into denervated adult rat soleus (SOL) muscles. As the efficiency i...

Aggregation of acetylcholine receptors (AChRs) in muscle fibers by nerve-derived agrin plays a key role in the formation of neuromuscular junctions. So far, the effects of agrin on muscle fibers have been studied in culture systems, transgenic animals, and in animals injected with agrin--cDNA constructs. We have applied purified recombinant chick n...

In innervated skeletal muscle fibers, dystrophin and beta-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 m...

The Golgi complex of skeletal muscle fibers is made of thousands of dispersed elements. The distributions of these elements and of the microtubules they associate with differ in fast compared with slow and in innervated compared with denervated fibers. To investigate the role of muscle impulse activity, we denervated fast extensor digitorum longus...

To identify intracellular signalling pathways that transduce muscle electrical activity, we have investigated the Protein Kinase A (PKA) pathway in fast and slow skeletal muscle. The slow soleus muscle (SOL) displayed approximately twice as much PKA catalytic activity and cAMP-binding compared to the fast Extensor Digitorum Longus (EDL) muscle. The...

Gene expression in skeletal muscle is regulated by the firing pattern of motor neurons, but the signalling systems involved in excitation-transcription coupling are unknown. Here, using in vivo transfection in regenerating muscle, we show that constitutively active Ras and a Ras mutant that selectively activates the MAPK(ERK) pathway are able to mi...

To study gene expression in differentiated adult motoneuron subtypes, we used fluorescent dextrans for both anterograde and retrograde axonal tracing in adult rat and mouse. Application of these dyes to the cut distal and proximal ends of small extramuscular nerve branches revealed both the peripheral ramifications and the cell bodies of subsets of...

Transplanted axons induced multiple, irregularly distributed acetylcholine receptor (AChR) aggregates on muscle fibers at early stages of ectopic neuromuscular junction formation in denervated adult rat soleus muscles. Subsequently, most AChR aggregates disappeared (the losers). A few aggregates survived (the winners) and, as part of the surviving...

We compared actylcholine receptor (AChR) aggregates induced by neural agrin released from transfected muscle fibers with AChR aggregates induced by transplanted axons in extrajunctional regions of denervated rat soleus muscles. Both neural agrin and transplanted axons induced multiple, irregularly distributed AChR aggregates on muscle fibers. Direc...

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We demonstrate by immunohistochemistry that at least two isoforms of neuregulin (NRG) are concentrated at neuromuscular junctions in adult rat muscles. One is NRGbeta3, a secreted protein which is bound to basal lamina that occupies the synaptic cleft. The other(s), NRG-a, is in the muscle fibers' plasma membrane. We show further that muscle NRG, i...

Denervated fast extensor digitorum longus (EDL) muscles of adult rats were stimulated electrically for up to 4 months with a ‘slow’ pattern resembling the activity in soleus (Sol) motor units and examined with antibodies against myosin heavy chains (MHCs). The normal EDL contained, on average, 45 % type IIB, 29 % type IIX, 23 % type IIA and 3 % typ...

We find that when extrajunctional regions of denervated soleus muscles in adult rats are transfected with cDNA encoding rat agrin isoform Y4Z8, which is normally secreted by motor neurons at adult neuromuscular junctions, the myofibers express and secrete the neural agrin. Muscle fibers in the vicinity of transfection form at their surface speciali...

We transfected the extrajunctional region of denervated soleus muscles in adult rats with neural agrin cDNA to induce myofibers to form postsynaptic-like apparatus containing acetylcholine receptor (AChR) aggregates. By 1 week approximately 30% of the AChR aggregates contained a mixture of epsilon-AChRs and gamma-AChRs while approximately 70% had o...

1. The number of acetylcholine receptors (AChRs) per neuromuscular junction in soleus muscles of adult rats was estimated from counts of 125I-alpha-bungarotoxin binding sites. The muscles were either denervated, denervated and electrically stimulated, paralysed by botulinum toxin (BoTX), or paralysed by tetrodotoxin (TTX). 2. After denervation, the...

The expression and content of calcitonin gene-related peptide (CGRP) and secretogranin II (SgII) in adult rat motor neurons were examined by in situ hybridization, Northern blot analysis, and immunocytochemistry. Normal motor nerve terminals did not contain detectable CGRP or SgII. Ten to 15 days after a peripheral nerve crush about 80% of the moto...

Neuromuscular junctions on fast and slow skeletal muscle fibers have different properties. Possible reasons for these differences were examined in adult rat soleus (SOL) muscle fibers reinnervated at new ectopic or old denervated sites by fast fibular (FIB) or slow SOL motoneurons. FIB motoneurons formed large ectopic junctions with a high density...

The effect of electrical stimulation on the stability of junctional ACh receptors (AChR) on soleus muscles of Wistar rats was compared to that of denervation and reinnervation. Denervation causes the degradation rate of the slowly degrading AChRs (Rs) at the neuromuscular junction to accelerate and be replaced by rapidly degrading AChRs (Rr), while...

The effects of in vivo stimulation via the sciatic nerve on Na+, K+ and calcium contents in slow-twitch and fast-twitch muscles were compared. Whereas intermittent stimulation for 24 h at 20 Hz caused only minor changes in soleus (SOL), a considerable loss of K+ (around 24%) and gain of Na+ (around 84%) was observed in extensor digitorum longus (ED...

The number and metabolic stability of acetylcholine receptors (AChRs) at neuromuscular junctions of rat tibialis anterior (TA) and soleus (SOL) muscles were examined after denervation, paralysis by continuous application of tetrodotoxin to the nerve, or denervation and direct stimulation of the muscle through implanted electrodes. After 18 days of...

The expression of 4 myosin heavy chain (MHC) isoforms was analyzed in the rat soleus (SOL) and extensor digitorum longus (EDL) muscles after denervation and chronic electric stimulation. The stimulation frequencies used were 20 and 150 Hz and the amount of stimulation was either large (20 Hz), intermediate (150 Hz), or small (150 Hz). These pattern...

Mammalian skeletal muscles consist of three main fibre types, type 1,2A and 2B fibres, with different myosin heavy chain (MHC) composition. We have now identified another fibre type, called type 2X fibre, characterized by a specific MHC isoform. Type 2X fibres, which are widely distributed in rat skeletal muscles, can be distinguished from 2A and 2...

This paper is a brief summary of some results obtained by stimulating denervated rat soleus (SOL) and extensor digitorum longus (EDL) muscles in vivo with different patterns of stimuli. It is concluded (1) that appropriate stimulation can maintain and restore normal properties in extrajunctional regions of denervated muscle; (2) that SOL and EDL re...

These experiments explore the relationship between patterned impulse activity and contractile properties of skeletal muscles. Soleus (SOL) and extensor digitorum longus (EDL) muscles of adult rats were denervated and stimulated directly from 4 to 15 weeks with the same number of pulse trains at different intratrain pulse frequencies (1-500 Hz), wit...

1. Adult soleus muscles were denervated and stimulated directly for 2-130 days with 'fast' (short pulse trains at 100 Hz) or 'slow' (continuously at 10 Hz, or long pulse trains at 15 Hz) stimulus patterns. 2. At the end of the period of stimulation isometric twitches and tetani and isotonic shortening velocities were measured. Frozen cross-sections...

Using immunofluorescence procedures with specific polyclonal and monoclonal antimyosin antibodies we have found that embryonic and neonatal myosin heavy chains (MHCs), which in rat skeletal muscle disappear during the first weeks after birth, are reexpressed in adult muscle after denervation. Reactivity for embryonic and neonatal MHCs was detected...

1. Fibre types, Ca2+-sequestering proteins (parvalbumin, sarcoplasmic reticulum Ca2+-ATPase), enzyme activities of energy metabolism, and lactate dehydrogenase isozymes were studied in extensor digitorum longus (EDL) and soleus muscles of adult rats after denervation and direct stimulation for 45-61 days. The stimulation resembled the firing patter...

Changes in the number and distribution of synaptic inputs and acetylcholine receptor clusters were studied during the formation of ectopic nerve-muscle junctions between the transplanted fibular nerve and the denervated soleus muscle of adult rats. The tibial nerve was cut 3 weeks after implanting the fibular nerve. New sites of transmission were f...

This chapter outlines the control of parvalbumin (PA) expression in rat skeletal muscle by motor-unit specific activity patterns. PA is a low-Mr cytosolic high-affinity Ca2+-binding protein identified in mammalian fast-twitch skeletal muscle fibers. The importance of nerve-muscle interactions for PA expression is evident from complete suppression o...

1. The formation of ectopic neuromuscular synapses was induced in rat soleus muscle by implantation of the fibular nerve into the proximal part of the muscle and subsequent sectioning of the soleus nerve. The gating properties of acetylcholine (ACh) receptors at the newly formed end-plates were examined by analysis of acetylcholine-induced membrane...

This study seeks to identify the mechanisms which motoneurones use to control the contractile force and speed of skeletal muscles. We have stimulated directly slow soleus (SOL) and fast extensor digitorum longus (EDL) muscles of adult rats intermittently at 100 Hz for 1-9 months. The muscles were either chronically denervated, denervated and reinne...

The discharge patterns of 16 motor units in extensor digitorum longus (EDL) and soleus (SOL) muscles of freely moving adult rats, described by Hennig & Lømo (1985), were further analysed with respect to their role in grading muscle force output. The units fell into three distinct classes, termed EDL-1, EDL-2 and SOL-1, probably corresponding to typ...

The distribution and the functional properties of the nicotinic acetylcholine receptors (AChR.s) in skeletal muscle depend strongly on the state of development of the muscle fibres. Before the embryonic muscle fibre is innervated, AChR.s are distributed over its entire surface. Following innervation, however, AChR.s are accumulated at high density...

The relative amount and distribution of acetylcholinesterase (AChE) molecular forms were studied in slow soleus and (less extensively) in fast extensor digitorum longus (EDL) muscles of the rat before and after denervation and direct stimulation. Normal EDL muscles showed higher total and specific AChE activity than normal soleus muscles and contai...

Skeletal muscles consist of motor units which may differ considerably in contractile properties and types of usage. Some units participate mainly in relatively rare, quick movements and contract rapidly and are easily fatigued (type FF); others contribute to the maintenance of posture and hence contract slowly and are fatigue-resistant (type S), wh...

Motor endplates in fast and slow skeletal muscles have different functional and morphological characteristics, and for brevity, are termed fast and slow respectively. We have examined the terminal arborization patterns of fast fibular and slow soleus axons 3-4 and 6 months after they reinnervated old preformed endplates or formed new ectopic endpla...

Spontaneous transmitter release, recorded as miniature end-plate potentials (m.e.p.p.s), was studied in rat extensor digitorum longus (e.d.l.) and soleus muscles partially or completely paralysed by botulinum toxin type A (BoTx). Normal unpoisoned muscles were examined for comparison. Analysis of m.e.p.p.s in both normal and BoTx-poisoned muscles c...

The development of ectopic n.m.j.s. between the transplanted superficial fibular nerve and the soleus muscle has been studied in adult rats. Impulse conduction in the sciatic nerve was blocked chronically and synapse formation between the blocked fibular nerve and the paralysed soleus was compared with synapse formation between non-blocked fibular...

1. The development of junctional ACh sensitivity has been studied during the formation of ectopic nerve-muscle junctions (n.m.j.s) between the superficial fibular nerve and the denervated soleus muscle of adult rats. 2. When the soleus nerve was cut 2 weeks or more after implanting the fibular nerve, spontaneous m.e.p.p.s and evoked e.p.p.s were fi...

1. The development of AChE at ectopic neuromuscular junctions forming between a transplanted foreign nerve (the superficial fibular nerve) and the denervated soleus muscle has been studied in adult rats. 2. Junctional AChE activity began to appear in the vicinity of the fibular nerve sprouts 6-7 days after section of the soleus nerve and 3-4 days a...

The formation of new synapses on a denervated muscle recapitulates many o f the processes observed during normal development. Here Terje Lømo outlines the physiological mechanisms underlying synapse formation, and suggests how the early multiple junctional contacts may be eliminated leading to the formation of a single mature synapse.

This chapter reviews recent contributions to the understanding of control of the motor innervation of mammalian skeletal muscle. Only fragments of the mechanisms underlying the establishment and maintenance of neuromuscular connections are known at present. The chapter emphasizes some aspects of neuromuscular development that appear particularly si...

1. The formation of ectopic junctions between the 'foreign' superficial fibular nerve and the soleus muscle of adult rats, and its relation to changes in extrajunctional sensitivity to acetylcholine (ACh), has been studied by denervating the muscle 3-6 weeks after implanting the foreign nerve. 2. The earliest signs of nerve-muscle transmission were...

Excerpt The effects of denervation and reinnervation on the sensitivity of muscle fibers to acetylcholine (ACh) illustrate in a dramatic way the importance of the nerve for maintaining normal muscular properties. In innervated fibers, only the membrane immediately underneath the nerve terminal is highly sensitive to ACh. Denervation causes the enti...

1. Denervated rat soleus muscles were stimulated directly through chronically implanted electrodes and the influence of different amounts and patterns of stimuli on the acetylcholine (ACh) sensitivity of the muscle was studied. The number of stimuli was varied by giving similar trains of stimuli (10 Hz for 10 sec) at different intervals (0 to 12 hr...

1. The fibular nerve was transplanted on to the soleus muscle of the rats. Interruption of the original soleus nerve then permitted cross-innervation, and subsequently, over a period of weeks, re-innervation by the original nerve. 2. Individual muscle fibres were often innervated by both the original and the foreign nerve. The original and foreign...

The denervated slow twitch rat soleus muscle was stimulated electrically for 3-6 weeks with brief trains of stimuli at 100 Hz or long trains at 10 Hz. In both cases the mean stimulation frequency was 2 Hz. Muscles stimulated at 100 Hz acquired several properties characteristic of fast muscle, whereas muscles stimulated at 10 Hz remained slow. The r...

COLCHICINE, a substance known to block axonal transport1,2, has been reported to mimic the effects of denervation on mammalian skeletal muscles3-5. These effects, which include an increased extrajunctional sensitivity to acetylcholine (Ach) and a fall in resting membrane potential, occur a few days after colchicine is applied locally to the nerve i...

MAMMALIAN skeletal muscle fibres normally receive input from single nerve fibres only, but will accept additional innervation from a foreign nerve if the original nerve is cut1,2 or anaesthetised3. We have been interested in the question of whether the extra innervation is repressed or displaced as the original innervation is re-established. Such s...

After the motor nerve to the rat soleus muscle was blocked reversibly by local anesthesia, individual muscle fibers became innervated by a transplanted motor nerve without losing their original innervation. Such cross-innervation of the denervated soleus muscle by the same foreign nerve was largely reduced by direct electrical stimulation of the mu...

1. The after‐effects of repetitive stimulation of the perforant path fibres to the dentate area of the hippocampal formation have been examined with extracellular micro‐electrodes in rabbits anaesthetized with urethane. 2. In fifteen out of eighteen rabbits the population response recorded from granule cells in the dentate area to single perforant...

1. Rat soleus and extensor digitorum longus (EDL) muscles were examined following complete blockade of sciatic nerve impulses with anaesthetics or diphtheria toxin for periods up to 14 days. 2. Muscles showed atrophy equivalent to that seen after similar periods of denervation. 3. Nerve blockade appeared to have little or no effect on neuromuscular...

1.In rabbits, anaesthetized with urethane/chloralose, stimulation with tungsten microelectrodes was employed to initiate a volley in the perforant path fibres which made en-passage contacts with the apical dendrites of dentate granule cells. The ensuing activation pattern was studied by recording the extracellular field potentials in the dentate ar...

1. In rabbits, initially anaesthetized by urethane/chloralose and maintained on urethane alone, the perforant path, contacting the apical dendrites of the dentate granule cells by way of boutons en-passage, was activated by paired stimuli. The effect of the first conditioning stimulus was studied by recording the extracellular field response and th...