Muscle pain in neuromuscular disorders and primary fibromyalgia

Muscle fiber degeneration and regeneration, inflammation in the intramuscular connective tissue and hypoxia in resting muscle are not necessarily associated with pain. However, when sustained or dynamic muscle contractions are performed in an ischaemic muscle, severe pain develops. In the chronic muscle pain syndrome called fibromyalgia (or fibrositis) the most likely cause of the pain is a combination of muscle tension and muscle hypoxia. This conclusion is supported by the finding of a pathological distribution of tissue oxygen pressure in painful muscles and a subjective feeling of muscle tension and muscle stiffness in the majority of patients. A decrease of high energy phosphates is found in biopsies from painful muscle. The most characteristic morphological finding is the so-called ragged red fiber, a finding that can be seen in mitochondrial disorders. The morphological and chemical findings are possibly a consequence of a long standing hypoxia. The possibility that sympathetic nerve activity is important for the development of chronic muscle pain is discussed.     

Muscle-nerve-muscle neurotization for the reinnervation of denervated somatic muscle

Muscle-Nerve-Muscle (MNM) is the reinnervation of a denervated (recipient) muscle via a nerve graft inserted into the belly of an innervated (donor) muscle. MNM is studied for the reinnervation of intrinsic denervated somatic skeletal muscle by evaluating both restored muscle contractile ability and innervation state. In a rat model, muscle function is tested following MNM neurotization from an innervated (donor), extensor digitorum longus muscle to a denervated (recipient), peroneus digit quinti (PDQ) muscle. PDQ muscle cross-sections labeled for neural cell adhesion molecule protein (NCAM), a marker for fiber denervation. MNM neurotization results in the recovery of PDQ muscle force generating capacity (58% of Normal-control) and a significantly lower percentage of residual muscle fiber denervation (38% denervated) compared with the Denervated-control (79% denervated) group. MNM neurotization reinnervates 62% of the previously denervated muscle fibers in the PDQ muscle. No decrement in force capacity is observed in the donor EDL muscle. Nerve grafting for MNM neurotization may restore modest contractile function to denervated muscle and reinnervate relatively more denervated muscle fibers than the Denervated-control.     

Electron-microscopic, cytochemical and biochemical studies of acetylcholinesterase and butyrylcholinesterase activity in muscle of dystrophic mice.

We have studied extrajunctional muscle of control and dystrophic mice by electron microscopic-cytochemistry and radiometric assay. We have found both a soluble and particulate AChE activity, which is similar proportionally in control and dystrophic muscle. The particulate AChE activity is probably due to the enzyme localized in the sarcotubular system. These sites are more numerous in muscle adjacent to the motor end-plant than in distally located extrajunctional muscle, and are increased markedly in the dystrophic mouse. Myoblasts and small muscle fibers in the dystrophic mouse also have AChE activity in the reticulum similar to fetal muscle. The soluble AChE activity identified radiometrically may represent those sites exhibiting random cytochemical end-product, such as some muscle nuclei, satellite cells, myogenic mononuclear cells in the connective tissue, and degenerating axonal boutons no longer associated with junctional folds of muscle. Enzyme activity is present in degenerating fibers, but it is randomly dispersed in the sarcoplasm rather than membrane-bound. AChE activity has not been found in debris of completely necrotic muscle. BuChE activity is higher and the number of BuChE-active sites in the sarcotubular system adjacent to the motor end-plates is greater in dystrophic muscle than in control muscle.     

The fusimotor innervation of muscle spindle endings in man

A feedback circuit for control of muscle contraction is provided by the stretch reflex wherein muscle spindle receptors in a stretched muscle send out a signal along-sensory nerves which activate motor nerves to cause a compensatory contraction of the stretched muscle. Superimposed on this is a servo mechanism by which the central nervous system can cause the muscle spindle to contract, and stimulate the stretch reflex arc as if the muscle had been stretched. It is this fusimotor control of the muscle spindles which will be discussed in this article.     

Opsoclonus-myoclonus syndrome associated with Mycoplasma pneumoniae infection in an elderly patient

Neurogenic muscle hypertrophy is very unusual and has been rarely described. We described a 25-year-old woman presented with proximal muscle weakness with calf muscle hypertrophy. Limb magnetic resonance imaging scans showed increased muscle bulk without fatty changes, and a muscle biopsy revealed prominent hypertrophic type II muscle fibers. A mutation in SMN1 was found in a genetic analysis. This is the first report of neurogenic muscle hypertrophy seen in genetically confirmed spinal muscular atrophy III.     

The fusimotor innervation of muscle spindle endings in man

A feedback circuit for control of muscle contraction is provided by the stretch reflex, wherein muscle spindle receptors in a stretched muscle send out a signal along sensory nerves which activate motor nerves to cause a compensatory contraction of the stretched muscle. Superimposed on this is a servo mechanism by which the central nervous system can cause the muscle spindle to contract, and stimulate the stretch reflex arc as if the muscle had been stretched. It is this fusimotor control of the muscle spindles which will be discussed in this article.     

Disuse muscle atrophy-improving effect of ninjin'yoeito in a mouse model

Disuse syndrome indicates psychosomatic hypofunction caused by excess rest and motionless and muscle atrophy is termed disuse muscle atrophy. Disuse muscle atrophy-induced muscle weakness and hypoactivity further induces muscle atrophy, leading to a vicious cycle, and this is considered a factor causing secondary sarcopenia and subsequently frailty. Since frailty finally leads to a bedridden state requiring nursing, in facing a super-aging society, intervention for a risk factor of frailty, disuse muscle atrophy, is important. However, the main treatment of disuse muscle atrophy is physical therapy and there are fewer effective preventive and therapeutic drugs. The objective of this study was to search for Kampo medicine with a disuse muscle atrophy-improving effect. Ninjin'yoeito is classified as a qi-blood sohozai (dual supplement) in Chinese herbal medicine, and it has an action supplementing the spleen related to muscle. In addition, improvement of muscle mass and muscle weakness by ninjin'yoeito in a clinical study has been reported. In this study, the effect of ninjin'yoeito on disuse muscle atrophy was investigated.A disuse muscle atrophy model was prepared using male ICR mice. After surgery applying a ring for tail suspension, a 1-week recovery period was set. Ninjin'yoeito was administered by mixing it in the diet for 1 week after the recovery period, followed by tail suspension for 14 days. Ninjin'yoeito administration was continued until autopsy including the hindlimb suspension period. The mice were euthanized and autopsied immediately after completion of tail suspension, and the hindlimb muscles were collected. The food and water intakes during the hindlimb unloaded period, wet weight of the collected muscle, and muscle synthesis and muscle degradation-related factors in blood and muscle were evaluated.Ingestion of ninjin'yoeito inhibited tail suspension-induced reduction of the soleus muscle wet weight. In addition, an increase in the blood level of a muscle synthesis-related factor, IGF-1, and promotion of phosphorylation of mTOR and 4E-BP1 in the soleus muscle were observed.It was suggested that ninjin'yoeito has a disuse muscle atrophy-improving action. Promotion of the muscle synthesis pathway was considered the action mechanism of this.     

Mechanisms of fatigue in normal intercostal muscle and muscle from patients with myasthenia gravis

Fatigue mechanisms in normal intercostal muscle and muscle from patients with myasthenia gravis (MG) were evaluated by monitoring the compound muscle action potential (CMAP) and tetanic tension responses to repetitive nerve or muscle stimulation in vitro. When fatigue was induced by nerve stimulation at 30 Hz for 0.5 s every 2.5 s, about half of the original tension decreased after 30 min in normal muscle and 5 min in MG muscle. Analysis of the changes in area of CMAPs and tension indicated that impairment of neuromuscular transmission, muscle membrane excitation, and excitation-contraction (E-C) coupling and contractility accounted for 40%, 29%, and 31% of fatigue in normal muscle, and 83%, 0%, and 17% of fatigue in MG muscle. When fatigue was induced by muscle stimulation at 30 Hz, tension declined by a quarter after 30 min in normal muscle, but by a half after 17 min in MG muscle. Impairment of muscle membrane excitation and E-C coupling and contractility accounted for 58% and 42% of fatigue in normal muscle, and 22% and 78% of fatigue in MG muscle. Thus, fatigue of normal muscle is caused by impairment of at least four processes, and enhanced fatigue of MG muscle is caused by greater impairment of neuromuscular transmission, E-C coupling, and contractility. © 1993 John Wiley & Sons, Inc.     

Contraction-induced muscle fiber damage is increased in soleus muscle of streptozotocin-diabetic rats and is associated with elevated expression of brain-derived neurotrophic factor mRNA in muscle fibers and activated satellite cells

The expression of brain-derived neurotrophic factor (BDNF) is elevated in the soleus muscle of streptozotocin-diabetic rats. To determine whether this diabetes-induced elevation was associated with or enhanced by muscle activity we have induced high-intensity muscle contraction by electrically stimulating the sciatic nerve. In 6-week diabetic rats, intense contraction of the soleus muscle resulted in a two- to four-fold elevation of BDNF mRNA and increased plasma levels of creatine kinase that were associated with severe focal muscle fiber damage and concomitant satellite cell activation. Focal muscle fiber damage and concomitant satellite cell activation were also observed in the soleus muscle of nonstimulated diabetic rats, but to a much lesser extent. No effects of muscle contraction, i.e., experimentally induced or during normal daily activity, on muscle fiber structure or BDNF mRNA expression were seen in diabetic extensor digitorum longus (EDL) muscle. Using a nonradioactive in situ hybridization technique for electron microscopy, the elevated expression of BDNF mRNA in the diabetic soleus muscle was localized within muscle fibers as well as activated satellite cells. This study shows that diabetic soleus muscle, in contrast to diabetic EDL and to soleus and EDL muscle of normal animals, is highly susceptible to contraction-induced damage. Intense contraction and the associated muscle fiber damage in the diabetic soleus muscle result in an upregulation of BDNF mRNA in muscle fibers and activated satellite cells, which may be involved in the restoration and/or maintenance of nerve/muscle integrity.     

Regenerative capacity of skeletal muscle

PURPOSE OF REVIEW: The aim of this review is to highlight advances in the field of skeletal muscle regeneration that have been made in the last year. RECENT FINDINGS: Studies have increased our understanding of the activation of satellite cells within their niche on the muscle fibre, the contribution of satellite cell-derived muscle precursor cells to skeletal muscle regeneration and the reduction of satellite cell function in old muscle. Although other stem cells, either bone marrow derived or present within skeletal muscle or other tissues, do contribute to muscle regeneration, recent studies have highlighted that this is at best minimal compared with the ability of satellite cells to regenerate skeletal muscle. The effect of the host muscle environment has been shown to have a profound effect on skeletal muscle regeneration. Age and denervation have a detrimental effect and certain types of muscle injury a positive effect. Work continues on the effect of growth factors on muscle cell lines in vitro and muscle regeneration in vivo. SUMMARY: Recent work has focused on the contribution of satellite-cell derived muscle precursor cells and other stem cells to skeletal muscle regeneration. The muscle environment has a profound effect on the regenerative capacity of resident and implanted cells. Muscle regeneration may be optimized by using the best stem cell population and by modifying the host muscle environment.     

Improvement of muscle healing through enhancement of muscle regeneration and prevention of fibrosis

Skeletal muscle is able to repair itself through regeneration. However, an injured muscle often does not fully recover its strength because complete muscle regeneration is hindered by the development of fibrosis. Biological approaches to improve muscle healing by enhancing muscle regeneration and reducing the formation of fibrosis are being investigated. Previously, we have determined that insulin-like growth factor-1 (IGF-1) can improve muscle regeneration in injured muscle. We also have investigated the use of an antifibrotic agent, decorin, to reduce muscle fibrosis following injury. The aim of this study was to combine these two therapeutic methods in an attempt to develop a new biological approach to promote efficient healing and recovery of strength after muscle injuries. Our findings indicate that further improvement in the healing of muscle lacerations is attained histologically by the combined administration of IGF-1 to enhance muscle regeneration and decorin to reduce the formation of fibrosis. This improvement was not associated with improved responses to physiological testing, at least at the time-points tested in this study.     

McArdle disease: the mystery of reappearing phosphorylase activity in muscle culture--a fetal isoenzyme.

To understand the apparently paradoxical appearance of phosphorylase in muscle cultured from patients with McArdle disease, the enzyme in muscle culture was studied immunologically and electrophoretically. Antibody against normal human muscle phosphorylase completely inhibited the enzyme of adult muscle, but it had no effect on phosphorylase activity of muscle cultures from normal individuals or patients with McArdle disease. Also, amounts of antibody that would completely inhibit phosphorylase in mature muscle left about 30% of the activity in muscle obtained from human fetus at four months' gestation. Acrylamide-disc and slab-gel electrophoresis showed a single band of phorphorylase activity in adult muscle and two bands in fetal muscle. This suggested that at four months' gestation, both fetal and mature forms are present but that only the mature isoenzyme is inhibited by the antibody. The enzyme from cultured muscle gave only a single band, with the electrophoretic mobility of the fetal isoenzyme. These data suggest that phosphorylase activity in muscle cultured from patients with McArdle disease is due to a fetal isoenzyme whose genetic control is different from that of the mature enzyme.     

Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease

Hereditary canine spinal muscular atrophy (HCSMA) features rapidly progressive muscle weakness that affects muscles in an apparent proximal-to-distal gradient. In the medial gastrocnemius (MG) muscle of homozygous HCSMA animals, motor unit tetanic failure is apparent before the appearance of muscle weakness and appears to be presynaptic in origin. We determined whether structural changes in neuromuscular junctions or muscle fibers were apparent at times when tetanic failure is prevalent. We were surprised to observe that, at ages when motor unit tetanic failure is common, the structure of neuromuscular junctions and the appearance of muscle fibers in the MG muscle were indistinguishable from those of symptom-free animals. In contrast, in more proximal muscles, many neuromuscular junctions were disassembled, with some postsynaptic specializations only partially occupied by motor nerve terminals, and muscle fiber atrophy and degeneration were also apparent. These observations suggest that the motor unit tetanic failure observed in the MG muscle in homozygous animals is not due to synaptic degeneration or to pathological processes that affect muscle fibers directly. Together with previous physiological analyses, our results suggest that motor unit failure is due to failure of neuromuscular synaptic transmission that precedes nerve or muscle degeneration.     

Motoneurone survival activity in extracts of denervated muscle reduced by prior stimulation of the muscle

Inactivation of skeletal muscle by denervation increases motoneurone survival activity in extracts of skeletal muscle. The present investigation shows that electrical stimulation of denervated muscle decreases motoneurone survival activity in extracts of these muscles. The result suggests that motoneurone survival is dependent on a factor(s) in muscle whose synthesis and/or release is regulated by muscle contraction.     

Regular alternation of fiber types in the transversus abdominis muscle of the garter snake

The snake transversus abdominis muscle is an extremely simple segmentally repeating muscle containing 80 to 100 muscle fibers in a single-fiber-thick sheet. This muscle exhibits a striking pattern of muscle fiber types: twitch fibers alternate with tonic fibers and, among the twitch fibers, slower and faster contracting subtypes also alternate. Thus, in many regions of the muscle the pattern of fiber types is: faster twitch, tonic, slower twitch, tonic, faster twitch, tonic, and so on. The existence of a spatial pattern of fiber types, perhaps discernible in this muscle because of the muscle's extreme geometrical simplicity, provides good evidence for an intrinsic component to muscle fiber differentiation.     

Outcome measures frequently used to assess muscle strength in patients with myotonic dystrophy type 1: a systematic review

Measurement of muscle strength is fundamental for the management of patients with myotonic dystrophy type 1 (DM1). Nevertheless, guidance on this topic is somewhat limited due to heterogeneous outcome measures used. This systematic literature review aimed to summarize the most frequent outcome measures to assess muscle strength in patients with DM1. We searched on Pubmed, Web of Science and Embase databases. Observational studies using measures of muscle strength assessment in adult patients with DM1 were included. From a total of 80 included studies, 24 measured cardiac, 45 skeletal and 23 respiratory muscle strength. The most common method and outcome measures used to assess cardiac muscle strength were echocardiography and ejection fraction, for skeletal muscle strength were quantitative muscle test, manual muscle test and maximum isometric torque and medical research council and for respiratory muscle strength were manometry and maximal inspiratory and expiratory pressure. We successfully gathered the more consensual methods and measures to evaluate muscle strength in future clinical studies, particularly to test muscle strength response to treatments in patients with DM1. Future consensus on a set of measures to evaluate muscle strength (core outcome set), is important for these patients.     

Measurements of muscle stiffness, the electromyogram and activity in single muscle spindles of human flexor muscles following conditioning by passive stretch or contraction

In experiments on adult human subjects we examined the effect on passive mechanical properties of a muscle by conditioning it with either an isometric contraction or passive muscle extension. The test measurement was the amount of muscle displacement (stiffness) and the accompanying EMG in response to a brief torque pulse. Two muscles were tested, flexor digitorum profundus (FDP) and brachialis. In FDP the discharge of single muscle spindles was recorded as well. After muscle extension and return to the initial length, passive stiffness was less than after an isometric contraction. The changes in stiffness were accompanied by changes in pattern of EMG and in the responses of muscle spindles. It is suggested that in resting muscle there are stable cross bridges between actin and myosin filaments of muscle fibres which largely determine the passive stiffness. Muscle extension leads to detachment of these cross bridges which then re-form at the longer length. Return of the muscle to its starting length leads to development of slack in muscle fibres because, stiffened by the presence of the stable cross bridges, they are unable to shorten. Slack in muscle fibres lowers their measured stiffness. Muscle contraction, on the other hand, will result in any preexisting slack being taken up by the actively shortening muscle fibres, thereby raising muscle stiffness. Stiffness in intrafusal fibres is likely to follow a similar pattern to that in extrafusal fibres, leading to changes in stretch responsiveness of muscle spindles and consequently in the reflex EMG. It is concluded that the changes in stiffness and accompanying reflexes observed in this study are likely to be seen, at least under some conditions, in normal movements.     

Terminal Schwann cell structure is altered in diaphragm of mdx mice

The diaphragm muscle of the mdx mouse is a model system of Duchenne muscular dystrophy, since it completely lacks dystrophin and shows severe fiber necrosis and loss of specific muscle force by 4-6 weeks of age. Changes in neuromuscular junction structure also become apparent around 4 weeks including postsynaptic acetylcholine receptor declustering, loss of postsynaptic junctional folds, abnormally complex presynaptic nerve terminals, and muscle fiber denervation. Normally, terminal Schwann cells (TSCs) cap both nerve terminals and acetylcholine receptors at the neuromuscular junction, and play a crucial role in regeneration of motor axons following muscle denervation by guiding axons to grow from innervated junctions to nearby denervated junctions. However, their role in restoring innervation in dystrophic muscle is unknown. We now show that TSCs fail to cap fully the neuromuscular junction in dystrophic muscle; TSCs extend processes, but the organization of these extensions is abnormal. TSC processes of dystrophic muscle do not form bridges from denervated fibers to nearby innervated endplates, but appear to be directed away from these endplates. Adequate signaling for TSC reactivity is present, since significant muscle fiber denervation and acetylcholine receptor declustering are present. Thus, significant structural denervation is present in the diaphragm of mdx mice and the ability of TSCs to form bridges between adjacent endplates to guide reinnervation of muscle fibers is impaired, possibly attenuating the ability of dystrophic muscle to recover from denervation and ultimately leading to muscle weakness.     

Distinct segregation of the pathogenic m.5667G>A mitochondrial tRNAAsn mutation in extraocular and skeletal muscle in chronic progressive external ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is a frequent clinical manifestation of disorders caused by pathogenic mitochondrial DNA mutations. However, for diagnostic purposes skeletal muscle tissue is used, since extraocular muscle tissue is usually not available for work-up. In the present study we aimed to identify causative factors that are responsible for extraocular muscle to be primarily affected in CPEO. We performed comparative histochemical and molecular genetic analyses of extraocular muscle and skeletal muscle single fibers in a case of isolated CPEO caused by the heteroplasmic m.5667G>A mutation in the mitochondrial tRNA^Asn gene (MT-TN). Histochemical analyses revealed higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle (41%) compared to skeletal muscle (10%). However, genetic analyses of single fibers revealed no significant difference either in the mutation loads between extraocular muscle and skeletal muscle cytochrome c oxidase deficient single fibers (extraocular muscle 86% ± 4.6%; skeletal muscle 87.8 %± 5.7%, p = 0.246) nor in the mutation threshold (extraocular muscle 74% ± 3%; skeletal muscle 74% ± 4%). We hypothesize that higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle compared to skeletal muscle might be due to facilitated segregation of the m.5667G>A mutation into extraocular muscle, which may explain the preferential ocular manifestation and clinically isolated CPEO.