Physical exercise in myasthenia gravis is safe and improves neuromuscular parameters and physical performance‐based measures: A pilot study

Introduction: Due to the shortage of exercise‐related research in Myasthenia Gravis (MG), there are no consensus guidelines on physical exercise for MG patients. Methods: In this prospective pilot study, 10 MG patients with mild disease performed supervised aerobic and resistance training twice weekly for 12 weeks. The Myasthenia Gravis Composite (MGC) score, compound motor action potential (CMAP), repetitive nerve stimulation, muscle force, physical performance‐based measures, serum levels of interleukin‐6, muscle enzymes, and immuno‐microRNAs miR‐150‐5p and miR‐21‐5p were assessed before and after the training period. Results: Physical exercise was well tolerated, and the MGC score was unchanged. Muscle resistance weights and CMAP amplitudes increased for biceps brachii and rectus femoris muscles, and physical performance‐based measures improved. Muscle enzymes remained normal, whereas disease‐specific microRNAs miR‐150‐5p and miR‐21‐5p were reduced after the training period. Conclusions: We propose that general recommendations regarding physical exercise can be applied safely to well‐regulated MG patients. Muscle Nerve 56 : 207–214, 2017     

The value of the CoughAssist® in the daily lives of children with neuromuscular disorders: Experiences of families,children and physiotherapists

Objectives: We explored parents’, children’s and physiotherapists’ experiences of regular CoughAssist® use, along with their perceptions of its value as an adjunct to in their daily, home respiratory management. Methods: All children in the care of a specialist neuromuscular service who regularly used a CoughAssist® device at home participated. Qualitative case study methods involved semi-structured interviews with three children with neuromuscular disorders (NMD), their parents and physiotherapist. Data were analysed using thematic content analysis. Results: Participants (n?=?9) perceived the CoughAssist® held benefits for physical, social and emotional aspects of living with NMD. Poor adherence was identified as the major barrier to effective use, governed by factors including child’s resistance, time constraints, treatment preference, practitioner support and fear of pressure trauma. Conclusions: Barriers to regular CoughAssist® use must be identified and individually addressed to enable uptake into respiratory care, accurately measure its effectiveness and realise its perceived benefits to children with NMD.     

Resistance strength training exercise in children with spinal muscular atrophy

Introduction: Preliminary evidence in adults with spinal muscular atrophy (SMA) and in SMA animal models suggests exercise has potential benefits in improving or stabilizing muscle strength and motor function. Methods: We evaluated feasibility, safety, and effects on strength and motor function of a home‐based, supervised progressive resistance strength training exercise program in children with SMA types II and III. Up to 14 bilateral proximal muscles were exercised 3 times weekly for 12 weeks. Results: Nine children with SMA, aged 10.4 ± 3.8 years, completed the resistance training exercise program. Ninety percent of visits occurred per protocol. Training sessions were pain‐free (99.8%), and no study‐related adverse events occurred. Trends in improved strength and motor function were observed. Conclusions: A 12‐week supervised, home‐based, 3‐day/week progressive resistance training exercise program is feasible, safe, and well tolerated in children with SMA. These findings can inform future studies of exercise in SMA. Muscle Nerve 52 : 559–567, 2015     

Lengthening our perspective: Morphological,cellular, and molecular responses to eccentric exercise

The response of skeletal muscle to unaccustomed eccentric exercise has been studied widely, yet it is incompletely understood. This review is intended to provide an up‐to‐date overview of our understanding of how skeletal muscle responds to eccentric actions, with particular emphasis on the underlying molecular and cellular mechanisms of damage and recovery. This review begins by addressing the question of whether eccentric actions result in physical damage to muscle fibers and/or connective tissue. We next review the symptomatic manifestations of eccentric exercise (i.e., indirect damage markers, such as delayed onset muscle soreness), with emphasis on their relatively poorly understood molecular underpinnings. We then highlight factors that potentially modify the muscle damage response following eccentric exercise. Finally, we explore the utility of using eccentric training to improve muscle function in populations of healthy and aging individuals, as well as those living with neuromuscular disorders. Muscle Nerve 49 : 155–170, 2014     

Acetylcholinesterase Adaptation to Voluntary Wheel Running is Proportional to the Volume of Activity in Fast, but not Slow, Rat Hindlimb Muscles

Chronic enhancement of neuromuscular activity by forced exercise training programmes results in selective adaptation of the G₄ acetylcholinesterase (AChE) molecular form in hindlimb fast muscles of the rat, with only minor and non-selective AChE changes in the soleus. In order to shed further light on the physiological significance of this G₄ adaptation to training, we turned to a voluntary exercise model. The impact of 5 days and 4 weeks of voluntary wheel cage running on AChE molecular forms was examined in four hindlimb fast muscles and the slow-twitch soleus from two rat strains. Inbred Fisher and Sprague– Dawley rats, placed in live-in wheel cages, exercised spontaneously for distances which progressively increased up to an average of ∼3 and 18 km/day, respectively, by the end of week 4. Fast muscles responded to this voluntary activity by massive G₄ increases (up to 420%) with almost no changes in A₁₂, so that by week 4 the tetramer became the main AChE component of these muscles. The additional G₄ was composed primarily of amphiphilic molecules, suggesting a membrane-bound state. The G₄ content of fast muscles was highly correlated with the distance covered by the rats during the 5 days before they were killed ( r = 0.850-0.879, P < 0.001 in three muscles). The soleus muscle, in turn, responded to wheel cage activity by a marked selective reduction of its asymmetric forms—up to 45% for A₁₂. This A₁₂ decline, already maximal by day 5 of wheel cage running, showed no relationship with the distance covered. The present results constitute strong new evidence suggesting that the role of AChE in neuromuscular transmission is not limited solely to the rapid inactivation of just-released acetylcholine.     

Evidence of Enhanced Kindliig and Hippocampal Neuronal Injury in Immature Rats with Neuronal Migration Disorders

Summary: Purpose: Neuronal migration disorders (NMD) are often found in patients with epilepsy. However, the mechanisms linking these two pathologies are not yet fully understood. In this study, we evaluated whether NMD increased kindling seizure susceptibility and seizure-induced acute neuronal damage in the immature brain.
Methods: Experimental NMD were produced by exposing pregnant rats (gestation day 15) to methylazoxymethanol acetate (MAM, 25 mg/kg, ip). Seizures were induced in rat pups (postnatal day 15) transplacentally exposed to MAM and controls by hippocampal kindling. Afterdischarge (AD) threshold and duration, seizure stage, and number of stimulations required to reach each seizure stage were recorded. Acute seizure-induced damage was histologically assessed in Nissl-stained and silver-impregnated hippocampal tissue 24 h after kindling.
Results: Rat pups with NMD had a significantly lower AD threshold than controls (91 ± 18 vs. 163 ± 23 μA; p < 0.05). Furthermore, rats with NMD required fewer stimulations to reach seizure stage 3.5 and 4 than did controls. Additionally, rats with NMD had longer AD the second day of stimulation (2,094 ± 416 s vs. 1,755 ± 353 s; p < 0.05). Histologic examination revealed that in rats with NMD, acute seizure-induced neuronal hippocampal damage occurred bilaterally in CA3 hippocampal neurons.
Conclusions: The lowered AD threshold and more rapid kindling to stages 3.5 and 4 indicate that in the presence of severe NMD, hippocampal kindling is facilitated. Furthermore, this study suggests that in the immature brain, seizure-induced hippocampal neuronal damage occurs if there is an underlying pre-existing pathology.     

Dose-dependent effects of inspiratory muscle training in neuromuscular disorders

The goal of this study was to show whether a correlation exists between the intensity of specific respiratory muscle training and the improvement of strength and endurance in inspiratory musculature in patients with neuromuscular disorders (NMD). Sixteen patients with NMD (13 with Duchenne muscular dystrophy and 3 with spinal muscular atrophy) performed inspiratory muscle training (IMT) at home with a special training apparatus for 9 months. Maximal inspiratory mouth pressure (PI(MAX)) and 12s-maximum voluntary ventilation (12s-MVV) test served as parameters for inspiratory muscle strength and endurance, respectively. In patients whose inspiratory vital capacity (VC(in)) declined by less than 10% during the year before training began (n = 10), a significant positive correlation was found between the number of successfully completed strength and endurance exercises and the improvement of PI(MAX) (P < 0.05) and 12s-MVV (P < 0.05). In patients whose VC(in)-decline exceeded 10% (n = 6), indicating more progressive respiratory system involvement of the disease, no significant correlation between the improvement of PI(MAX) and 12s-MVV and the intensity of training was found. In patients with NMD, the effects of IMT-runs are dose-dependent, provided that the respiratory system involvement of the disease is only slowly progressive.     

Double trouble (McArdle's disease and myasthenia gravis): How can exercise help?

We report a 29-year-old patient with McArdle's disease and myasthenia gravis. She had been debilitated with McArdle's disease since childhood (with marked rhabdomyolysis) and was obese. Myasthenia gravis was diagnosed at 24 years of age. After 3 months of aerobic exercise training, her exercise capacity increased significantly and she regained the ability to live independently. We conclude that even patients with profound neuromuscular diseases may benefit from carefully prescribed exercise training.     

A new de novo SYT2 mutation presenting as distal weakness. Neuropathy or neuromuscular junction dysfunction?

We report the case of a patient with a clinical phenotype characterized by distal lower limb weakness and pes cavus. The electrophysiological study showed slightly reduced or normal amplitude of motor potentials, a decremental response to repetitive nerve stimulation and post‐exercise facilitation. Muscle biopsy showed only mild neurogenic features. Genetic analysis included a clinical exome sequencing, followed by Sanger analysis. Three‐dimensional (3D) models were generated with a SwissModel ( https://swissmodel.expasy.org/ ) to explain the clinical observations and reinforce the pathogenic nature of the genetic variant identified. Genetic analysis demonstrated a new de novo heterozygous in frame deletion of the SYT2 gene (NM_177402.4: c.1082_1096del), confirmed by Sanger sequencing, which removes five aminoacids in the C2B domain of synaptotagmin‐2 protein, that cause a profound effect on the structure and function of this synaptic vesicle protein. We identified a de novo genetic variant in the SYT2 gene, further supporting its association with a highly stereotyped clinical and electrophysiological phenotype. Our case showed electrophysiological features consistent with a presynaptic dysfunction in the neuromuscular junction with normal post‐exercise amplitudes, not supporting the presence of predominant axonal damage. Although the analysis of SYT2 gene should be included in genetic analysis of patients presenting with this clinical phenotype that mimics motor neuropathy, clinicians have to consider the study of neuromuscular transmission to early identify this potentially treatable condition.     

Aerobic training in patients with anoctamin 5 myopathy and hyperckemia

Introduction: Anoctamin 5 deficiency has recently been defined to cause limb‐girdle muscular dystrophy type 2L (LGMD2L) with pronounced hyperCKemia. No treatment interventions have been made so far in this condition. Methods: In 6 patients with LGMD2L, we studied the effect of home‐based, pulse‐watch monitored, moderate‐intensity exercise on a cycle ergometer for 30 minutes, 3 times weekly, for 10 weeks. Plasma creatine kinase (CK) was assessed before, during, and after the program as a marker of muscle damage. Primary outcome measures were maximum oxygen uptake (VO_2max) and time in the 5‐repetitions‐sit‐to‐stand test (FRSTST). Results: Training resulted in improvements in VO_2max (27 ± 7%; P = 0.0001) and FRSTST time (35 ± 12%; P = 0.007). Improvements in physiologic and functional muscle testing were accompanied by stable CK levels and no reports of adverse effects. Conclusions: These findings suggest that supervised aerobic exercise training is safe and effective in improving oxidative capacity and muscle function in patients with anoctamin 5 deficiency. Muscle Nerve 50 : 119–123, 2014     

Spatial memory in sedentary and trained diabetic rats: Molecular mechanisms

Diabetes mellitus is a chronic disease that has been associated with memory loss, neurological disorders, and Alzheimer's disease. Some studies show the importance of physical exercise to prevent and minimize various neurological disorders. It is believed that the positive effects of exercise on brain functions are mediated by brain insulin and insulin‐like growth factor‐1 (IGF‐1) signaling. In this study, we investigate the role of swimming exercise training on hippocampus proteins related to insulin/IGF‐1 signaling pathway in Type 1 diabetic rats and its effects on spatial memory. Wistar rats were divided into four groups namely sedentary control, trained control, sedentary diabetic (SD), and trained diabetic (TD). Diabetes was induced by Alloxan (ALX) (32 mg/kg b.w.). The training program consisted in swimming 5 days/week, 1 h/day, per 6 weeks, supporting an overload corresponding to 90% of the anaerobic threshold. We employed ALX‐induced diabetic rats to explore learning and memory abilities using Morris water maze test. At the end of the training period, the rats were sacrificed 48 h after their last exercise bout when blood samples were collected for serum glucose, insulin, and IGF‐1 determinations. Hippocampus was extracted to determinate protein expression (IR, IGF‐1R, and APP) and phosphorylation (AKT‐1, AKT‐2, Tau, and β‐amyloide proteins) by Western Blot analysis. All dependent variables were analyzed by two‐way analysis of variance with significance level of 5%. Diabetes resulted in hyperglycemia and hypoinsulinemia in both SD and TD groups (P < 0.05); however, in the training‐induced group, there was a reduction in blood glucose in TD. The average frequency in finding the platform decreased in SD rats; however, exercise training improved this parameter in TD rats. Aerobic exercise decreased Tau phosphorylation and APP expression, and increased some proteins related to insulin/IGF‐1 pathway in hippocampus of diabetic rats. Thus, these molecular adaptations from exercise training might contribute to improved spatial learning and memory in diabetic organisms. © 2014 Wiley Periodicals, Inc.     

Next generation sequencing for molecular diagnosis of neuromuscular diseases

Inherited neuromuscular disorders (NMD) are chronic genetic diseases posing a significant burden on patients and the health care system. Despite tremendous research and clinical efforts, the molecular causes remain unknown for nearly half of the patients, due to genetic heterogeneity and conventional molecular diagnosis based on a gene-by-gene approach. We aimed to test next generation sequencing (NGS) as an efficient and cost-effective strategy to accelerate patient diagnosis. We designed a capture library to target the coding and splice site sequences of all known NMD genes and used NGS and DNA multiplexing to retrieve the pathogenic mutations in patients with heterogeneous NMD with or without known mutations. We retrieved all known mutations, including point mutations and small indels, intronic and exonic mutations, and a large deletion in a patient with Duchenne muscular dystrophy, validating the sensitivity and reproducibility of this strategy on a heterogeneous subset of NMD with different genetic inheritance. Most pathogenic mutations were ranked on top in our blind bioinformatic pipeline. Following the same strategy, we characterized probable TTN, RYR1 and COL6A3 mutations in several patients without previous molecular diagnosis. The cost was less than conventional testing for a single large gene. With appropriate adaptations, this strategy could be implemented into a routine genetic diagnosis set-up as a first screening approach to detect most kind of mutations, potentially before the need of more invasive and specific clinical investigations. An earlier genetic diagnosis should provide improved disease management and higher quality genetic counseling, and ease access to therapy or inclusion into therapeutic trials.     

Differential regulation by exercise of BDNF and NT-3 in rat spinal cord and skeletal muscle

We have investigated the impact of neuromuscular activity on the expression of neurotrophins in the lumbar spinal cord region and innervating skeletal muscle of adult rats. Rats were exercised on a treadmill for 1 day or 5 consecutive days and euthanized at 0, 2 or 6 h after the last bout of exercise. By Day 1, there was no clear evidence of an increase in brain-derived neurotrophic factor (BDNF) mRNA in the spinal cord or the soleus muscle. By Day 5, there was a significant increase in BDNF mRNA in the spinal cord at 2 h post-training, and the soleus muscle showed a robust increase between 0 and 6 h post-training. Immunoassays showed significant increases in BDNF protein in the soleus muscle by training Day 5. Immunohistochemical analyses showed elevated BDNF levels in motoneuron cell bodies and axons in the ventral horn. Neurotrophin-3 (NT-3) mRNA was measured to determine whether selected neurotrophins respond with a selective pattern of induction to neuromuscular activity. In the spinal cord, there was a progressive post-training decrease in NT-3 mRNA following a single bout of training, while there was a significant increase in NT-3 mRNA at 2 h post-training by Day 5. The soleus muscle showed a progressive increase in NT-3 mRNA by Days 1 and 5 following training. These results show that neuromuscular activity has specific effects on the BDNF and NT-3 systems, and that repetitive exercise affects the magnitude and stability of these responses.     

A novel protocol for assessing exercise performance and dystropathophysiology in the mdx mouse

Introduction: Dystrophinopathy in the young mdx mouse model of Duchenne muscular dystrophy is comparatively mild, requires induction, and is rarely assessed with tests of systemic muscle function in whole animals. Methods: A modified TREAT‐NMD induction protocol was used to evaluate respiratory and exercise performance, starting and ending with maximum oxygen consumption (VO _2max) tests. Results: The initial and/or final VO _2max, time to exhaustion, speed at exhaustion, and total expended calories were significantly lower in mdx mice. Episodic VO ₂ and VCO ₂ fluctuations occurred during training and resulted in dissociated patterns of VO ₂ and respiratory exchange ratio (RER). These fluctuations further resulted in significantly greater VO ₂ coefficient of variation and RER values and lower minimal VO ₂ values. Conclusions: Quantifying respiratory performance during exercise is a potentially useful means for studying pathophysiology in mdx mice, as it assesses intact animals over time, is more sensitive than some histological markers, and assesses systemic muscle function. Muscle Nerve 50: 541–548, 2014     

Transplacentally induced neuronal migration disorders: An animal model for the study of the epilepsies

Recent clinical and laboratory data suggest that there is a link between neuronal migration disorders (NMD) and increased seizure threshold. To characterize an animal model with features similar to human NMD and to assess seizure susceptibility, NMD were induced in the rat at the time of neuroblastic division (PG15) and three other gestational ages (PG 13, PG14, PG16) by transplacental exposure to methylaxozymethanol (MAM, 25 mg/kg). Offspring pups were monitored for spontaneous and electrographic seizures. At postnatal day 14, randomly selected rat pups were sacrificed for histological examination. In other MAM-exposed pups and controls, status epilepticus was induced by intraperitoneal administration of kainic acid. On histology, NMD were found in all PG 15 MAM-exposed rats, in comparison to 63% of PG 13, 70% of PG 14, 80% of PG16. Histological features included cortical laminar disorganization, ectopic neurons in the subcortical white matter and in cortical layer I, persistent granular layer, marginal glioneuronal heterotopia, and discrete areas of neuronal ectopia in the CA1 subfield of the hippocampus. Based on the severity of the neuronal migration abnormalities, rats were divided into three categories: severe, moderate, and mild. Severe and moderate NMD were only found in the PG 15 MAM-exposed rats. EEG recording in rats with NMD did not disclose spontaneous seizures; however, rats with severe NMD had higher slow wave activity compared to controls (P < .05). MAM-exposed rats with severe NMD were more susceptible to kainic-induced seizures compared to controls (P < .05). In rats with severe NMD, kainic acid-induced status epilepticus produced hippocampal damage in the CA3/4 region. These results demonstrate that MAM-induced NMD have histological and electrographic characteristics similar to human NMD. The severity of neuronal abnormality depends on the time of transplacental exposure as the most severe NMD were found after exposure to MAM at the time of neuroblastic division. The degree of NMD positively correlates with seizure susceptibility, since only rats with severe NMD have decreased seizure threshold. The occurrence of status epilepticus-induced hippocampal damage in pups with severe NMD suggests that the severely compromised hippocampus is less resistant to seizure-induced injury than the normal developing brain. J. Neurosci. Res. 51:473–488, 1998. © 1998 Wiley-Liss, Inc.     

Treadmill exercise training augments brain norepinephrine response to familiar and novel stress

In a test of hypothalamic-pituitary-adrenal (HPA) cortical and hypothalamic-pituitary-gonadal (HPG) interaction during familiar and novel stress, we previously reported that treadmill exercise training led to blunted plasma adrenocorticotrophin (ACTH) response to acute treadmill running but a hyper-responsiveness of ACTH after novel immobilization. In this follow-up analysis, we examined whether those results might be plausibly explained by a similar effect of treadmill exercise training on increased levels of norepinephrine (NE) in hypothalamic and limbic brain regions which synergize to modulate the release of ACTH during stress. Ovariectomized Sprague-Dawley rats that had been exercise trained by treadmill running or remained sedentary for 6 weeks received intramuscular injections of estradiol benzoate (Eb) or sesame oil on each of 3 days prior to 15 min of familiar treadmill running or novel immobilization. Treadmill exercise training, regardless of Eb treatment or type of stress, increased NE levels in the paraventricular (PVN), arcuate, medial preoptic, and ventromedial areas of the hypothalamus and protected against depletion of NE in the locus coeruleus, amygdala, and hippocampus. We conclude that treadmill exercise training has a hyperadrenergic effect in brain areas that modulate hypothalamic regulation of ACTH release during stress that is independent of HPA-HPG interaction and novelty of the stressor. To help elucidate these findings, the effects of treadmill exercise training on A1-A2 nuclei which innervate the PVN and their relationship with the limbic and hypothalamic responses we report require study.     

Resistance training and aerobic training improve muscle strength and aerobic capacity in chronic inflammatory demyelinating polyneuropathy

Introduction: We investigated the effects of aerobic and resistance exercise in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Eighteen CIDP patients treated with subcutaneous immunoglobulin performed 12 weeks of aerobic exercise and 12 weeks of resistance exercise after a run‐in period of 12 weeks without exercise. Three times weekly the participants performed aerobic exercise on an ergometer bike or resistance exercise with unilateral training of knee and elbow flexion/extension. Primary outcomes were maximal oxygen consumption velocity (VO₂‐max) and maximal combined isokinetic muscle strength (cIKS) of knee and elbow flexion/extension. Results: VO₂‐max and muscle strength were unchanged during run‐in (?4.9% ± 10.3%, P = 0.80 and ?3.7% ± 10.1%, P = 0.17, respectively). Aerobic exercise increased VO₂‐max by 11.0% ± 14.7% (P = 0.02). Resistance exercise resulted in an increase of 13.8% ± 16.0% (P = 0.0004) in cIKS. Discussion: Aerobic exercise training and resistance exercise training improve fitness and strength in CIDP patients. Muscle Nerve 57 : 70–76, 2018