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Posts tagged neuromuscular junction

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Researchers Identify New Rare Neuromuscular Disease

An international team of researchers has identified a new inherited neuromuscular disorder. The rare condition is the result of a genetic mutation that interferes with the communication between nerves and muscles, resulting in impaired muscle control. 

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The new disease was diagnosed in two families – one in the U.S. and the other in Great Britain – and afflicts multiple generations. The discovery was published in the American Journal of Human Genetics.

“This discovery gives us new insight into the mechanisms of diseases that are caused by a breakdown in neuromuscular signal transmission,” said David Herrmann, M.B.B.Ch., a professor in the Department of Neurology at the University of Rochester School of Medicine and Dentistry and co-lead author of the study. “It is our hope that these findings will help identify new targets for therapies that can eventually be used to treat these diseases.”

The focus of the research is the neuromuscular junction, the point at which the axon fibers that extend from peripheral nerves meet the muscle cells. The chemical signals that pass across the junction are essential for motor function. 

There are a number of disorders  – both acquired and inherited – that interfere with the communication that occurs at the neuromuscular junction. For example, in Lambert-Eaton myasthenic syndrome, which is most commonly triggered by certain cancers, the body’s own immune system attacks the neuromuscular junction, interrupting signal transmission. These diseases, which are rare, result in muscle weakness and fatigue, primarily in the limbs.  

While the families in the study had at one point been diagnosed with other neuromuscular conditions, the researchers identified them as unique, due to their particular motor abnormalities, including problems resembling Lambert-Eaton, and because the disease was passed from one generation to the next. 

The researchers compiled a genetic profile of the family members. Specifically, they analyzed the section of DNA code responsible for creating proteins using a technique called whole exome sequencing. 

They discovered that the two different families had mutations in the code that creates the protein synaptotagmin 2 (SYT2). Scientists have long understood the function of this protein, but it had never before been associated with a disease in humans.

SYT2 is present at the pre-synaptic terminal, the end of the nerve cell that sits at the neuromuscular junction and helps the cells sense fluctuations in calcium levels. Calcium plays an important role in the electrical function of cells and, in the case of the neuromuscular junction, helps dictate the release of acetylcholine, a chemical responsible for passing communication between the nerve and muscle cells.

In the two families, the mutation disrupted the ability of the nerve cells to sense the changes in calcium levels that would normally trigger the release of acetylcholine. As a result, communication was disrupted and muscle control was impaired. 

The authors have used the mutation in SYT2 to create a fruit fly (drosophila) model of the disease. Fruit flies are an important research tool and the study of their neurobiology has contributed greatly to our understanding of neurological development and diseases and the researchers see this as a first step to the development of potential new therapies to treat the condition.

(Source: urmc.rochester.edu)

Filed under neuromuscular junction muscle cells neuromuscular diseases synaptotagmin 2 gene mutation neuroscience science

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Sport makes muscles and nerves fit Endurance sport does not only change the condition and fitness of muscles but also simultaneously improves the neuronal connections to the muscle fibers based on a muscle-induced feedback. This link has been discovered by Christoph Handschin’s research group at the Biozentrum of the University of Basel. The group was also able to induce the same effect through raising the protein concentration of PGC1α in the muscle. Their findings, which are also interesting in regard to muscle and nerve disorders such as muscle wasting and ALS, have been published in the current issue of the journal “Nature Communications”. It’s springtime – the start signal for all joggers. It is well known that a regular run through the forest makes your muscles fit. Responsible for this effect is the protein PGC1α, which plays a central role in the adaptation of muscles to training. The research team led by Prof. Christoph Handschin has discovered that such endurance training not only affects the condition of the muscles but also the upstream synaptic neuronal connections in a muscle-dependent manner. PGC1α does not only make muscles fit… How do muscles change during muscle training or in muscle disease? Christoph Handschin and his team have been addressing this question for some years. In the past, they have already shown that the protein PGC1α plays a key role in the adaptation of the muscle by regulating the genes that cause the muscles to change accordingly to meet the more demanding requirements. When muscle is inactive or ill, only a low concentration of PGC1α is present. However, when the muscle is challenged, the PGC1α level increases. Through artificial elevation of the PGC1α concentration, it is possible to stimulate muscle endurance. … but also the nerve connections Now, the scientists have been able to demonstrate that the increase in muscle PGC1α concentration also improves the upstream synaptic nerve connections to the result of this feedback from muscle to the motor neuron: The health of the synapse improves and its activation pattern adapts to meet the requirements of the muscle. Until now, the influence of the muscle on the synaptic connection was primarily recognized in embryonic development. “That in adults, where the nerve and muscular systems are fully developed, not only the muscle changes due to an increase in PGC1α concentration but also a muscle-controlled improvement in the entire nerve and muscular system takes place, was completely unexpected and a great surprise to us”, says Handschin. “Our current aim is to identify the exact signal that leads to this stabilization of the synaptic connections, in order to apply this for treating muscle disorders.” …and helps in the treatment of muscle and nerve disorders A direct therapeutic application of the research findings in illnesses such as muscle wasting and amyotrophic lateral sclerosis (ALS) is already conceivable for Christoph Handschin. “In patients, whose muscles due to their illness are too weak to move on their own, an increase in PGC1α levels could strengthen muscles and nerves until the patients can move enough to finally do some physical therapy and to further improve their mobility”, he explains. After the pharmacological improvement of the health status of the muscles and nerves, the patient could independently continue their treatment through practicing endurance sports.

Sport makes muscles and nerves fit

Endurance sport does not only change the condition and fitness of muscles but also simultaneously improves the neuronal connections to the muscle fibers based on a muscle-induced feedback. This link has been discovered by Christoph Handschin’s research group at the Biozentrum of the University of Basel. The group was also able to induce the same effect through raising the protein concentration of PGC1α in the muscle. Their findings, which are also interesting in regard to muscle and nerve disorders such as muscle wasting and ALS, have been published in the current issue of the journal “Nature Communications”.

It’s springtime – the start signal for all joggers. It is well known that a regular run through the forest makes your muscles fit. Responsible for this effect is the protein PGC1α, which plays a central role in the adaptation of muscles to training. The research team led by Prof. Christoph Handschin has discovered that such endurance training not only affects the condition of the muscles but also the upstream synaptic neuronal connections in a muscle-dependent manner.

PGC1α does not only make muscles fit…

How do muscles change during muscle training or in muscle disease? Christoph Handschin and his team have been addressing this question for some years. In the past, they have already shown that the protein PGC1α plays a key role in the adaptation of the muscle by regulating the genes that cause the muscles to change accordingly to meet the more demanding requirements. When muscle is inactive or ill, only a low concentration of PGC1α is present. However, when the muscle is challenged, the PGC1α level increases. Through artificial elevation of the PGC1α concentration, it is possible to stimulate muscle endurance.

… but also the nerve connections

Now, the scientists have been able to demonstrate that the increase in muscle PGC1α concentration also improves the upstream synaptic nerve connections to the result of this feedback from muscle to the motor neuron: The health of the synapse improves and its activation pattern adapts to meet the requirements of the muscle. Until now, the influence of the muscle on the synaptic connection was primarily recognized in embryonic development. “That in adults, where the nerve and muscular systems are fully developed, not only the muscle changes due to an increase in PGC1α concentration but also a muscle-controlled improvement in the entire nerve and muscular system takes place, was completely unexpected and a great surprise to us”, says Handschin. “Our current aim is to identify the exact signal that leads to this stabilization of the synaptic connections, in order to apply this for treating muscle disorders.”

…and helps in the treatment of muscle and nerve disorders

A direct therapeutic application of the research findings in illnesses such as muscle wasting and amyotrophic lateral sclerosis (ALS) is already conceivable for Christoph Handschin. “In patients, whose muscles due to their illness are too weak to move on their own, an increase in PGC1α levels could strengthen muscles and nerves until the patients can move enough to finally do some physical therapy and to further improve their mobility”, he explains. After the pharmacological improvement of the health status of the muscles and nerves, the patient could independently continue their treatment through practicing endurance sports.

Filed under neuromuscular junction ALS muscle disorders PGC1α nerve disorders endurance sports psychology neuroscience science

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New cause found for muscle-weakening disease myasthenia gravis An antibody to a protein critical to enabling the brain to talk to muscles has been identified as a cause of myasthenia gravis, researchers report. The finding that an antibody to LRP4 is a cause of the most common disease affecting brain-muscle interaction helps explain why as many as 10 percent of patients have classic symptoms, like drooping eyelids and generalized muscle weakness, yet their blood provides no clue of the cause, said Dr. Lin Mei, Director of the Institute of Molecular Medicine and Genetics at the Medical College of Georgia at Georgia Regents University. "You end up with patients who have no real diagnosis," Mei said. The finding also shows that LRP4 is important, not only to the formation of the neuromuscular junction – where the brain and muscle talk – but also maintaining this important connection, said Mei, corresponding author of the paper in The Journal of Clinical Investigation. Mei and his colleagues first reported antibodies to LRP4 in the blood of myasthenia gravis patients in the Archives of Neurology in 2012. For the new study, they went back to animals to determine whether the antibodies were harmless or actually caused the disease. When they gave healthy mice LRP4 antibodies, they experienced classic symptoms of the disease along with clear evidence of degradation of the neuromuscular junction. LRP4 antibodies are the third cause identified for the autoimmune disease, which affects about 20 out of 100,000 people, primarily women under 40 and men over age 60, according to the National Institutes of Health and Myasthenia Gravis Foundation of America, Inc. An antibody to the acetylcholine receptor is causative in about 80 percent of patients, said Dr. Michael H. Rivner, MCG neurologist and Director of the Electrodiagnostic Medicine Laboratory, who follows about 250 patients with myasthenia gravis. Acetylcholine is a chemical released by neurons which act on receptors on the muscle to activate the muscle. More recently, it was found that maybe 10 percent of patients have an antibody to MuSK, an enzyme that supports the clustering of these receptors on the surface of muscle cells. "That leaves us with only about 10 percent of patients who are double negative, which means patients lack antibodies to acetylcholine receptors and MuSK," said Rivner, a troubling scenario for physicians and patients alike. "This is pretty exciting because it is a new form of the disease," Rivner said of the LRP4 finding. Currently, physicians like Rivner tell patients who lack antibody evidence that clinically they appear to have the disease. Identifying specific causes enables a more complete diagnosis for more patients in the short term and hopefully will lead to development of more targeted therapies with fewer side effects, Rivner said. To learn more about the role of the LRP4 antibody, Mei now wants to know if there are defining characteristics of patients who have it, such as more severe disease or whether it’s found more commonly in a certain age or sex. He and Rivner have teamed up to develop a network of 17 centers, like GR Medical Center, where patients are treated to get these questions answered. They are currently pursuing federal funding for studies they hope will include examining blood, physical characteristics, therapies and more. Regardless of the specific cause, disease symptoms tend to respond well to therapy, which typically includes chronic use of drugs that suppress the immune response, Rivner said. However, immunosuppressive drugs carry significant risk, including infection and cancer, he said. Removal of the thymus, a sort of classroom where T cells, which direct the immune response, learn early in life what to attack and what to ignore, is another common therapy for myasthenia gravis. While the gland usually atrophies in adults, patients with myasthenia gravis tend to have enlarged glands. Rivner is part of an NIH-funded study to determine whether gland removal really benefits patients. Other therapies include a plasma exchange for acutely ill patients.

New cause found for muscle-weakening disease myasthenia gravis

An antibody to a protein critical to enabling the brain to talk to muscles has been identified as a cause of myasthenia gravis, researchers report.

The finding that an antibody to LRP4 is a cause of the most common disease affecting brain-muscle interaction helps explain why as many as 10 percent of patients have classic symptoms, like drooping eyelids and generalized muscle weakness, yet their blood provides no clue of the cause, said Dr. Lin Mei, Director of the Institute of Molecular Medicine and Genetics at the Medical College of Georgia at Georgia Regents University.

"You end up with patients who have no real diagnosis," Mei said.

The finding also shows that LRP4 is important, not only to the formation of the neuromuscular junction – where the brain and muscle talk – but also maintaining this important connection, said Mei, corresponding author of the paper in The Journal of Clinical Investigation.

Mei and his colleagues first reported antibodies to LRP4 in the blood of myasthenia gravis patients in the Archives of Neurology in 2012. For the new study, they went back to animals to determine whether the antibodies were harmless or actually caused the disease. When they gave healthy mice LRP4 antibodies, they experienced classic symptoms of the disease along with clear evidence of degradation of the neuromuscular junction.

LRP4 antibodies are the third cause identified for the autoimmune disease, which affects about 20 out of 100,000 people, primarily women under 40 and men over age 60, according to the National Institutes of Health and Myasthenia Gravis Foundation of America, Inc.

An antibody to the acetylcholine receptor is causative in about 80 percent of patients, said Dr. Michael H. Rivner, MCG neurologist and Director of the Electrodiagnostic Medicine Laboratory, who follows about 250 patients with myasthenia gravis. Acetylcholine is a chemical released by neurons which act on receptors on the muscle to activate the muscle. More recently, it was found that maybe 10 percent of patients have an antibody to MuSK, an enzyme that supports the clustering of these receptors on the surface of muscle cells.

"That leaves us with only about 10 percent of patients who are double negative, which means patients lack antibodies to acetylcholine receptors and MuSK," said Rivner, a troubling scenario for physicians and patients alike. "This is pretty exciting because it is a new form of the disease," Rivner said of the LRP4 finding.

Currently, physicians like Rivner tell patients who lack antibody evidence that clinically they appear to have the disease. Identifying specific causes enables a more complete diagnosis for more patients in the short term and hopefully will lead to development of more targeted therapies with fewer side effects, Rivner said.

To learn more about the role of the LRP4 antibody, Mei now wants to know if there are defining characteristics of patients who have it, such as more severe disease or whether it’s found more commonly in a certain age or sex. He and Rivner have teamed up to develop a network of 17 centers, like GR Medical Center, where patients are treated to get these questions answered. They are currently pursuing federal funding for studies they hope will include examining blood, physical characteristics, therapies and more.

Regardless of the specific cause, disease symptoms tend to respond well to therapy, which typically includes chronic use of drugs that suppress the immune response, Rivner said. However, immunosuppressive drugs carry significant risk, including infection and cancer, he said.

Removal of the thymus, a sort of classroom where T cells, which direct the immune response, learn early in life what to attack and what to ignore, is another common therapy for myasthenia gravis. While the gland usually atrophies in adults, patients with myasthenia gravis tend to have enlarged glands. Rivner is part of an NIH-funded study to determine whether gland removal really benefits patients. Other therapies include a plasma exchange for acutely ill patients.

Filed under myasthenia gravis muscle weakness LRP4 antibodies neuromuscular junction neuroscience science

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'Singing' rats show hope for older humans with age-related voice problems A new study shows that the vocal training of older rats reduces some of the voice problems related to their aging, such as the loss of vocal intensity that accompanies changes in the muscles of the larynx. This is an animal model of a vocal pathology that many humans face as they age. The researchers hope that in the future, voice therapy in aging humans will help improve their quality of life. The research appears in The Journals of Gerontology. University of Illinois speech and hearing science professor Aaron Johnson, who led the new study along with his colleagues at the University of Wisconsin, said that aging can cause the muscles of the larynx, the organ that contains the vocal folds, to atrophy. This condition, called presbyphonia, may be treatable with vocal training, he said. Johnson said in a healthy, young larynx the vocal folds completely close and open during vibration. This creates little puffs of air we hear as sound. In people with presbyphonia, however, the atrophied vocal folds do not close properly, resulting in a gap during vocal fold vibration. Degradation of the neuromuscular junction, or the interface between the nerve that signals the vocal muscle to work and the muscle itself, also contributes to the symptoms of presbyphonia, Johnson said. In a healthy human, when the signal reaches the neuromuscular junction, it triggers a release of chemicals that signal the muscle to contract. But an age-related decline in the neuromuscular junction can cause weakness and fatigue in the muscle, and may result in a person having a breathy or weak voice and to become fatigued as a result of the extra effort needed to communicate. Surgery and injections may help correct the gap between the vocal folds seen in presbyphonia, but these invasive procedures are often not viable in the elderly population, Johnson said. His previous experience working with the elderly as a former classical singer and voice teacher propelled Johnson to “become interested in what we can do as we get older to keep our voices healthy and strong.” “We know exercise strengthens the limb musculature, but we wanted to know if vocal exercise can strengthen the muscles of the voice,” Johnson said. To find out if vocal training could have an effect on the strength and physiology of the vocal muscles in humans, Johnson turned to a rat model. Rats make ultrasonic vocalizations that are above the range of human hearing, but special recording equipment and a computer that lowers the frequency of the rat calls allows humans to perceive them. (They sound a bit like bird calls). Because rats and humans utilize similar neuromuscular mechanisms to vocalize, the rats make ideal subjects for the study of human vocal characteristics, Johnson said. Both the treatment and control groups contained old and young male rats. In the treatment group, a female rat was placed into a cage with a male rat. When the male expressed interest in her, the female was removed from the cage, causing the male rat to vocalize. The male was rewarded with food for these vocalizations, and after eight weeks of this operant conditioning in which rewards were only given for certain responses, all of the rats in the treatment group had been trained to increase their number of vocalizations during a training session. At the end of the eight-week period, the researchers measured the intensity of the rats’ vocalizations and analyzed the animals’ larynges to see whether the training had any effect on the condition of their neuromuscular junctions.  The researchers found the trained old and young rats had similar average vocal intensities, but the untrained older rats had lower average intensities than both the trained rats and the young rats that had not been trained. They also found several age-related differences within the groups’ neuromuscular mechanisms. “Other research has found that in the elderly, there is a dispersion, or breaking apart, of the neuromuscular junction at the side that is on the muscle itself,” Johnson said. “We found that in the older rats that received training, it wasn’t as dispersed.” These “singing rats” are the “first evidence that vocal use and vocal training can change the neuromuscular system of the larynx,” Johnson said.  “While this isn’t a human study, I think this tells us that we can train ourselves to use our voices and not only reduce the effects of age on the muscles of our voices, but actually improve voices that have degraded,” Johnson said.

'Singing' rats show hope for older humans with age-related voice problems

A new study shows that the vocal training of older rats reduces some of the voice problems related to their aging, such as the loss of vocal intensity that accompanies changes in the muscles of the larynx. This is an animal model of a vocal pathology that many humans face as they age. The researchers hope that in the future, voice therapy in aging humans will help improve their quality of life.

The research appears in The Journals of Gerontology.

University of Illinois speech and hearing science professor Aaron Johnson, who led the new study along with his colleagues at the University of Wisconsin, said that aging can cause the muscles of the larynx, the organ that contains the vocal folds, to atrophy. This condition, called presbyphonia, may be treatable with vocal training, he said.

Johnson said in a healthy, young larynx the vocal folds completely close and open during vibration. This creates little puffs of air we hear as sound. In people with presbyphonia, however, the atrophied vocal folds do not close properly, resulting in a gap during vocal fold vibration.

Degradation of the neuromuscular junction, or the interface between the nerve that signals the vocal muscle to work and the muscle itself, also contributes to the symptoms of presbyphonia, Johnson said. In a healthy human, when the signal reaches the neuromuscular junction, it triggers a release of chemicals that signal the muscle to contract. But an age-related decline in the neuromuscular junction can cause weakness and fatigue in the muscle, and may result in a person having a breathy or weak voice and to become fatigued as a result of the extra effort needed to communicate.

Surgery and injections may help correct the gap between the vocal folds seen in presbyphonia, but these invasive procedures are often not viable in the elderly population, Johnson said.

His previous experience working with the elderly as a former classical singer and voice teacher propelled Johnson to “become interested in what we can do as we get older to keep our voices healthy and strong.”

“We know exercise strengthens the limb musculature, but we wanted to know if vocal exercise can strengthen the muscles of the voice,” Johnson said.

To find out if vocal training could have an effect on the strength and physiology of the vocal muscles in humans, Johnson turned to a rat model. Rats make ultrasonic vocalizations that are above the range of human hearing, but special recording equipment and a computer that lowers the frequency of the rat calls allows humans to perceive them. (They sound a bit like bird calls).

Because rats and humans utilize similar neuromuscular mechanisms to vocalize, the rats make ideal subjects for the study of human vocal characteristics, Johnson said.

Both the treatment and control groups contained old and young male rats. In the treatment group, a female rat was placed into a cage with a male rat. When the male expressed interest in her, the female was removed from the cage, causing the male rat to vocalize. The male was rewarded with food for these vocalizations, and after eight weeks of this operant conditioning in which rewards were only given for certain responses, all of the rats in the treatment group had been trained to increase their number of vocalizations during a training session.

At the end of the eight-week period, the researchers measured the intensity of the rats’ vocalizations and analyzed the animals’ larynges to see whether the training had any effect on the condition of their neuromuscular junctions. 

The researchers found the trained old and young rats had similar average vocal intensities, but the untrained older rats had lower average intensities than both the trained rats and the young rats that had not been trained. They also found several age-related differences within the groups’ neuromuscular mechanisms.

“Other research has found that in the elderly, there is a dispersion, or breaking apart, of the neuromuscular junction at the side that is on the muscle itself,” Johnson said. “We found that in the older rats that received training, it wasn’t as dispersed.”

These “singing rats” are the “first evidence that vocal use and vocal training can change the neuromuscular system of the larynx,” Johnson said. 

“While this isn’t a human study, I think this tells us that we can train ourselves to use our voices and not only reduce the effects of age on the muscles of our voices, but actually improve voices that have degraded,” Johnson said.

Filed under aging neuromuscular junction presbyphonia vocal intensity voice neuroscience science

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