Muscle communication may lead to a novel treatment for amyotrophic lateral sclerosis

Disease and treatment 11. nov 2021 3 min Professor Jorge Ruas Written by Kristian Sjøgren

New research reveals that muscle cells can communicate with neurons through neurturin, a signalling protein. Neurturin could become a new way to treat amyotrophic lateral sclerosis (ALS) and prevent muscle ageing.

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The body’s cells constantly exchange signals.

When muscles need to perform an action, motor neurons send messages to the muscles about what to do, when to contract and when to relax.

Conversely, the muscles also emit signalling proteins into the environment. Untrained muscles emit many inflammation signals into the environment, which is not optimal. Well-trained muscles do not do this.

The fact that motor neurons communicate with muscles is well known, but the question of whether the muscles also communicate with the neurons has long been unanswered.

New research shows that the muscles do communicate back, with extensive clinical implications.

“People with ALS have less crosstalk between the motor neurons and the muscles, leading to paralysis and ultimately death. If the muscles send survival signals back to the motor neurons, we can use this to maintain the crosstalk between the motor neurons and the muscles, which could be developed into ALS therapies or could reduce muscle atrophy that occurs with ageing,” explains an author of the new study, Jorge Ruas, Professor, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

The research has been published in Cell Metabolism.

Mice improved exercise performance by 100%

A few years ago, the researchers in Jorge Ruas’s group examined the molecular signature of the networks formed between neurons and muscle cells.

They found that muscle cells can release neurturin, leading to the creation of networks between the neurons and the muscles.

In the new research, the researchers went a step further and investigated the other effects of neurturin by genetically engineering mice to constantly release neurturin from their muscles.

The result was astonishing.

The murine muscles became extremely energy-efficient, which shows that neurturin not only communicates with the neuromuscular networks but also strongly affects the muscles.

“The mice improved their exercise performance by 100%. They were very slim and had very energy-demanding muscles that used all the energy from the fat tissue,” says Jorge Ruas.

Direct communication with the motor neuron cell nucleus

Different kinds of muscles are linked with different kinds of motor neurons. Slow endurance muscles have slow motor neurons (such as among marathon runners), whereas more rapid and explosive muscles have fast and explosive motor neurons (such as among bodybuilders).

In the genetically engineered mice, the motor neurons had shifted towards a slow motor neuron identity to match the slow muscle cells, and this dramatically improved exercise performance.

The neuromuscular network affected by neurturin is located far from the cell nucleus of the neuron, which determines whether the neuron is slow or fast.

“The cell bodies and nuclei of motor neurons are in the spinal cord, which can be very far away from the muscles they innervate. But neurturin is released from the muscles on the neuromuscular network close to the muscles. This signal somehow reaches all the way along the neuromuscular network to the cell nucleus of the neuron. This is very interesting because it proves that the communication between muscles and neurons flows both ways. The motor neurons send signals to the muscles, but the muscles communicate back, and this can affect the behaviour of the neurons,” explains Jorge Ruas.

Neurturin might help people with ALS

The clinical perspective is that neurturin stimulates the creation of slow muscles with associated slow motor neurons, which are more resistant to degeneration in ALS.

In addition, neurturin already naturally functions outside the body’s cells, so researchers do not even have to develop a protein that resembles neurturin. They can use nature’s own evolution in striving to cure ALS.

The researchers are doing this in new research, in which they give neurturin to mice with ALS to determine whether it can slow the progression of ALS and extend their life.

“If giving mice neurturin does not work, we at least know about the signalling pathways involved, and this could lead to other types of treatment,” says Jorge Ruas.

Counteracting the effects of ageing

Jorge Ruas says that the new discovery has other pharmaceutical perspectives.

Muscular dysfunction is involved in the development of many diseases, and perhaps neurturin or the signalling pathways in which it is involved can correct or improve muscle function.

One of the diseases in this context may be diabetes, because well-functioning muscles have a greater potential for absorbing glucose from the blood than untrained muscles. All other things being equal, increasing glucose intake will improve diabetes.

Another option is repairing muscles injured in surgery, accidents and sports.

“Investigating ageing could also be useful. After we turn 35 years, we lose about 1% of our muscle mass per year, which eventually makes us more frail and dependent on other people. Stimulating muscle conditioning in a healthy way could counteract the negative effects of ageing,” concludes Jorge Ruas.

Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity” has been published in Cell Metabolism. I 2016, the Novo Nordisk Foundation awarded a grant to Jorge Ruas for the project Molecular Mechanisms Regulating Skeletal Muscle Function and their Systemic Impact.

Professor of Molecular Physiology and group leader for the Molecular and Cellular Exercise Physiology research group. Jorge Ruas received his Pharm.D....

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