Summary: Neurturin, a muscle-produced protein, improves muscular metabolism, motor coordination, and exercise performance in mouse models. The discovery could have implications for treating ALS and other disorders associated with neurological disorders that affect muscles.
Source: Karolinska Institute
Researchers at Karolinska Institutet in Sweden have identified a protein that improves muscular metabolism, motor coordination and exercise performance in mice. The findings, published in Cell Metabolism, could be of therapeutic value for patients with muscle and neurological diseases, such as ALS.
Muscle health is a major determinant of overall health and the best way to keep muscles healthy is to exercise regularly. However, for some patients with debilitating diseases, exercise is not always possible. For that reason, researchers are looking for molecules that can by themselves bring about some of the benefits of physical exercise.
In the current study, researchers at Karolinska Institutet wanted to know how a muscle-produced protein called neurturin affects neuromuscular function. Understanding what signals mediate motor neuron and muscle communication is essential for exploring new treatments for muscle-related and neurological diseases, such as amyotrophic lateral sclerosis (ALS).
“We wanted to know if muscles can talk back to motor neurons by sending their own messages, and to find out what are the consequences of those signals,” says Jorge Ruas, professor at the Department of Physiology and Pharmacology, Karolinska Institutet, and corresponding author.
The researchers found that mice that were genetically modified to produce more neurturin in muscle cells significantly improved their muscle metabolism, exercise performance and motor coordination compared to regular mice. The high neurturin mice also had an increased number of motor neurons of a type that is more resistant to degeneration in diseases like ALS.
“To find out that a molecule released from muscle fibres can actually change motor neuron identity, shifting them to a type that is associated with more resistance to degeneration opens really exciting possibilities for the future,” Jorge Ruas adds.
As a next step, the researchers are hoping to explore the therapeutic possibilities of neurturin in mouse models of type 2 diabetes, obesity and ALS. They are also working on modifying the administration of neurturin to allow it to be used as a potential drug.
“There’s much to be done, but we believe this could be of therapeutic value for patients with metabolic and neuromuscular diseases, such as type 2 diabetes and ALS,” says the study’s first author Jorge Correia, researcher at the Department of Physiology and Pharmacology, Karolinska Institutet.
The researchers note there were some limitations to the study, including the use of genetic tools and viral vectors to increase the levels of neurturin, which isn’t directly applicable from a therapeutic standpoint.
This study was financed by the Swedish Research Council, the Novo Nordisk Foundation, the Swedish Diabetes Foundation, the Strategic Research Program (SRP) in Diabetes, and The Lars Hiertas Memorial Foundation. Sandra Kleiner, Michael Stec and Naveen Khan are employees and shareholders of Regeneron Pharmaceuticals, Inc. Jorge Lira Ruas is a consultant for Bayer AG. There are no other reported conflicts of interest.
NRTN improves systemic metabolism, exercise performance, and motor coordination
Endurance exercise promotes skeletal muscle vascularization, oxidative metabolism, fiber-type switching, and neuromuscular junction integrity. Importantly, the metabolic and contractile properties of the muscle fiber must be coupled to the identity of the innervating motor neuron (MN).
Here, we show that muscle-derived neurturin (NRTN) acts on muscle fibers and MNs to couple their characteristics.
Using a muscle-specific NRTN transgenic mouse (HSA-NRTN) and RNA sequencing of MN somas, we observed that retrograde NRTN signaling promotes a shift toward a slow MN identity. In muscle, NRTN increased capillary density and oxidative capacity and induced a transcriptional reprograming favoring fatty acid metabolism over glycolysis. This combination of effects on muscle and MNs makes HSA-NRTN mice lean with remarkable exercise performance and motor coordination. Interestingly, HSA-NRTN mice largely recapitulate the phenotype of mice with muscle-specific expression of its upstream regulator PGC-1ɑ1.
This work identifies NRTN as a myokine that couples muscle oxidative capacity to slow MN identity.