Boosting key brain chemical cuts fatigue in mice

Scientists have ‘engineered’ a mouse that can run on a treadmill twice as long as a normal mouse by increasing its supply of acetylcholine, the neurotransmitter essential for muscle contraction.

The finding could lead to new treatments for neuromuscular disorders such as myasthenia gravis, which occurs when cholinergic nerve signals fail to reach the muscles, said Randy Blakely, director of the Vanderbilt Center for Molecular Neuroscience.

Blakely and his colleagues inserted a gene into mice that increased the production of a protein called the choline transporter at the neuromuscular junction.

The choline transporter is vital to the capacity for muscle contraction, including the ability to breathe, because it regulates the supply of choline, the precursor to acetylcholine.

“We reasoned that giving more of this protein might enhance muscle function and reduce nerve-dependent fatigue,” said Blakely.

Other researchers have manipulated the gene for the muscle tissue growth factor myostatin to produce animals with greater strength and endurance, but Blakely said this might be the first time ‘neural endurance’ was enhanced by manipulating the nerves that innervate muscle.

Drugs that increase choline transporter activity could represent a novel therapeutic strategy for myasthenia gravis and a wide range of other disorders that involve cholinergic signaling deficits, said Blakely.

These disorders include muscular dystrophy, congestive heart failure, depression, schizophrenia, Alzheimer's disease and attention-deficit hyperactivity disorder (ADHD).

“The brain uses acetylcholine for a wide variety of functions, including the ability to sustain attention,” said Blakely.

Last year, Blakely and his colleagues reported that a variation in the choline transporter gene is associated with the ‘combined’ type of ADHD, which is characterized by both inattention and hyperactivity/impulsivity.

The finding is published in the journal Neuroscience.