Scientists have created a genetically engineered mouse that runs twice as long on a treadmill as normal mice after inserting a gene that increases the amount of choline transporter in nerve terminals. The higher level of transporter raises the availability of acetylcholine at neuromuscular junctions, the chemical messenger that drives muscle contraction, and the result is markedly improved endurance in these mice.
By boosting the choline transporter protein, the engineered animals take up more choline — the precursor needed to make acetylcholine — so more neurotransmitter is available for repeated nerve-to-muscle signaling. That stronger, sustained cholinergic signaling appears to reduce the nerve-dependent fatigue that limits continued muscle activity.
These findings could inform new approaches to treating a variety of disorders involving cholinergic dysfunction. Conditions that may benefit from therapies that enhance choline transporter activity include myasthenia gravis, muscular dystrophy, congestive heart failure, depression, schizophrenia, Alzheimer’s disease and attention-deficit hyperactivity disorder (ADHD), among other illnesses that rely on acetylcholine signaling. Further details about this “marathon mouse” research are summarized below.
Boosting supply of key brain chemical reduces fatigue in mice
Vanderbilt study could lead to new treatments for neuromuscular diseases
Researchers at Vanderbilt University engineered mice to overexpress the choline transporter at the neuromuscular junction, the critical site where motor nerves communicate with muscle fibers. The altered mice ran on a treadmill twice as long as control animals, a striking demonstration that increasing presynaptic choline uptake can enhance sustained muscle performance.
The study, reported in the journal Neuroscience, was led by Randy Blakely, Ph.D., director of the Vanderbilt Center for Molecular Neuroscience. Blakely and colleagues reasoned that increasing the amount of the choline transporter — the protein responsible for recycling choline into nerve terminals so it can be converted into acetylcholine — should boost the nerve terminal’s capacity to maintain transmitter release during repeated activation.
Acetylcholine is the neurotransmitter that initiates and maintains muscle contractions, including those that control essential functions such as breathing. When cholinergic signaling is compromised, muscles tire more quickly and their ability to respond to continued nerve stimulation is reduced. By raising transporter levels, the researchers found they could prolong neuromuscular signaling and delay fatigue in behaving animals.
Previous experimental approaches to increasing strength and endurance have focused on the muscle itself — for example, by modifying myostatin, a regulator of muscle growth. The Vanderbilt study differs by targeting the nerve-muscle interface: rather than enlarging muscle mass, it enhances the nerve’s ability to supply the chemical signals that sustain contraction. In that sense, the work illustrates a novel way to increase “neural endurance.”
Blakely suggests that drugs designed to enhance choline transporter function might offer a new therapeutic avenue for disorders characterized by deficient cholinergic transmission. Because acetylcholine plays diverse roles across the nervous system — from sustaining attention to regulating autonomic and motor functions — pharmacological modulation of choline uptake could have broad clinical relevance.
Notably, Blakely and his team previously reported a genetic variation in the choline transporter that is associated with the combined type of ADHD, a form of the disorder that includes both inattention and hyperactivity/impulsivity. That human genetic link, together with the current mouse model results, supports further exploration of choline transporter–targeted strategies for neuropsychiatric and neuromuscular conditions.
Notes about the research:
The study was supported by the National Institutes of Health (NIH). With NIH funding, the Vanderbilt team is developing compounds that target the choline transporter as potential leads for new medications addressing neuromuscular and central nervous system disorders.
Contributors to the current paper included David Lund, Alicia Ruggiero, Ph.D., Jan Wright, Brett English, Pharm.D., Ph.D., Peter Reisz, Sarah Whitaker and Amanda Peltier, M.D., all from Vanderbilt, and Shawn Ferguson, Ph.D., now at Yale University. The research reported in Neuroscience represents a collaborative effort to translate molecular insights about cholinergic signaling into possible therapeutic directions.
Contact: Bill Snyder – Vanderbilt University Medical Center
Source: Vanderbilt University Medical Center