Increasing the levels of brain-derived neurotrophic factor (BDNF) — a molecule involved in the communication between nerve cells and muscle — specifically in muscle delayed symptom onset and slowed disease progression in a mouse model of spinal and bulbar muscular atrophy (SBMA), a study has found.
BDNF’s benefits differed between muscle fiber types, data showed. The molecule was also the only protein of its family of neurotrophic factors to be altered in SBMA patients, suggesting that it may be a potential therapeutic target for this condition.
While loss of motor neurons — specialized nerve cells that control skeletal, or voluntary, muscle movements — is a hallmark of the disease, increasing evidence suggests that muscle damage plays a major role, supporting the development of muscle-targeted therapies for SBMA.
A previous study has shown that the levels of BDNF — a key factor for the function and communication between motor neurons and muscles — were markedly reduced in skeletal muscles of two mouse models of SBMA (called “97Q” and “myogenic”) and associated with a loss in motor function.
These findings suggested that a muscle-specific deficiency in BDNF may underlie or contribute to motor dysfunction in SBMA.
Now, researchers at Michigan State University, along with colleagues in Japan, set out to assess whether increasing BDNF levels specifically in skeletal muscle would result in therapeutic benefits in the 97Q mouse model.
The results showed that promoting higher muscle levels of BDNF delayed disease onset and slowed disease progression by twofold in these mice, compared with normal SBMA mice. This was assessed through the validated hang test, which measures how long mice can hold their bodyweight using an overhanging bar.
Improvements in several key cellular and molecular mechanisms regulating neuromuscular function were also observed in mice with higher BDNF levels.
Notably, these benefits differed between the two types of skeletal muscle fibers: slow-twitch, which support endurance activities, and fast-twitch, which support quick, powerful movements.
Increasing BDNF levels in SBMA mice significantly increased nerve-muscle communication only in slow-twitch muscle, while significantly improving muscle contractile strength in fast-twitch fibers only.
These findings helped to pinpoint the molecular targets that both underlie motor dysfunction and respond to BDNF therapy in SBMA. They show that the disease “unfolds differently in fast- versus slow-twitch muscle fibers, and may require distinct therapeutic agents,” the researchers wrote.
In addition, and contrary to expectation, the team found that the levels of BDNF (but not other members of the neurotrophin family) were significantly increased in skeletal muscle samples from SBMA patients.
The same increase was observed in a mouse model with milder disease that may more closely resemble what happens in patients.
The researchers hypothesized that raising the production of BDNF may be an early compensatory mechanism to improve neuromuscular function in the presence of SBMA that later disappears, explaining the drop in BDNF levels in the more severe 97Q mouse model.
“Our data suggests that a secondary effect of disease is to impair the very mechanisms that are augmented to combat disease,” the researchers wrote, arguing that “boosting nature’s own mechanism of selfheal” may improve motor function in people with SBMA.
These researchers report “important findings suggesting for the first time that muscle BDNF may delay disease onset and endpoint in the 97Q mouse model of [Kennedy’s disease],” a team of other researchers in Canada wrote in the same journal.
Further studies are needed to confirm these findings, including whether BDNF is the only neurotrophin dysregulated in SBMA patients, its potential therapeutic benefits, and the tissues to target for optimal benefit.