Exercise appears to benefit people with amyotrophic lateral sclerosis (ALS) by normalizing molecular changes that occur at the junction of nerves and muscles, but by degrees that depend on the type of exercise, a study in a mouse model of ALS suggests.
While running and swimming both lessened the profound molecular changes seen in these mice, only swimming was able to slow the loss of larger motor neurons.
“Running and swimming prevent the deregulation of the BDNF/TrkB neurotrophic signalling at the neuromuscular junction in mice with amyotrophic lateral sclerosis” was published in Cellular and Molecular Life Sciences.
The neuromuscular junction (NMJ) is where nerves come into contact with muscles. The nerves deliver signals to the muscles through the junction, telling the muscles when to contract. NMJs are known to be impaired in ALS, and this is thought to be related to the loss of motor neurons in the disease – although the underlying mechanisms are still poorly understood.
A previous study using SOD1-G93A mice — a mouse model of ALS — demonstrated that one particular NMJ signaling pathway, broadly referred to as BDNF-NT4/TrkB after its main molecular players (BDNF and NT4, which are signaling molecules, and TrkB, their receptor), is abnormal in ALS even before symptoms are evident.
Moderate exercise is thought to be neuroprotective for ALS patients, but “its recommendation is still controversial, probably due to differential effects depending on exercise types, protocols and intensities,” the researchers wrote.
In this specific mouse model, a separate study showed that it improves lifespan and eases ALS symptoms.
The researchers wanted to see the “molecular” effects of two established exercise protocols: running and swimming. They assigned SOD1-G93A mice to an exercise regimen based either on running or on swimming, or to no exercise as a comparison group. Exercises started when ALS symptoms first appeared in the animals.
Running-based training “is a low-amplitude and frequency exercise that preferentially triggers slow motor units integrated by small motoneurons, and … a swimming-based training … is a high-amplitude and frequency exercise that, in addition, recruits fast motor units integrated by large motoneurons,” they wrote.
In mice without any exercise regimen, researchers found abnormally high levels of both BDNF and NT4 at neuromuscular junctions. The running exercise regimen somewhat lowered BDNF levels, and the swimming regimen decreased these levels to near those found in healthy mice. In contrast, NT4 levels were even higher in mice that exercised, regardless of the exercise type.
Changes in TrkB in these mice were also seen. There are a few different versions of TrkB and these can be further modified, but the gist of the findings for TrkB were similar to those for BDNF and NT4: each exercise regimen normalized some changes but not others, and the specific changes differed between the two regimens.
Similar findings were identified for other proteins involved in NMJ function, though the extent to which these changes are related to BDNF-NT4/TrkB signaling, or completely independent of it, remains unclear.
“[T]he two training protocols have differential influence over molecular changes of ALS to maintain the protein levels inside the control values to limit disease progression,” the researchers wrote.
“Interestingly,” they added, “the alterations that the trainings could not prevent are the ones that were already found at the presymptomatic stage.” In other words, molecular changes that occurred before the mice developed evident disease symptoms remained whether or not they exercised, but exercise did help to ease changes that came after symptom onset.
The researchers also looked at motor neurons in the mice to see whether these molecular changes translated into differences in motor neuron survival. Mice without exercise have relatively more small motor neurons than larger motor neurons — a result of dying off of the larger motor neurons.
Larger motor nerve cells innervate “faster” muscle fibers, and are “preferentially” affected by ALS, the study noted.
Mice on the running regimen had similar loses, but those in the swimming regimen had comparatively more larger neurons, indicating that this loss is prevented to some extent by the swimming exercises. “However,” the team noted, “the proportion of the biggest [motor neurons] is significantly decreased in the three groups, indicating that they are lost despite the training.”
“Altogether,” the researchers concluded, “despite the controversial opinions on physical exercise as therapy in ALS, it seems that it is always beneficial, but with precise exercise-dependent outcomes.”
More studies “would be useful as the differences among [exercise] protocols are essential to target specific molecular changes.”
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