Exercise Helps to Slow Motor Neuron Loss in ALS, Study Suggests, But Type of Activity May Be Key

Exercise Helps to Slow Motor Neuron Loss in ALS, Study Suggests, But Type of Activity May Be Key

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.”

Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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Inês Martins holds a BSc in Cell and Molecular Biology from Universidade Nova de Lisboa and is currently finishing her PhD in Biomedical Sciences at Universidade de Lisboa. Her work has been focused on blood vessels and their role in both hematopoiesis and cancer development.
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Marisa holds an MS in Cellular and Molecular Pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. She specializes in cancer biology, immunology, and genetics. Marisa began working with BioNews in 2018, and has written about science and health for SelfHacked and the Genetics Society of America. She also writes/composes musicals and coaches the University of Pittsburgh fencing club.
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5 comments

  1. How many with Als can run? Give us that is helpful. I agree aquatic therapy is beneficial as I improved during the time I was doing it. But I took my doctor and surgeon’s advice and had a feeding tube. during
    the time I was healing, my heALTH DECLINED. Now 8 mos later I am still eating regular food and gaining weight but it is a hassel to deal with feeding tube and extra expense for waterproof pads plus the risk of infection so I stopped aquatic therapy. I have decline more. I feel I would be healthier if I used my instinct and avoided the feeding tube. With all this money why can’t WE bE ADVISED WHAT EXERCISE TO DO tIME IS RUNNING OUT FOR PATIENTS

  2. Dagmar Munn says:

    Several pALS asked me about this article, thinking this was a recommendation of swimming for those with ALS. But having read through the actual study, I now understand the premise and results. Unfortunately, the author of the article added to everyone’s confusion ☹ So, let’s unpack this issue:

    1.There is no controversy regarding the benefits of exercise for pALS. Ten years of published research (on human pALS, not mice) exist. ALS News Today has this page: https://alsnewstoday.com/als-and-exercise/ and, I wrote about it last year: https://alsnewstoday.com/2017/07/18/als-and-exercise-webinar-gives-a-resounding-thumbs-up/ And here is the link to the webinar that reviewed 10 years of research: https://www.neals.org/for-people-with-als-caregivers/educational-webinars/exercise-and-als-a-discussion-of-research-and-practical-recommendations

    2. Don’t get hung up on the “running vs. swimming” concept. This wasn’t a study comparing exercise modalities, rather “fast vs. slow” neurons. Mice cannot do Tai Chi (slow twitch/neuron) or bicycle (fast twitch/neuron); only swim, run or hang on a metal rod (mainly used for strength studies!). So, the running for mice represented human biking, dancing, jumping, etc. – focusing on small (or fast twitch muscle fibers) neurons.

    3. The results showed that exercise stimulated the cell walls and prevented motor neuron death. It could not restore motor neurons lost pre-diagnosis (pre-symptomatic), but was beneficial for keeping alive what motor neurons we have left.

    This is why I am such a proponent of DAILY moderate & varied exercise movements. Our muscles need the constant stimulation. As for the constant question of “but what type of exercise?” The webinar I linked above goes in-depth on this issue. In a nutshell:

    “These guidelines stress individualized programming and are intended for early stage ALS. The ACSM (American College of Sports Medicine) guidelines recommend aerobic exercise 3 times a week for up to 30 minutes at an intensity of 50–80% of their age predicted peak heart rate. Strength training should be done on non-aerobic days at a low to moderate intensity with a load that allows 8–12 repetitions for 1–2 sets in good form. Flexibility exercises are recommended to be performed 1–2 times every day.”

    Quoted from: Dal Bello-Haas V, Krivickas LS, American College of Sports Medicine. Amyotrophic Lateral Sclerosis. 3rd ed In: Durstine JL, of Sports Medicine AC, et al., editors. ACSM’s exercise management for persons with chronic diseases and disabilities, Ch 44. Champaign: Human Kinetics: 2009. p. 419–26.

    Note that these guidelines were published in 2009!

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