Longevity Briefs: A New Way To Reverse Muscle Weakness In Old Age

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Sarcopenia is the age-related decline in muscle mass and strength and is a major cause of falls, fractures and even death in old age. But why do our muscles become weaker with age? Most research focusses on changes within muscle tissue itself, such as the deterioration of satellite cells – the stem cells responsible for repairing damaged muscle tissue. Yet research increasingly points towards another important contributor to muscle strength – the neuromuscular junction, or NMJ for short. This is the site where a motor neuron (nerve) connects to the muscle tissue – when an electrical signal from the brain reaches the NMJ, a neurotransmitter called acetylcholine (ACh) is released from the nerve terminal. Acetylcholine binds to receptors on the surface of muscle cells, triggering another electrical signal that results in muscle contraction.

Researchers believe that this neuromuscular transmission process may become disrupted with age. Studies in old mice have shown that electrically stimulating the nerve fibres produces a weaker muscle contraction than stimulating muscle tissue directly, and that this ‘transmission failure’ worsens in older age. However, this technique has never been used to study NMJ transmission in humans, and the exact mechanisms behind transmission failure are not fully understood. In this study, researchers not only provide direct evidence that transmission failure does occur in humans, but also identify an underlying mechanism (at least in rodents) and show that targeting that mechanism can reverse muscle weakness.

The discovery:

Researchers started by using direct nerve stimulation to measure NMJ transmission in 10 participants with a mean (average) age of 85.9, comparing them to a comparison group of 8 participants with a mean age of 29.5. Just as in previous rodent experiments, older adults had impaired NMJ transmission compared to younger people, including higher rates of ‘blocking’ – that is to say, when stimulating the nerve failed to produce an electrical signal in the muscle, indicating a complete transmission failure.

Next, researchers investigated the mechanism behind this impaired transmission. The muscle side of the NMJ contains a particularly high density of a voltage-gated sodium channel called Na_v1.4. This is a protein channel that opens in response to the initial electrical signal triggered by acetylcholine, allowing positive sodium ions to flood into the muscle cell and trigger a stronger electrical signal. Essentially, the elevated presence of Na_v1.4 at the neuromuscular junction amplifies the initial, smaller electrical signal and helps to ensure reliable NMJ transmission. Researchers hypothesised that the decline in NMJ transmission with age might be a result of a loss of Na_v1.4 at the neuromuscular junction. Measurements using staining techniques and measurements of gene expression confirmed this to be the case in mouse, rat and human cells alike. Furthermore, treating adult rats with a toxin that blocked Na_v1.4 reproduced the impaired transmission observed in older animals.

With evidence now pointing to loss of Na_v1.4 as an important contributor to impaired transmission, the next step was to see if this knowledge could be used to restore transmission. To do this, researchers chose to target a different channel called CLC-1. This channel allows negative chloride ions to leak into the muscle cell during the electrical signal, which helps to restore the resting electrical state of the muscle after contraction. CLC-1 channels are the main negative regulators of muscle excitability, and blocking them with drugs has been shown to enhance muscle contraction force in diseases that affect the NMJ. Researchers treated twelve 22 month-old rats (roughly ‘equivalent’ to humans in their 60s) with a CLC-1 inhibitor called NMD1226. They found that muscle contractions produced by nerve stimulation were on average 14% stronger than in untreated old rats. Compared to young rats, NMD1226 restored around 50% of the contraction force that was lost during ageing.

Finally, a separate experiment was conducted to test the effects of NMD1226 on voluntary muscle contraction. Grip strength was measured in nine 20 month-old rats, 5 of which were treated with NMD1226 for 7 days while the remaining 4 were given a control treatment. The grip strength of the treated mice increased significantly during the treatment period, but quickly dropped back down to the level of the control mice by day 8 after treatment had ended.

The implications:

This study provides clear evidence that NMJ transmission is indeed impaired in older humans with muscle weakness, and also showed that ageing is accompanied by a decline in Na_v1.4 channel density on the muscular side of the NMJ. This offers a potential mechanistic explanation for how transmission fails. Perhaps most importantly, they show that blocking CLC-1 (the main channel that dampens muscle excitation) can significantly improve muscle strength in ageing rats.

Since there is already clinical evidence suggesting that CLC-1 inhibition can improve muscle strength in people with certain neuromuscular disorders, there is reason to be optimistic that it might also work for age-related muscle loss, but this has yet to be tested in humans. If you want to preserve NMJ function, research suggest that regular physical exercise helps to maintain NMJ integrity in old age.