Oct. 10, 2023
In this Q&A, Nathan J. Hellyer, Ph.D., P.T., shares insights into the basic mechanisms regulating neuromuscular processes. Dr. Hellyer is a researcher and educator at Mayo Clinic's campus in Rochester, Minnesota.
What elements are involved with human movement?
The human movement system comprises not just nerve and muscle but also other systems. If we just concentrate on the musculoskeletal nervous systems, a motor unit is a single motor neuron and the muscle fibers that it enervates. Muscle fibers within a unit are size-matched to their motor neurons. The various motor units then are regulated by recruitment and rate coding, which dictates which motor units contract and in what sequence.
We also know that movement requires an orderly recruitment of muscle fibers. Smaller, lower force-generating muscle fibers are recruited first, followed by larger, higher force-generating muscle fibers. Interestingly, the fibers that are used the most are often the smallest, and these are usually more resistant to fatigue due to mechanical and biochemical properties. And the muscles that are used the least and that have the least activity are the largest fibers. These fibers are generally more prone to fatigue.
How does aging factor into this process of muscle recruitment?
Sarcopenia is an age-related reduction in muscle mass and function. Alongside, we also see a decline in motor neurons as people age. With aging, we see patterns that look like denervation of skeletal muscle. And these patterns of denervation share similarities to what we see in many neuromuscular pathologies.
When we think about aging and pathology, the larger muscle fibers seem to be more susceptible to age-related changes than do the smaller muscle fibers. Endurance training primarily recruits the smaller fibers. Resistance training recruits larger fibers. Often, for our patients, we're training muscle to generate both strength and endurance. However, we must be very specific in prescribing exercise to our patients. If we want to improve strength and power, we must target the larger fibers. Strength and power are necessary to get out of a chair and to climb stairs.
What else do we need to understand about muscle recruitment?
Smaller muscle fibers are connected to smaller motor neurons. And larger motor neurons connect with larger muscle fibers. This match has been heavily studied and it's been attributed to perhaps some genetic programming activity or activation patterns, including neuronal-derived influence and muscle-derived trophic influences. And in addition to signals that trigger muscle contractions, there's communication going back and forth between the two, not only during development but throughout the life span.
What is neuregulin and how does it and other trophic factors influence motor units?
Neuregulin, abbreviated NRG-1, is a molecule that's expressed throughout the body, but it's highly expressed in motor neurons. It's released at the synaptic terminals of motor neurons and binds to a class of proteins called ErbB receptors.
We believe that neuregulin may positively influence protein balance by binding to ErbB receptors on skeletal muscle. When this happens, there are phosphorylation events intracellularly, and the receptor recruits an enzyme called PI3 kinase, which goes on to phosphorylate and recruit a protein called AKT. AKT is a known driver of protein synthesis and an inhibitor of protein degradation. When we denervate muscle, we may be cutting off neuregulin and therefore blocking this pathway that would facilitate the suppression of protein degradation. If we take away all growth factors, protein degradation does go up. These observations suggest that neuregulin binds to the receptor, activates PI3 kinase, activates AKT and increases protein synthesis.
Another molecule of interest is a protein called FOXO. AKT inhibits FOXO, and in doing so it can inhibit protein degradation. Administering intrapleural neuregulin to a denervated rat diaphragm for a week will attenuate FOXO expression and activity.
So through animal studies, we have observed that neuregulin increases muscle protein synthesis, decreases muscle protein degradation and restores the FOXO suppression in a denervated muscle.
Are there other processes that could potentially mediate the effects of aging on muscle?
Autophagy is a cellular process that aids in protein degradation and recycling. And we know that as aging occurs, autophagy can become impaired, possibly due to a decline in trophic factor signaling.
We know that there are targeted proteins that are fed into autophagocytic vacuoles. As vacuoles merge with lysosomes, faulty proteins are degraded. The process is quite complex, and more research is needed to determine if it's an outcome of aging or whether it's driving the aging process.
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