In general, the term ‘fatigue’ is used to describe any exercise-induced decline in the ability of a muscle to generate force. To identify the causes of fatigue, it is common to examine two divisions of the body that might be affected during exercise. The central component of fatigue includes the many nerves that travel throughout the brain to the spinal cord. The peripheral component predominantly reflects elements in the muscle itself. If there is a problem with either of these components, the ability to contract a muscle might be compromised. For many years, there has been suggestion that central fatigue is heavily influenced by neurotransmitters that get released in the central nervous system (such as dopamine and serotonin). However, little research has been performed in this area.
Serotonin is a chemical that can improve mood, and increasing the amount of serotonin that circulates in the brain is a common therapy for depression. However, serotonin also plays a vital role in activating neurons in the spinal cord which tell the muscle to contract. With the correct amount of serotonin release, a muscle will activate efficiently. However, if too much serotonin is released, there is a possibility that the muscle will rapidly fatigue. Recent animal studies indicate that moderate amounts of serotonin release, which are common during exercise, can promote muscle contractions (Cotel et al. 2013). However, massive serotonin release, which may occur with very large bouts of exercise, could further exacerbate the already fatigued muscle (Perrier et al. 2018).
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. These medications keep serotonin levels high in the central nervous system by stopping the chemical from being reabsorbed by nerves (reuptake inhibition). Instead of using SSRIs to relieve symptoms of depression, we used them in our recent study (Kavanagh et al. 2019) to elevate serotonin in the central nervous system, and then determine if characteristics of fatigue are enhanced when serotonin is elevated. We performed three experiments that used maximal voluntary contractions of the biceps muscle to cause fatigue in healthy young individuals. Our main goal was to determine if excessive serotonin limits the amount of exercise that can be performed, and then determine which central or peripheral component was compromised by excessive serotonin.
WHAT DID WE FIND?
Given that SSRIs influence neurotransmitters in the central nervous system, it was not surprising that peripheral fatigue was unaltered by the medication. However, central fatigue was influenced with enhanced serotonin. The time that a maximum voluntary contraction could be held was reduced with enhanced serotonin, whereby the ability of the central nervous system to drive the muscle was compromised by 2-5%. We further explored the location of dysfunction and found that the neurons in the spinal cord that activate the muscle were 4-18% less excitable when fatiguing contractions were performed in the presence of enhanced serotonin.
SIGNIFICANCE AND IMPLICATIONS
The central nervous system is diverse, and the fatigue that is experienced during exercise is not just restricted to the brain. Instead, the spinal cord plays an integral role in activating muscles, and mechanisms of fatigue also occur in these lower, often overlooked, neural circuits. This is the first study to provide evidence that serotonin released onto the motoneurones contributes to central fatigue in humans.
Kavanagh JJ, McFarland AJ, Taylor JL. Enhanced availability of serotonin increases activation of unfatigued muscle but exacerbates central fatigue during prolonged sustained contractions. J Physiol. 597:319-332, 2019.
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Cotel F, Exley R, Cragg SJ, Perrier JF. Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation. Proc Natl Acad Sci U S A. 110:4774-4779, 2013.
Perrier JF, Rasmussen HB, Jørgensen LK, Berg RW. Intense activity of the raphe spinal pathway depresses motor activity via a serotonin dependent mechanism. Front Neural Circuits. 11:111, 2018.
Associate Professor Justin Kavanagh is a researcher and lecturer at Griffith University. His team explores how the central nervous system controls voluntary and involuntary movement, and he has particular interests in understanding how medications can be used to study mechanisms of human movement.