Lack of Skeletal Muscle Serotonin Impairs Physical Performance

Abstract

Low levels of the neurotransmitter serotonin have been associated with the onset of depression. While traditional treatments include antidepressants, physical exercise has emerged as an alternative for patients with depressive disorders. Yet there remains the fundamental question of how exercise is sensed by the brain. The existence of a muscle–brain endocrine loop has been proposed: according to this scenario, exercise modulates metabolization of tryptophan into kynurenine within skeletal muscle, which in turn affects the brain, enhancing resistance to depression. But the breakdown of tryptophan into kynurenine during exercise may also alter serotonin synthesis and help limit depression. In this study, we investigated whether peripheral serotonin might play a role in muscle–brain communication permitting adaptation for endurance training. We first quantified tryptophan metabolites in the blood of 4 trained athletes before and after a long-distance trail race and correlated changes in tryptophan metabolism with physical performance. In parallel, to assess exercise capacity and endurance in trained control and peripheral serotonin–deficient mice, we used a treadmill incremental test. Peripheral serotonin–deficient mice exhibited a significant drop in physical performance despite endurance training. Brain levels of tryptophan metabolites were similar in wild-type and peripheral serotonin–deficient animals, and no products of muscle-induced tryptophan metabolism were found in the plasma or brains of peripheral serotonin–deficient mice. But mass spectrometric analyses revealed a significant decrease in levels of 5-hydroxyindoleacetic acid (5-HIAA), the main serotonin metabolite, in both the soleus and plantaris muscles, demonstrating that metabolization of tryptophan into serotonin in muscles is essential for adaptation to endurance training. In light of these findings, the breakdown of tryptophan into peripheral but not brain serotonin appears to be the rate-limiting step for muscle adaptation to endurance training. The data suggest that there is a peripheral mechanism responsible for the positive effects of exercise, and that muscles are secretory organs with autocrine-paracrine roles in which serotonin has a local effect.

Effects of Tryptophan Supplementation and Exercise on the Fate of Kynurenine Metabolites in Mice and Humans

“…In humans, those reports seem to be somewhat contradictory [ 22 , 23 ]. Recent studies suggest that skeletal muscle serotonin levels are important for exercise performance [ 24 ]. Although we did not measure peripheral or central serotonin levels, it is tempting to speculate that the TRP supplementation could have affected serotonin levels, and thus increasing wheel running activity.…”

Common Markers of Muscle Damage are Associated with Divergent Gene Expression Patterns after Eccentric Contractions

“…Yet serotonin also exists as so-called peripheral serotonin where it functions in autocrine, paracrine, and endocrine signaling, affecting a variety of organ systems and physiological functions including systemic metabolism, vascular tone, and blood clotting, energy metabolism, substrate availability, and handling (40). In skeletal muscle, there is evidence that peripheral serotonin plays a role in adaptation to endurance exercise; peripheral serotonin–deficient mice failed to acquire endurance adaptations despite training (41). Moreover, this study found that skeletal muscle-derived peripheral serotonin was required to acquire adaptations to endurance exercise.…”

Is the anti-aging effect of ACE2 due to its role in the renin-angiotensin system?—Findings from a comparison of the aging phenotypes of ACE2-deficient, Tsukuba hypertensive, and Mas-deficient mice—

“…The major metabolic pathways for tryptophan include the kynurenine pathway, the serotonin pathway, and the indole pathway involving the gut microbiota. Serotonin in the brain and blood is known to be decreased in ACE2 KO mice, while peripheral serotonin has been reported to be important for muscle adaptation to endurance training [ 77 ]. There are a number of previous reports on its relationship to aging that support the possibility that tryptophan and its metabolites may contribute to the regulation of aging [ 78 ].…”