Mechanisms of inter-organ crosstalk mediated by tryptophan metabolism

Abstract

Physical exercise and nutrition balance the “energy in-energy out” equilibrium that keeps the system at a dynamic homeostasis, energetically speaking. However, this is a simplistic vision of a dynamic system that is in a constant fine-tuning of all of its parts. Physical exercise benefits for metabolic health go beyond its “energy out” role: it modulates whole body metabolism, insulin sensitivity and induces favorable remodeling in other tissues through secreted factors. Old age and disease negatively impact muscle mass, which in turn has negative consequences on long-term health and quality of life. In the same fashion, nutrition goes beyond “energy in”. Many nutrients’ role goes beyond supplying energy or becoming building blocks for cells – they can also contribute as signaling molecules, and/or can be metabolized to bioactives. Such is the case for tryptophan (TRP). TRP is an essential amino-acid and is also the precursor for the neurotransmitters serotonin and melatonin. The majority of TRP is metabolized through the kynurenine pathway of TRP degradation (KP). Some KP intermediaries have been linked to inflammation, neuroinflammation, cancer, immune evasion, depression and other neurological diseases. Other intermediaries have been linked to improved energy metabolism, neuroprotection, immune-regulation, and fat depot browning. Interestingly, endurance physical exercise has been shown to tilt the metabolism of the KP towards the protective branch.

In paper I, we investigated if excess TRP supplementation in diet has an effect in physiology and behavior in a rodent model, and if access to a running wheel influenced the observations. All mice in TRP diet had increased KP metabolites in circulation, but access to a wheel ameliorated the load of most metabolites. Comparing the “+wheel” groups, mice with the TRP supplementation run more, but show no further muscle adaptations to exercise when compared to control-fed mice. Mice also displayed no difference in behavior tests nor brain gene expression markers when compared to the sedentary groups (without wheels). TRP metabolites had short half-life in circulation, returning to normal values 4 hours after the inactivity period started. Our results suggest that the increased TRP dosage supplemented in diet, without further inflammatory stimuli, is still within the body´s capacity of metabolization.

In paper II, we measured the KP metabolites in stroke patients in the early rehabilitation phase. KP is dysregulated immediately after stroke, but its long-term behavior and effects on outcome are unknown. We observed that in ischemic stroke, most metabolites of the pathway show a tendency to slowly decline over the primary rehabilitation phase. The pathway is thus still active and recovering, and this may influence response to therapy. In a small subgroup of patients suffering from hemorrhagic stroke, we observed the opposite behavior in the metabolites, i.e. they were slowly increasing. This indicates that ischemic and hemorrhagic stroke are not only different in entomology but also in recovery, which suggests different therapeutic approaches may be necessary for optimal recovery.

In paper III, we investigated the role of LMCD1 in skeletal muscle by ectopically expressing LMCD1 in mice with an intramuscular injection of adenovirus. LMCD1 improved force and resistance to fatigue with less calcium requirements, indicating improved calcium signaling. This event is dependent on calcineurin and that the LMCD1-calcineurin induces repression of myoregulin, an inhibitor of SERCA. LMCD1 also increases markers of muscle mass like IGF- 1 and PGC-1α4, and pathway activity related to muscle mass of mTOR and MAPK.