Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression

Abstract

Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

Exercise and the microbiota

“…Increased expression of muscle-specific PGC-1a1 in transgenic mice is associated with greater resilience to chronic stress and stress-induced CNS inflammation. 50 Thus, there are several points at which exercise biology and accompanying dietary adjustments may interact directly or indirectly with host-microbe interactions in the gut (Figure 1).…”

A randomized clinical trial investigating the efficacy of targeted nutrition as adjunct to exercise training in COPD

“…Alternatively, a positive effect of n‐3 fatty acid enriched protein‐dense supplements could be implicated as in cachectic patients with pancreatic cancer n‐3 FA supplementation also increased physical activity level assessed by doubly labelled water independent of muscle mass 24. Next to exercise, n‐3 FA additionally stimulate the PGC‐1α‐PPARα/δ pathway in muscle resulting not only in enhanced muscle (fat) oxidative metabolism25 and decreased muscle fatigue, but also in enhanced conversion of peripheral kynurenine into kynurenic acid, which is unable to cross the blood–brain barrier 26. Reducing plasma kynurenine protects the brain by mediating resilience to stress induced depression.…”

Altered Microbiota Composition Mediates Depressive Behavior During Chronic Stress

“…Moreover, our data suggest that the production of H2O2 by Lactobacillus may be protective against the development of despair behavior by direct inhibition of IDO1 expression and decrease in the circulating level of kynurenine, a metabolite associated with depressive behavior (Fig. 11) 84,[172][173][174] .…”

“…7e). Evidence of dysregulation of this pathway in depressed patients, as well as its recently described role in the initiation of despair behaviors 84 , have made the tryptophankynurenine pathway particularly compelling as part of the potential mechanism mediating the microbiome effects on behavior. Intriguingly, a recent study 166 showed that Lactobacillus can directly modulate kynurenine metabolism, by inhibiting the pathway initiating enzyme IDO1 via production of reactive oxygen species (i.e.…”

“…In addition, factors such as exercise and metabolism have recently been receiving a lot of attention for the roles they might play in modulating depressive symptoms [84][85][86][87] . Exercise has been shown to have many beneficial effects for depression outcomes in patients, with pre-clinical studies indicating that exercise can improve many aspects of physiology, from metabolism to adult neurogenesis 84,88,89 . On the other hand, in a nutrition and obesity-conscious society, nutritional imbalances are increasingly suspected of mediating or modulating depressive behaviors [85][86][87]90 .…”