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

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 (PPARGC1A)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.