Muscle over mind

Abstract

Depression is associated with elevated kynurenine levels, a tryptophan metabolite generated under stress and inflammatory conditions. Agudelo et al. (2014) now reveal how PGC-1α1 overexpression in muscle mimics anti-depressant effects of exercise by promoting kynurenine aminotransferase expression, likely preventing kynurenine from crossing the blood brain barrier to disrupt neural plasticity.

Figure 1

Schematic of the Role of Muscle-Specific (mck)-PGC-1α1 Overexpression in a Mouse Model of Depression Caused by Chronic Mild Stress (A) Plasma kynurenine (KYN) levels are elevated by chronic mild stress (top) in wild-type (WT) mice. KYN crosses the blood-brain barrier (middle panel) and reduces neuronal plasticity by increasing neuro-inflammation (bottom)—and, in turn, causes depression-like behaviors. (B) Activation of the skeletal muscle AMPK - PGC-1α1 pathway influences secretion of proteins involved in muscle adaptation. Agudelo et al. show that mck-PGC-1α1 mice are protected from exhibiting depressive-like behavior induced by chronic mild stress through upregulation of the PPARα/δ-KAT-Kynurenine pathway. (C) The discovery of a novel paracrine mechanism mediating communication between skeletal muscle and brain may provide insight into the beneficial effects of exercise on cognition and mood. Future studies may lead to identification of key molecules for brain function, induced by muscle PGC-1α1 overexpression or AMPK activation during exercise.