Abstract: The recent studies on depression indicated that skeletal muscle peroxisome proliferator-activated receptor γ activating factor 1α (PGC-1α) improves tryptophan metabolism, reduces the central nervous inflammation, and increases the expression of brain-derived neurotrophic factor, thereby exerting antidepressant effects.Based on theories of integrative biology, this review describes the role of skeletal muscle PGC-1α in the antidepressant effects of exercise and the related underlying mechanisms, and proposes a research hypothesis of PGC-1α-mediated crosstalk between skeletal muscle and brain.In addition, some possible pathways of muscle-brain crosstalk are suggested for the role of exercise in the other neurodegenerative diseases.