Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden.
Department of Physiology and Pharmacology, Molecular and Cellular Exercise Physiology, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden.
Cell. 2014 Sep 25;159(1):33-45. doi: 10.1016/j.cell.2014.07.051.
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.
抑郁症是一种使人虚弱的疾病，对全世界数百万人的生活质量产生了深远的影响。体育锻炼被用作许多患者的治疗策略，但它的有益效果的机制仍不清楚。在这里，我们描述了运动训练诱导的骨骼肌 PGC-1α1 通过改变犬尿氨酸代谢来保护机体免受应激诱导的抑郁症的机制。PGC-1α1-PPARα/δ 通路的激活增加了骨骼肌中犬尿氨酸氨基转移酶的表达，从而增强了犬尿氨酸转化为犬尿氨酸酸的过程，犬尿氨酸酸是一种不能穿过血脑屏障的代谢物。减少血浆犬尿氨酸可保护大脑免受与抑郁症相关的应激诱导变化，并使骨骼肌特异性 PGC-1α1 转基因小鼠对慢性轻度应激或直接犬尿氨酸给药引起的抑郁症产生抗性。这项研究为通过靶向骨骼肌中的 PGC-1α1-PPAR 轴来治疗抑郁症开辟了治疗途径，而无需穿过血脑屏障。
