Targeting the DP2 receptor alleviates muscle atrophy and diet‐induced obesity in mice through oxidative myofiber transition

作者：Huying Ning, Huiwen Ren, Yan Zhao, HaiFang Yin, Zhenji Gan, Yujun Shen, Ying Yu · 发表于：Journal of Cachexia Sarcopenia and Muscle · 年份：2022 · DOI：10.1002/jcsm.13136 · 被引用次数：16 · 研究领域：Muscle Physiology and Disorders、Adipose Tissue and Metabolism、Signaling Pathways in Disease

Abstract Background Mammalian skeletal muscles consist of two main fibre types: slow‐twitch (type I, oxidative) and fast‐twitch (type IIa, fast oxidative; type IIb/IIx, fast glycolytic). Muscle fibre composition switch is closely associated with chronic diseases such as muscle atrophy, obesity, type II diabetes and athletic performance. Prostaglandin D 2 (PGD 2 ) is a bioactive lipid derived from arachidonic acid that aggravates muscle damage and wasting during muscle atrophy. This study aimed to investigate the precise mechanisms underlying PGD 2 ‐mediated muscle homeostasis and myogenesis. Methods Skeletal muscle‐specific PGD 2 receptor DP2‐deficient mice (DP2 fl/fl HSA Cre ) and their littermate controls (DP2 fl/fl ) were subjected to exhaustive exercise and fed a high‐fat diet (HFD). X‐linked muscular dystrophy (MDX) mice and HFD‐challenged mice were treated with the selective DP2 inhibitor CAY10471. Exercise tolerance, body weight, glycometabolism and skeletal muscle fibre composition were measured to determine the role of the skeletal muscle PGD 2 /DP2 signalling axis in obesity and muscle disorders. Multiple genetic and pharmacological approaches were also used to investigate the intracellular signalling cascades underlying the PGD 2 /DP2‐mediated skeletal muscle fibre transition. Results PGD 2 generation and DP2 expression were significantly upregulated in the hindlimb muscles of HFD‐fed mice ( P < 0.05 or P < 0.01 vs. normal chow diet). Compared with DP2 fl/fl ...