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

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) mice, DP2(fl/fl)HSA(Cre) mice exhibited remarkable glycolytic‐to‐oxidative fibre‐type transition in hindlimb muscles and were fatigue resistant during endurance exercise (154.9 ± 6.0 vs. 124.2 ± 8.1 min, P < 0.05). DP2(fl/fl)HSA(Cre) mice fed an HFD showed less weight gain (P < 0.05) and hepatic lipid accumulation (P < 0.01), reduced insulin resistance and enhanced energy expenditure (P < 0.05) compared with DP2(fl/fl) mice. Mechanistically, DP2 deletion promoted the nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) by suppressing RhoA/Rho‐associated kinase 2 (ROCK2) signalling, which led to enhanced oxidative fibre‐specific gene transcription in muscle cells. Treatment with CAY10471 enhanced NFATc1 activity in the skeletal muscles and ameliorated HFD‐induced obesity (P < 0.05 vs. saline) and insulin resistance in mice. CAY10471 also enhanced exercise tolerance in MDX mice (100.8 ± 8.0 vs. 68.9 ± 11.1 min, P < 0.05 vs. saline) by increasing the oxidative fibre‐type ratio in the muscles (45.1 ± 2.3% vs. 32.3 ± 2.6%, P < 0.05 vs. saline). CONCLUSIONS: DP2 activation suppresses oxidative fibre transition via RhoA/ROCK2/NFATc1 signalling. The inhibition of DP2 may be a potential therapeutic approach against obesity and muscle disorders.