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

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 D2 (PGD2) 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 PGD2‐mediated muscle homeostasis and myogenesis. Methods Skeletal muscle‐specific PGD2 receptor DP2‐deficient mice (DP2fl/flHSACre) and their littermate controls (DP2fl/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 PGD2/DP2 signalling axis in obesity and muscle disorders. Multiple genetic and pharmacological approaches were also used to investigate the intracellular signalling cascades underlying the PGD2/DP2‐mediated skeletal muscle fibre transition. Results PGD2 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 DP2fl/fl mice, DP2fl/flHSACre 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). DP2fl/flHSACre 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 DP2fl/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.

Type 2 diabetes mellitus related sarcopenia: a type of muscle loss distinct from sarcopenia and disuse muscle atrophy

“…Upregulation of PGs may be associated with ferroptosis and iron metabolism disorders, leading to metabolic abnormalities and functional impairments in muscles (114,115). PGs may also influence changes in muscle fiber types in T2DM patients and play a role in muscle growth and development (116,117). Insulin-like growth factor (IGF-1) and growth hormone (GH) have been studied in relation to muscle mass and sarcopenia.…”

Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases

“…274,275 Likewise, mice with DP2 ablation in muscle cells exhibit effective amelioration of obesity and metabolic disorders by blocking the RhoA/ROCK2/ NFATc1 axis. 276 However, global depletion of PGDS leads to significantly increased body weight gain and glucose intolerance in mice, suggesting a tissue-specific role of the PGDS/PGD2/DP2 axis during metabolic disorders.…”

Transcriptome profiling of fast/glycolytic and slow/oxidative muscle fibers in aging and obesity

“…Recent researches highlight the importance of these fibers. Through muscle-specific knockouts of DP2 or Sox6, enhancements in endurance and insulin sensitivity are achieved by increasing the number of slow/oxidative fibers [ 2 , 3 ]. Additionally, constitutive activation of Akt elevates fast/glycolytic fibers, promoting muscle hypertrophy and strength gains [ 4 ].…”