Celecoxib Enhances Oxidative Muscle Fibre Formation and Improves Muscle Functions Through Prokr1 Activation in Mice.

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Muscle diseases pose significant health challenges.
• Prokineticin receptor 1 (PROKR1) is a potential therapeutic target for enhancing muscle oxidative fibers.
• No clinically applicable synthetic PROKR1 agonists are currently available.

Purpose of the Study:

• To identify and evaluate synthetic PROKR1 agonists for potential therapeutic applications in muscle disorders.
• To investigate the effects of celecoxib on PROKR1 signaling and muscle function.

Main Methods:

• Connectivity Map (CMap) analysis was used to discover drugs with prokineticin 2 (PK2) biological properties.
• Molecular docking, PROKR1 signaling assays, and competitive binding assays were employed to assess drug effects on PROKR1.
• Animal studies involved administering celecoxib to pregnant dams and offspring, followed by high-fat diets (HFD) and comprehensive physiological and histological analyses.

Main Results:

• Celecoxib demonstrated potent PROKR1 agonistic activity, selectively activating Gs signaling and inhibiting PK2 binding.
• In vitro and in vivo studies showed celecoxib increased Prokr1 levels, promoted oxidative muscle fiber formation (elevated Myh7 index), and enhanced mitochondrial content and fatty acid oxidation.
• Offspring exposed to celecoxib exhibited improved lean mass, grip strength, insulin resistance, and energy expenditure, even under HFD conditions, with effects persisting to 20 weeks of age.

Conclusions:

• Celecoxib functions as a PROKR1 agonist with potential for treating muscular disorders.
• The findings suggest celecoxib as a clinically applicable exercise mimetic, offering a novel therapeutic avenue for muscle-related conditions.