Abstract Body: Introduction: Sarcopenia is an age-associated loss of skeletal muscle mass and function, with no FDA-approved therapies available. Growing evidence suggests that age-related impairment of the skeletal muscle microvasculature and endothelial signaling also plays a critical role in limiting muscle function. Prostaglandin E2 (PGE2) is a bioactive lipid that supports tissue repair and vascular function, but its therapeutic potential is constrained by rapid degradation via 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Pharmacological inhibition of 15-PGDH with the small-molecule inhibitor SW033291 stabilizes PGE2 and emerges as a promising therapeutic target to enhance muscle and vascular function during aging. Exercise is also well established to improve muscle performance and vascular remodeling. However, whether PGE2 signaling can synergize with exercise to enhance muscle microvascularization and ameliorate sarcopenia remains unclear.
Methods: We evaluated the combined effects of SW033291 and rehabilitative treadmill exercise in young (3-mon) and aged (>18-mon) mice. Animals were randomized into four experimental groups: 1) SW033291 with exercise, 2) SW033291 without exercise, 3) vehicle control with exercise, and 4) vehicle control without exercise. These groups enable the assessment of independent and combined contributions of pharmacologic and mechanical stimuli on muscle and vascular function.
Results: SW033291 and exercise independently improve skeletal muscle mass and physiological performance, with more pronounced effects in aged mice. Notably, the combination of SW033291 and exercise produced significant additive benefits in muscle force generation and muscle mass, exceeding those observed with either intervention alone. Importantly, the microvascular density of the muscle also revealed significantly higher vessel density when treated with both SW033291 and exercise, indicating enhanced endothelial or capillary-associated responses. These vascular effects were most prominent in aged muscle and showed a clear additive increase with the combined intervention.
Conclusion: Our findings suggest that targeting the PGE2 axis in conjunction with exercise enhances both muscle function and microvascular-associated adaptations in aging skeletal muscle. This work highlights a novel, vascular-focused therapeutic strategy for combating sarcopenia by coupling pharmacologic stabilization of pro-regenerative signaling with exercise-induced hemodynamic stimuli.