Inhibition of the Gerozyme 15-PGDH Promotes Recovery from Disuse Atrophy and Muscle Weakness

Aging causes a decline in muscle mass and function, which in extreme cases results in sarcopenia. Sarcopenia is associated with a higher risk of falls, hospitalizations, and surgeries that lead to periods of bed rest and muscle disuse. Periods of disuse exacerbate muscle atrophy and weakness from which elderly patients are often unable to fully recover, triggering a vicious cycle that increases frailty and loss of independence. The neuromuscular junction (NMJ) is the interface by which the nervous system signals contraction to muscles. Both aging and disuse alter muscle composition, performance, and NMJ structural and functional stability. The Blau lab recently reported that the gerozyme 15-prostaglandin dehydrogenase (15-PGDH) is upregulated in aged muscle tissue, and its inhibition rejuvenates skeletal muscle by improving muscle mass, strength, and NMJ innervation lost in aging. We aimed to test whether 15-PGDH is further upregulated in old mice undergoing muscle disuse, hypothesizing that 15-PGDH inhibition promotes recovery post-disuse. To model disuse, we relied on a hindlimb unloading protocol that prevented mice from using their hindlimbs. We utilized force measurements to assess muscle strength and immunofluorescence to assess innervation, NMJ morphology, and muscle atrophy after 3, 7, and 14 days of unloading. Unloading reduced NMJ endplate area and decreased force generated by nerve stimulation vs muscle stimulation, indicating inhibition of neuromuscular transmission. We also observed a reduction in muscle force and mass. To determine if 15-PGDH could improve recovery after unloading, unloaded mice were treated with a 15-PGDH inhibitor throughout a 14-day re-loading (recovery) period. Relative to vehicle-treated controls, the muscles of old treated mice were able to exert more force and force per muscle unit. More investigation is needed to determine the effect of treatment on the NMJ. Together, these data indicate that 15-PGDH inhibition is a potential therapy to recover muscle function following disuse.