GCPII inhibition preserved muscle mass and function against sarcopenia in C57BL6/J mice


Translational Research

Poster Number: Virtual


Yu Su, MD, PhD, Johns Hopkins University

Sarcopenia is age-related skeletal muscle atrophy and weakness which reduces the quality of life in the elderly, and there’s still a lack of therapy for this disease. glutamate carboxypeptidase II (GCPII) is a neuropeptidase that cleaves NAAG into NAA and glutamate, its activity has been observed to regulate glutamatergic transmission and drive synaptic pruning at the NMJ during development. We previously demonstrated that GCPII inhibition with potent inhibitor 2-(Phosphonomethyl)-pentanedioic acid (2-PMPA) significantly delayed muscle function loss and NMJ denervation in an ALS mouse model. As normal aging muscles shared the similarity of NMJ deterioration as ALS, we questioned whether 2-PMPA treatment could preserve muscle function during aging. To test the role of GCPII in muscle aging and the effect of GCPII inhibition, we treated 15-month-old mice with 100mg/kg of 2-PMPA IP daily for 5 months and monitored muscle function. We observed the activity of GCPII is low in 4-month-old mice gastrocnemius muscles but significantly increased in 20-month-old mice (2009±317 vs. 3188±182 fmol/mg/h). 5-months of 2-PMPA treatment delayed age-related loss in muscle mass (164.8±5.6 vs. 143.6±6.4 mg) and grip strength (-4.75±3.22% vs. -20.98±3.73%) compared to vehicle. 2-PMPA-treated muscle showed a slight but significant increase in the mean single-fiber cross-sectional area compared to aged control (759.4±5.2 vs. 722.4±5.1 um2), as 2-PMPA delayed the shift to smaller fibers. 2-PMPA treatment also delayed compound muscle action potential (CMAP) amplitude decline (-7.37±6.16% vs. -26.05±3.71%), and elevated ambulation in the open-field test (3941±153 vs. 3216±188 beam brakes). More interestingly, immunofluorescent staining showed that GCPII expression in aged muscle is associated with infiltrated macrophage, indicating inflammation as one potential target for the role of 2-PMPA in preserving muscle function during aging. Overall, our current results support that excessive GCPII activity is associated with muscle aging, and GCPII inhibition is a potential therapeutic strategy for sarcopenia.