GCPII Inhibition in Macrophages Delays Age-related Muscle Atrophy in Mice

• DOI: 10.1152/physiol.2024.39.s1.2379
• Publication Date: 2024-05-21T14:57:50Z
• Authors: Yu Su; Carolyn Tallon; Ajit Thomas; Kaitlyn Huizar; Meixiang Huang; Lukas Tenora; Wathsala Liyanage
• Keywords: Muscle Atrophy

Age-related loss of muscle mass and strength (Sarcopenia) significantly impairs quality life in the elderly, yet lacks effective treatments. We previously demonstrated that inhibition GCPII delayed function decline neuromuscular junction (NMJ) denervation an amyotrophic lateral sclerosis (ALS) animal model. As sarcopenia shares NMJ deterioration with ALS, we tested potent inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA) aging mice, found it also preserved integrity. By immunofluorescent staining, aged mice muscles were associated GCPII-positive infiltrating macrophages. next developed a macrophage-targeting delivery system by covalently attaching 2-PMPA to 4 th -generation polyamidoamine (G4-PAMAM) dendrimers (D-2-PMPA). The D-2-PMPA was inhibit IC50= 3.50±0.05 nM. Aged showed increased activity specifically CD11b + enriched macrophage cells (138.6±3.0 vs. 336.6±52.9; p<0.05) but not − cells. Systemic therapy (20 mg/kg equivalent; IP 3 × /week) completely inhibited elevated (336.5±52.8 21.8±9.2 fmol/mg/h; p<0.001). 5-months initiated 15-month-old calf volume (95.0±0.8% 90.4±0.7%; p <0.001), enhanced isometric force (230.2±13.3 184.0±9.0 mN, female p<0.05; 257.3±21.0 189.7±19.3 male p<0.05), improved grip (96.1±1.6 90.2±2.2 % maximum p<0.001) rotarod latency (119.0±6.6 93.5±9.3 s, 104.5±5.2 79.3±4.2 nerve signal conductivity as observed compound action potential (CMAP) (1.28±0.02 1.38±0.04 ms; p< 0.05) amplitude (15.2±0.5 1.27±0.6 mV; p<0.01). Furthermore, integrity treatment single fiber jitter (5.4±0.3 7.5±0.5 μs; Overall, our current results support excessive macrophages is age-related atrophy, which inhibition. This study highlights new therapeutic approach delay sarcopenia. R01AG078181, R01AG068130, R01NS093416. full abstract presented at American Physiology Summit 2024 meeting only available HTML format. There are no additional versions or content for this abstract. involved peer review process.