Inhibiting mTORC1 to improve proteostatic maintenance and mitochondrial dysfunction in aged muscle after disuse atrophy

Sarcopenia is a major contributor to frailty and poor recovery after hospitalization. In older adults, even short periods of disuse, like bed rest, cause muscle loss that does not fully recover. We have shown that the failure of aged muscle to recover after disuse is not because of limitations in protein synthesis but may instead result from high levels of protein synthesis and compromised protein degradation due to high mTORC1 activity. We hypothesized that reducing mTORC1 activity would therefore enhance recovery of aged skeletal muscle following disuse. Methods: Adult (9 month) and old (26 month) male and female OKC-HET rats were fed control or rapamycin (an mTORC1 inhibitor) chow and were hindlimb unloaded for 14 days, then reloaded for 14 days. Lower limb muscle mass/size was assessed, along with mitochondrial respiration, oxidative damage, protein fractional synthesis rates (FSR) using deuterium oxide (D2O) labeling, and proteostatic mechanisms through aggregate protein accumulation. Results: Compared to adult rats, old rats had higher skeletal muscle mitochondrial (1.99 ±0.09 FSR (%/day) vs. 2.71 ±0.16 FSR (%/day), p< 0.001) and myofibrillar (1.92 ±0.05 FSR (%/day) vs. 2.86 ±0.22 FSR (%/day), p< 0.001) protein synthesis rates. Additionally, old rats accumulated more p62 aggregates in muscle compared to adults (0.063 ±0.023 A.U. vs. 0.965 ±0.19 A.U., p< 0.001). Rapamycin treatment resulted in lower mitochondrial (2.81 ±0.12 FSR (%/day) vs. 2.26 ±0.11 FSR (%/day), p< 0.01) and myofibrillar (2.74 ±0.11 FSR (%/day) vs. 2.31 ±0.12 FSR (%/day), p< 0.05) protein synthesis rates in old muscle, and despite lower protein synthesis, there were no differences in muscle mass vs. old controls (29.4 ±1.2 g/TL vs. 28.3 ±0.8 g/TL, p=0.46). Lastly, old rapamycin treated muscle had higher mitochondrial respiration with disuse compared to old controls (71.8 ±5.8 pmol/(s*mg) vs. 94.8 ±9.3 pmol/(s*mg), p< 0.05), which was associated with lower F2-isoprostane concentration (a biomarker of oxidative damage) in old female rats treated with rapamycin compared to old controls (2.21 ±0.34 pg/mg vs. 1.36 ±0.14 pg/mg, p< 0.05). Conclusions: Together, these data indicate that proteostatic maintenance is compromised in aged muscle and that mTORC1 inhibition may support proteostatic maintenance, mitochondrial respiration, and redox balance in aged muscle during recovery from disuse. Therefore, interventions aimed at improving skeletal muscle recovery after disuse atrophy should focus on improving proteostatic mechanisms instead of simply increasing protein synthesis alone. Funding NIA K99/R00 MOSAIC: 1K99AG086524-01A1 NIA Training Grant: 5T32AG052363-04 VA Merit Award: VA I01 BX005592 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.