Impaired proteostatic mechanisms other than protein synthesis limit aged skeletal muscle recovery after disuse atrophy

Abstract

Older individuals undergo more frequent hospitalizations and periods of bedrest compared to younger persons, causing rapid loss of muscle mass and strength. We and others have shown that old muscle fails to completely regrow following disuse, despite having similar levels of muscle loss during disuse and equal or higher myofibrillar protein synthesis during recovery. Therefore, we hypothesized that a failure of proteostatic mechanisms other than protein synthesis contributes to the inability of old muscle to fully recover after a period of disuse atrophy. Methods: Adult (10 month) and old (30 month) male F344BN rats were hindlimb unloaded for 14 days and then reloaded for up to 60 days. We used a combination of deuterium oxide (D2O) labeling, proteomics, and biochemical analyses to study proteostasis during recovery. Results: There was a failure of old muscle to maintain proteostasis as evident by a greater accumulation of insoluble protein aggregates ( 1.02 ±0.06 vs. 1.22 ±0.06, p<0.05), insoluble collagen ( 4.0 ±1.1 vs. 9.2 ±0.9, p<0.01) and higher amount of advanced glycation end products (AGEs) ( 1.0 ±0.06 vs. 1.5 ±0.08, p<0.001) compared to adult. Old muscle had higher rates of myofibrillar protein synthesis than adult muscle ( 0.029 k/day ±0.002 vs. 0.039 k/day ±0.002, p<0.0001), but also higher rates of breakdown (0.017 1/t ±0.002 vs. 0.028 1/t ±0.004, p<0.05). Differences in the synthesis of collagen were less apparent between adult and old muscle, implying that there was a failure of collagen breakdown in old muscle leading to greater accumulation. Lastly, pathway analysis of proteomic data showed that there were differences in the proteins that accumulated in aggregates between adult and old muscle, and that the synthesis of proteins that regulate proteostasis were different with age. Conclusions: Together, these data indicate that in old muscle altered proteostatic mechanisms other than myofibrillar protein synthesis led to failure to recover from atrophy. Interventions should therefore be targeted at these novel mechanisms instead of protein synthesis alone. NIA Training Grant: 5T32AG052363-04, APS Postdoctoral Fellowship MML, F31AT01147201 ZRH, R01(NCCIH AT009268) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.