Abstract
Loss of protein homeostasis (proteostasis) and is a driver of age-related musculoskeletal decline. Hartley guinea pigs (HGPs) model the progressive knee osteoarthritis and concomitant skeletal muscle decline often observed in aging humans. Nuclear factor erythroid factor 2-related factor 2 (Nrf2) is a transcription factor at the nexus of redox homeostasis. We have previously reported that the Nrf2 activator, PB125, increased protein synthesis related to maintenance of the proteome, in female HGPs. However, we are unsure if other components of proteome integrity were improved with PB125 treatment.
PURPOSE: The purpose of this study was to examine if PB125 treatment from 5- to 15 mo, a period during which musculoskeletal function and mobility decline, would alter ribosomal biogenesis, another component of proteostasis that contributes to translational capacity and efficiency, in the tibialis anterior of HGPs.
METHODS: We assessed ribosomal biogenesis with the stable isotope deuterium for 30 days. We measured translation regulator activity by assessing phosphorylation of eIF2 with western blotting.
RESULTS: PB125 increased rates of ribosomal biogenesis in male HGPs (CON vs. PB125; 0.70 ± 0.08 vs. 0.81 ± 0.12 %/day; p = 0.0467). However, PB125 did not increase ribosomal biogenesis in female HGPs (CON vs. PB125; 0.74 ± 0.11 vs. 0.74 ± 0.08 %/day p = 0.9984). Despite a significant increase in ribosomal biogenesis, PB125 did not increase the ratio of phosphorylated to total eIF2 in male (CON vs. PB125; 1.0 ± 0.33 vs. 0.82 ± 0.24 arbitrary units; p = 0.4866) or female (CON vs. PB125; 0.99 ± 0.27 vs. 0.86 ± 0.19 arbitrary units; p = 0.7335) HGPs.
CONCLUSIONS: Similar to our previous findings, PB125 elicited sex-specific effects on mechanisms of proteostasis. While PB125 increased protein synthesis related to proteome maintenance in females, our present study highlights that PB125 increases ribosomal biogenesis, which may be necessary to maintain translational capacity and fidelity. Importantly, we also demonstrate that relying upon markers and snapshots of translation do not accurately reflect dynamic cellular changes. Future research should consider whether these changes in components of proteostasis yield improvements in proteome integrity.
PURPOSE: The purpose of this study was to examine if PB125 treatment from 5- to 15 mo, a period during which musculoskeletal function and mobility decline, would alter ribosomal biogenesis, another component of proteostasis that contributes to translational capacity and efficiency, in the tibialis anterior of HGPs.
METHODS: We assessed ribosomal biogenesis with the stable isotope deuterium for 30 days. We measured translation regulator activity by assessing phosphorylation of eIF2 with western blotting.
RESULTS: PB125 increased rates of ribosomal biogenesis in male HGPs (CON vs. PB125; 0.70 ± 0.08 vs. 0.81 ± 0.12 %/day; p = 0.0467). However, PB125 did not increase ribosomal biogenesis in female HGPs (CON vs. PB125; 0.74 ± 0.11 vs. 0.74 ± 0.08 %/day p = 0.9984). Despite a significant increase in ribosomal biogenesis, PB125 did not increase the ratio of phosphorylated to total eIF2 in male (CON vs. PB125; 1.0 ± 0.33 vs. 0.82 ± 0.24 arbitrary units; p = 0.4866) or female (CON vs. PB125; 0.99 ± 0.27 vs. 0.86 ± 0.19 arbitrary units; p = 0.7335) HGPs.
CONCLUSIONS: Similar to our previous findings, PB125 elicited sex-specific effects on mechanisms of proteostasis. While PB125 increased protein synthesis related to proteome maintenance in females, our present study highlights that PB125 increases ribosomal biogenesis, which may be necessary to maintain translational capacity and fidelity. Importantly, we also demonstrate that relying upon markers and snapshots of translation do not accurately reflect dynamic cellular changes. Future research should consider whether these changes in components of proteostasis yield improvements in proteome integrity.
| Original language | English |
|---|---|
| Pages (from-to) | 423-424 |
| Number of pages | 1 |
| Journal | Medicine and Science in Sports and Exercise |
| Volume | 56 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2024 |