Document Type
Article
Publication Date
2023
Abstract
Impaired mitochondrial function and disrupted proteostasis contribute to musculoskeletal dysfunction. However, few interventions simultaneously target these two drivers to prevent musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) activates a transcriptional programme promoting cytoprotection, metabolism, and proteostasis. We hypothesized daily treatment with a purported Nrf2 activator, PB125, in Hartley guinea pigs, a model of musculoskeletal decline, would attenuate the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis and preserve musculoskeletal function. We treated 2- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical compound PB125. Longitudinal assessments of voluntary mobility were measured using Any-MazeTM open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in soleus muscles was measured using high resolution respirometry. In both sexes, PB125 (1) increased electron transfer system capacity; (2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and (3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial and cytosolic subfractions of the soleus. These effects were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, treatment with PB125 contributed to maintenance of skeletal muscle mitochondrial respiration and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these documented effects of PB125 are also accompanied by slowed progression of other aspects of musculoskeletal dysfunction.
Original Publication Citation
Musci, R. V., Andrie, K. M., Walsh, M. A., Valenti, Z. J., Linden, M. A., Afzali, M. F., Bork, S., Campbell, M., Johnson, T., Kail, T. E., Martinez, R., Nguyen, T., Sanford, J., Wist, S., Murrell, M. D., McCord, J. M., Hybertson, B. M., Zhang, Q., Javors, M. A., … Hamilton, K. L. (2023). Phytochemical compound PB125 attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a model of musculoskeletal decline. The Journal of Physiology, 601(11), 2189–2216. https://doi.org/10.1113/JP282273
Publisher Statement
© 2022 The Authors.
Digital Commons @ LMU & LLS Citation
Musci, Robert V.; Andrie, Kendra M.; Walsh, Maureen A.; Valenti, Zackary J.; Linden, Melissa A.; Afzali, Maryam F.; Bork, Sydney; Campbell, Margaret; Johnson, Taylor; Kail, Thomas E.; Martinez, Richard; Nguyen, Tessa; Sanford, Joseph; Wist, Sara; Murrell, Meredith D.; McCord, Joe M.; Hybertson, Brooks M.; Zhang, Qian; Javors, Martin A.; Santangelo, Kelly S.; and Hamilton, Karyn L., "Phytochemical compound PB125 attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a model of musculoskeletal decline" (2023). Health and Human Sciences Faculty Works. 103.
https://digitalcommons.lmu.edu/hhsc_fac/103
