Phytochemical compound PB125 attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a model of musculoskeletal decline

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. Key points Aside from exercise, there are no effective interventions for musculoskeletal decline, which begins in the fifth decade of life and contributes to disability and cardiometabolic diseases. Targeting both mitochondrial dysfunction and impaired protein homeostasis (proteostasis), which contribute to the age and disease process, may mitigate the progressive decline in overall musculoskeletal function (e.g. gait, strength). A potential intervention to target disease drivers is to stimulate nuclear factor erythroid 2‐related factor 2 (Nrf2) activation, which leads to the transcription of genes responsible for redox homeostasis, proteome maintenance and mitochondrial energetics. Here, we tested a purported phytochemical Nrf2 activator, PB125, to improve mitochondrial function and proteostasis in male and female Hartley guinea pigs, which are a model for musculoskeletal ageing. PB125 improved mitochondrial respiration and attenuated disease‐ and age‐related declines in skeletal muscle protein synthesis, a component of proteostasis, in both male and female Hartley guinea pigs.

Plants powering muscle: The effects of phytochemical PB125 on mitochondrial function and skeletal muscle health

“…The present study demonstrated that long‐term (10 months) treatment of Hartley guinea pigs with PB125 did not alter the body mass or muscle mass of the soleus and gastrocnemius muscles; however, improvements in mitochondrial respiration were observed (Musci et al. 2022). Long‐term PB125 treatment enhanced State 3 [CI‐IV] and State 4 [CI‐IV] respiration in permeabilized muscle fibres from the soleus of 15‐month‐old animals.…”

“…Therefore, PB125 treatment may serve as an enhancer of mitochondrial turnover and quality control through activation of mitochondrial biogenesis and mitophagy, albeit more data are needed to fully test this idea. Musci et al (2022) have shown that Hartley guinea pigs demonstrate a decrease in protein synthesis with age similar to other rodent models. To examine changes in fractional synthesis rate (FSR), the authors measured deuterium labelled alanine after 30 days of exposure in subfractions of skeletal muscle.…”

“…Musci et al. (2022) have shown that Hartley guinea pigs demonstrate a decrease in protein synthesis with age similar to other rodent models. To examine changes in fractional synthesis rate (FSR), the authors measured deuterium labelled alanine after 30 days of exposure in subfractions of skeletal muscle.…”

“…A recent article published in The Journal of Physiology by Musci et al. (2022) provided key insights into the roles of phytochemical treatment on skeletal muscle ageing. The authors utilized a unique model of accelerated skeletal muscle ageing to study the effects of a nuclear respiratory factor 2 (NRF2) activator called PB125.…”

Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review

“…Another approach to restore mitochondrial function in critical illness-induced muscle weakness is to promote mitochondrial biogenesis and to preserve the fusion–fission balance in mitochondrial dynamics. Pharmacologically-induced activation of NRF2 has been evaluated in an attempt to promote mitochondrial biogenesis and, therefore, to restore mitochondrial count, with positive results [ 213 , 214 ]. This seems conclusive, since a reduction in the mitochondrial content of the overall skeletal muscles is frequently observed in critical illness [ 101 , 102 ].…”