Differential effects of vitamin C or protandim on skeletal muscle adaptation to exercise

Abstract

Maintaining proteostasis is a key mechanism for preserving cell function. Exercise-stimulated proteostasis is regulated, in part, by redox-sensitive signaling. Several studies suggest that supplementation with exogenous antioxidants blunts exercise-induced cellular adaptations, although this conclusion lacks consensus. Our group uses a fundamentally different approach to maintain redox balance by treatment with bioactive phytochemicals to activate the transcription factor nuclear factor (erythroid-derived 2)-like 2 and downstream endogenous antioxidant pathways. We hypothesized that vitamin C (VitC) would interfere with redox-sensitive proteostatic mechanisms in skeletal muscle, whereas phytochemical treatment would permit proteostatic maintenance. We measured protein and DNA synthesis in skeletal muscle from high-volume voluntary wheel-running rats. Whereas phytochemical treatment permitted mitochondrial and other proteostatic adaptations to exercise, VitC treatment did not. During an in vitro oxidative challenge, phytochemical treatment helped maintain proteostasis, including the mitochondrial fraction while VitC did not. Our findings support the conclusion that VitC can blunt some of the beneficial adaptations to exercise. We propose that regulation of endogenous antioxidants represents a novel approach to maintain redox balance while still permitting redox-sensitive proteostatic adaptations. NEW & NOTEWORTHY Whether vitamin C blocks aerobic exercise adaptions lacks consensus, perhaps because of approaches that only assess markers of mitochondrial biogenesis. By directly measuring mitochondrial biogenesis, we demonstrate that vitamin C blunts exercise-induced adaptations. Furthermore, we show that treatment with Protandim, a purported nuclear factor (erythroid-derived 2)-like 2 activator that upregulates endogenous antioxidants, permits mitochondrial biogenesis. We confirm that vitamin C blunts aerobic exercise adaptions, whereas Protandim does not, suggesting targeting the endogenous antioxidant network facilitates adaptations to exercise.

Improving biologic predictors of cycling endurance performance with near‐infrared spectroscopy derived measures of skeletal muscle respiration: E pluribus unum

“…Alternatively, abrogating training‐induced improvements in skeletal muscle oxidative potential reciprocally blunts improvements in cardiorespiratory fitness, endurance capacity, and, sometimes, measures of whole‐body health. Supplementation of exogenous vitamin C with exercise training can blunt mitochondrial biogenesis in skeletal muscle (Bruns et al, ; Gomez‐Cabrera et al, ) and minimize improvements in VO 2max and/or endurance performance in both humans and rats (Gomez‐Cabrera et al, ). Diminished skeletal muscle mitochondrial protein is reported to parallel increases in heart rate, ventilation, respiratory exchange ratio, and blood lactate concentrations at the same absolute submaximal exercise intensity following 84 days of detraining (Coyle, Martin, Bloomfield, Lowry, & Holloszy, ).…”

Mitochondria as a Target for Mitigating Sarcopenia

“…Other studies have examined the effects of exogenous antioxidants, such as vitamin C, on muscle quality and oxidative stress. Vitamin C supplementation improves muscle function in at least one model of aged muscle (Ryan et al., 2010), but vitamin C is known to inhibit the redox signaling that leads to positive mitochondrial responses (Gomez-Cabrera et al., 2008; Paulsen et al., 2014; Bruns et al., 2018). Meta-analyses investigating the efficacy of long-term vitamin C supplementation conclude that supplementation actually increases the risk for disease and mortality (Bjelakovic et al., 2012).…”

“…Other strategies targeting antioxidant mechanisms are promising though. For example, studies using a purported Nrf2 activator that increases endogenous antioxidants produces lifespan in male mice (Strong et al., 2016) and enhances protein synthesis during aerobic exercise training (Bruns et al., 2018).…”

Exercise-Induced Mitohormesis for the Maintenance of Skeletal Muscle and Healthspan Extension

“…As highlighted, exogenous antioxidant supplementation seems to abrogate many of the mitohormetic effects of exercise. However, there appears to be some additive effect of improving cellular antioxidant capacity to exercise, as demonstrated by our work in which Nrf2 activators enhanced mitochondrial proteostasis in active rats [134] and increased proteostatic mechanisms in the skeletal muscle of older adults [135]. However, it remains unclear how a Nrf2 activator affects redox homeostasis.…”

“…Our lab has demonstrated that treatment with Protandim protects coronary endothelial cells and cardiomyocytes from oxidative stress challenges [132,133]. Again, in contrast to exogenous antioxidant supplements, treatment with Protandim also enhanced proteostatic mechanisms and permitted the mitohormetic adaptations to physical activity [134]. Finally, our lab has demonstrated that treatment with a similar phytochemical Nrf2 activator enhanced the proteostatic maintenance of skeletal muscle contractile proteins in sedentary, healthy older adults [135].…”