Maximal Oxidative Capacity during Exercise Is Associated with Skeletal Muscle Fuel Selection and Dynamic Changes in Mitochondrial Protein Acetylation

Abstract

Summary Maximal exercise-associated oxidative capacity is strongly correlated with health and longevity in humans. Rats selectively bred for high running capacity (HCR) have improved metabolic health and are longer-lived than their low capacity counterparts (LCR). Using metabolomic and proteomic profiling, we show that HCR efficiently oxidize fatty acids (FA) and branched-chain amino acid (BCAA), sparing glycogen and reducing accumulation of short- and medium-chain acylcarnitines. HCR mitochondria have reduced acetylation of mitochondrial proteins within oxidative pathways at rest, and there is rapid protein deacetylation with exercise, which is greater in HCR than LCR. Fluxomic analysis of valine degradation with exercise demonstrates a functional role of differential protein acetylation in HCR and LCR. Our data suggest efficient FA and BCAA utilization contribute to high intrinsic exercise capacity and the health and longevity benefits associated with enhanced fitness.

Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins

“…SIRT3 in general is linked to elevated metabolism, fatty acid oxidation and oxidative phosphorylation , which previously have been established in HCRs Overmyer et al 2015;Kivelä et al 2010).…”

“…SIRT3 in general is linked to elevated metabolism, fatty-acid oxidation and oxidative phosphorylation , which have been established in HCRs Novak et al, 2010b;Overmyer et al, 2015). A recent study of Overmyer et al showed that HCRs have lower mitochondrial protein acetylation in gastrocnemius muscle during rest and exercise than LCRs; however, they did not find a difference in the SIRT3 level (Overmyer et al, 2015). Since the rats utilized in Overmyer's study were three month old male rats, whereas our rats were nine month old females, it is possible that the age and gender difference may contribute to the different results.…”

“…The higher SIRT3 level and/or activation of HCRs may promote increased deacetylation in mitochondria, thereby increasing the activity of enzymes of oxidative pathways. Thus, compared to LCRs, HCRs are able to more efficiently continue ATP production through oxidative phosphorylation especially during exercise (Overmyer et al, 2015).…”

“…The difference in fuel selection has been associated to the healthy phenotype of HCRs, which more efficiently oxidizes fatty acids and branched-chain amino acids than LCRs (Overmyer et al 2015). HCRs also seem to be protected against certain negative metabolic changes related to environmental and hormonal factors, such as high-fat diet and ovariectomy (Vieira-Potter et al 2015;Noland et al 2007;Morris et al 2014).…”

“…The higher SIRT3 level of HCRs in turn may promote increased deacetylation in mitochondria, thus, increasing the activity of enzymes of oxidative pathways. Hence, compared to LCRs, HCRs are able to more efficiently continue to produce ATP through oxidative phosphorylation, especially during exercise (Overmyer et al 2015). As LCRs are considered as an animal model for metabolic syndrome, it is also worth noting that skeletal muscle from obese subjects or from type 2 diabetic patients' show reduced mitochondrial oxidative capacity (Mogensen et al 2007;Kelley et al 2002;Bakkman et al 2010).…”