Dataset Information

PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle.

ABSTRACT: Rapid alterations in cellular metabolism allow tissues to maintain homeostasis during changes in energy availability. The central metabolic regulator acetyl-CoA carboxylase 2 (ACC2) is robustly phosphorylated during cellular energy stress by AMP-activated protein kinase (AMPK) to relieve its suppression of fat oxidation. While ACC2 can also be hydroxylated by prolyl hydroxylase 3 (PHD3), the physiological consequence thereof is poorly understood. We find that ACC2 phosphorylation and hydroxylation occur in an inverse fashion. ACC2 hydroxylation occurs in conditions of high energy and represses fatty acid oxidation. PHD3-null mice demonstrate loss of ACC2 hydroxylation in heart and skeletal muscle and display elevated fatty acid oxidation. Whole body or skeletal muscle-specific PHD3 loss enhances exercise capacity during an endurance exercise challenge. In sum, these data identify an unexpected link between AMPK and PHD3, and a role for PHD3 in acute exercise endurance capacity and skeletal muscle metabolism.

SUBMITTER: Yoon H

PROVIDER: S-EPMC8065255 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle.

Yoon Haejin H Spinelli Jessica B JB Zaganjor Elma E Wong Samantha J SJ German Natalie J NJ Randall Elizabeth C EC Dean Afsah A Clermont Allen A Paulo Joao A JA Garcia Daniel D Li Hao H Rombold Olivia O Agar Nathalie Y R NYR Goodyear Laurie J LJ Shaw Reuben J RJ Gygi Steven P SP Auwerx Johan J Haigis Marcia C MC

Cell metabolism 20200713 2

Rapid alterations in cellular metabolism allow tissues to maintain homeostasis during changes in energy availability. The central metabolic regulator acetyl-CoA carboxylase 2 (ACC2) is robustly phosphorylated during cellular energy stress by AMP-activated protein kinase (AMPK) to relieve its suppression of fat oxidation. While ACC2 can also be hydroxylated by prolyl hydroxylase 3 (PHD3), the physiological consequence thereof is poorly understood. We find that ACC2 phosphorylation and hydroxylati ...[more]

PMID: 32663458

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Project description:Purpose:The present study aimed to determine whether whole-body fat oxidation and muscle deoxygenation kinetics parameters during exercise were related in individuals with different aerobic fitness levels. Methods:Eleven cyclists [peak oxygen uptake ( V.O2?p?e?a?k ): 64.9 ± 3.9 mL?kg-1?min-1] and 11 active individuals ( V.O2?p?e?a?k : 49.1 ± 7.4 mL?kg-1?min-1) performed a maximal incremental cycling test to determine V.O2?p?e?a?k and a submaximal incremental cycling test to assess whole-body fat oxidation using indirect calorimetry and muscle deoxygenation kinetics of the vastus lateralis (VL) using near-infrared spectroscopy (NIRS). A sinusoidal (SIN) model was used to characterize fat oxidation kinetics and to determine the intensity (Fatmax) eliciting maximal fat oxidation (MFO). The muscle deoxygenation response was fitted with a double linear model. The slope of the first parts of the kinetics (a 1) and the breakpoint ([HHb]BP) were determined. Results:MFO (p = 0.01) and absolute fat oxidation rates between 20 and 65% V.O2?p?e?a?k were higher in cyclists than in active participants (p < 0.05), while Fatmax occurred at a higher absolute exercise intensity (p = 0.01). a 1 was lower in cyclists (p = 0.02) and [HHb]BP occurred at a higher absolute intensity (p < 0.001) than in active individuals. V.O2?p?e?a?k was strongly correlated with MFO, Fatmax, and [HHb]BP (r = 0.65-0.88, p ? 0.001). MFO and Fatmax were both correlated with [HHb]BP (r = 0.66, p = 0.01 and r = 0.68, p < 0.001, respectively) and tended to be negatively correlated with a 1 (r = -0.41, p = 0.06 for both). Conclusion:This study showed that whole-body fat oxidation and muscle deoxygenation kinetics were both related to aerobic fitness and that a relationship between the two kinetics exists. Individuals with greater aerobic fitness may have a delayed reliance on glycolytic metabolism at higher exercise intensities because of a longer maintained balance between O2 delivery and consumption supporting higher fat oxidation rates.

Dataset Information

PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle.

Publications

PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle.

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