High-Phosphate Diet Induces Exercise Intolerance and Impairs Fatty Acid Metabolism in Mice
Creators: name: Poghni Peri-Okonny
name: Iwamoto, Gary
name: Mitchell, Jere
name: Smith, Scott A.
name: Han-Kyul Kim
name: Szweda, Luke I.
name: Bassel-Duby, Rhonda
name: Fujikawa, Teppei
name: Castorena, Carlos M.
name: Richardson, James A.
name: Shelton, John Michael
name: Ayers, Colby
name: Jarett D. Berry
name: Malladi, Venkat S.
name: Hu, Ming-Chang
name: Moe, Orson W.
name: Scherer, Philipp E.
name: Wanpen Vongpatanasin
name: Kedryn Baskin
Publisher: name: Health Research Alliance
Year: 2019
Subjects: subject: 60802 Animal Cell and Molecular Biology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: 60603 Animal Physiology - Systems
subject: 60602 Animal Physiology - Cell
subject: Cardiology
subject: 60104 Cell Metabolism
subject: 60405 Gene Expression (incl. Microarray and other genome-wide approaches)
subject: Physiology

description: BACKGROUND: Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, is associated with increased cardiovascular morbidity and mortality. It is unknown whether dietary Pi excess contributes to exercise intolerance and physical inactivity. METHODS: To determine an association between Pi excess and physical activity in humans, we assessed the relationship between serum Pi and actigraphy-determined physical activity level, as well as left ventricular function by cardiac magnetic resonance imaging, in DHS-2 (Dallas Heart Study phase 2) participants after adjusting for relevant variables. To determine direct effects of dietary Pi on exercise capacity, oxygen uptake, serum nonesterified fatty acid, and glucose were measured during exercise treadmill test in C57/BL6 mice fed either a high-Pi (2%) or normal-Pi (0.6%) diet for 12 weeks. To determine the direct effect of Pi on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in differentiated C2C12 myotubes were conducted after subjecting to media containing 1 to 3 mmol/L Pi (pH 7.0) to simulate in vivo phosphate conditions. RESULTS: In participants of the DHS-2 (n=1603), higher serum Pi was independently associated with reduced time spent in moderate to vigorous physical activity (P=0.01) and increased sedentary time (P=0.004). There was no association between serum Pi and left ventricular ejection fraction or volumes. In animal studies, compared with the control diet, consumption of high-Pi diet for 12 weeks did not alter body weight or left ventricular function but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, and fatty acid levels and led to downregulation of genes involved in fatty acid synthesis, release, and oxidation, including Fabp4, Hsl, Fasn, and Pparγ, in muscle. Similar results were recapitulated in vitro by incubating C2C12 myotubes with high-Pi media. CONCLUSIONS: Our data demonstrate a detrimental effect of dietary Pi excess on skeletal muscle fatty acid metabolism and exercise capacity that is independent of obesity and cardiac contractile function. Dietary Pi may represent a novel and modifiable target to reduce physical inactivity associated with the Western diet.