High Phosphate Diet Induces Exercise Intolerance and Impairs Fatty Acid Metabolism in Mice
Authors: Peri‐Okonny Poghni Allen , Baskin Kedryn K. , Iwamoto Gary , Mitchell Jere H. , Smith Scott A. , Kim Han Kyul Allen , Szweda Luke I , Bassel‐Duby Rhonda , Fujikawa Teppei , Castro Carlos M. , Richardson James , Shelton John M , Ayers Colby , Berry Jarett D. , Malladi Venkat S. , Hu Ming‐Chang , Moe Orson W. , Scherer Phillip E , Vongpatanasin Wanpen 
Published: June 2021

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 if dietary Pi excess contributes to exercise intolerance and physical inactivity.

Methods

We used multivariable linear regression (adjusted for age, sex, race, body mass index, systolic blood pressure, eGFR, fasting plasma glucose, and HDL cholesterol) to assess the relationship between serum Pi and actigraphy‐determined physical activity level as well as left ventricular function by cardiac magnetic resonance imaging in the Dallas Heart Study‐2 (DHS) participants. To determine direct effects of dietary Pi on exercise capacity, we measured oxygen uptake, serum non‐esterified fatty acid (NEFA) and glucose during exercise treadmill test and compared between C57/BL6 mice fed either a high Pi (2%) or normal Pi (0.6%) diet for 12 weeks. Skeletal muscle gene expression profiles for genes involved in fatty acid (FA) metabolism were compared between groups after 12 weeks of normal or high Pi diet. To further determine direct effect of Pi on muscle metabolism and expression of genes involved in FA metabolism, additional studies were conducted after subjecting differentiated C2C12 myotubes to media containing 1–3 mM Pi (pH 7.0) to simulate in vivo high phosphate conditions.

Results

In participants of the DHS (n = 1,603), 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 to 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, fatty acid (FA) levels and led to downregulation of genes involved in FA synthesis, release, and oxidation, including Fabp4, Hsl, Fasn, and Pparg in muscle (p<0.05 for all). Similar results are recapitulated in vitro by incubating C2C12 myotubes with high Pi media.

Conclusion

Our data demonstrate a detrimental effect of dietary Pi excess on skeletal muscle FA metabolism and exercise capacity, which 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.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.