TY - JOUR
T1 - High-Phosphate Diet Induces Exercise Intolerance and Impairs Fatty Acid Metabolism in Mice
AU - Peri-Okonny, Poghni
AU - Baskin, Kedryn K.
AU - Iwamoto, Gary
AU - Mitchell, Jere H.
AU - Smith, Scott A.
AU - Kim, Han Kyul
AU - Szweda, Luke I.
AU - Bassel-Duby, Rhonda
AU - Fujikawa, Teppei
AU - Castorena, Carlos M.
AU - Richardson, James
AU - Shelton, John M.
AU - Ayers, Colby
AU - Berry, Jarett D.
AU - Malladi, Venkat S.
AU - Hu, Ming Chang
AU - Moe, Orson W.
AU - Scherer, Philipp E.
AU - Vongpatanasin, Wanpen
N1 - Publisher Copyright:
© 2019 Lippincott Williams and Wilkins. All rights reserved.
PY - 2019/3/12
Y1 - 2019/3/12
N2 - 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.
AB - 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.
KW - Diet
KW - Exercise
KW - Fatty acids
KW - Gene expression
KW - Metabolism
KW - Phosphates
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U2 - 10.1161/CIRCULATIONAHA.118.037550
DO - 10.1161/CIRCULATIONAHA.118.037550
M3 - Article
C2 - 30612451
AN - SCOPUS:85062885879
SN - 0009-7322
VL - 139
SP - 1422
EP - 1434
JO - Circulation
JF - Circulation
IS - 11
ER -