Pesta 2014 Abstract MiP 2014
|Dysregulation of muscle ATP synthesis in hypophosphatemic mouse models and in a patient with hypophosphatemia due to a mutation in NaPi2c.|
Previous studies have demonstrated that young lean insulin resistant offspring of parents with type II diabetes have decreased insulin-stimulated rates of muscle mitochondrial ATP production, but the mechanism responsible for this phenomenon remains unclear . In this study we examine the potential role of decreased insulin-stimulated phosphate transport in this process.
To examine this hypothesis we assessed the impact of hypophosphatemia on basal and insulin-stimulated rates of muscle ATP synthesis in vivo, using 31P NMR saturation transfer experiments. We applied this 31P NMR method to assess rates of muscle ATP synthesis in two mouse models of hypophosphatemia: a diet-induced mouse model of hypophosphatemia and a renal phosphate transporter knock out mouse model of hypophosphatemia (NaPi2a-/-). Using this approach, we observed a strong association between serum phosphate levels with Pi-ATP flux (JATP) in skeletal muscle in both mouse models of hypophosphatemia. Low plasma Pi levels in these animals led to decreased JATP, while restoration of Pi to normophosphatemic levels concomitantly normalized JATP. Furthermore, insulin-stimulation increased muscle JATP by ~20% (P<0.05) in wild type mice but did not increase JATP in the hypophosphatemic NaPi2a-/- mice, indicating an important role of Pi mediating insulin’s anabolic effects on ATP synthase flux.
The same pattern was observed in a patient with hypophosphatemia due to a mutation in the renal phosphate transporter NaPi2c gene. This patient, presented with hypophosphatemia and manifested low muscle JATP, assessed by 31P NMR saturation transfer experiments, compared to normophosphatemic age-weight matched control subjects. Furthermore, the low JATP in this patient normalized following supplementation with oral phosphate salts and normalization of his plasma phosphate concentrations.
Taken together, these results demonstrate an important role for phosphate in the regulation of basal and insulin-stimulated rates of muscle ATP synthesis and may, in part, explain the symptoms of muscle fatigue in patients with genetic disorders of phosphate metabolism.
Labels: MiParea: Exercise physiology;nutrition;life style, Patients Pathology: Diabetes
Organism: Human, Mouse Tissue;cell: Skeletal muscle
Regulation: ATP production
Event: A1, Oral MiP2014
1-Dep Internal Medicine, CellularMol Physiol, Pediatrics, Diagnostic Radiology Biomed Engineering, Howard Hughes Medical Institute, Yale Univ School Medicine, New Haven, CT, USA; 2-Dep Endocrinology, Diabetes Nutrition, Center Cardiovascular Research, Charité, Univ School Medicine, Berlin, Germany. - Dominik.Pesta@yale.edu
References and acknowledgements
DP was supported by the Austrian Science Fund (FWF), project number J 3267
- Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350: 664-71.