Phosphate depletion in insulin-insensitive skeletal muscle drives AMPD activation and sarcopenia in chronic kidney disease
Ana Andres-Hernando,
Christina Cicerchi,
Gabriela E. Garcia,
David J. Orlicky,
Peter Stenvinkel,
Richard J. Johnson,
Miguel A. Lanaspa
Affiliations
Ana Andres-Hernando
Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Division of Nephrology, Rocky Mountain VA Medical Center, Aurora, CO, USA
Christina Cicerchi
Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Gabriela E. Garcia
Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Division of Nephrology, Rocky Mountain VA Medical Center, Aurora, CO, USA
David J. Orlicky
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Peter Stenvinkel
Department of Renal Medicine M99, Karolinska University Hospital, SE-141 86Stockholm, Sweden
Richard J. Johnson
Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Division of Nephrology, Rocky Mountain VA Medical Center, Aurora, CO, USA
Miguel A. Lanaspa
Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Corresponding author
Summary: Sarcopenia is a common and devastating condition in patients with chronic kidney disease (CKD). Here, we provide evidence that the kidney-muscle crosstalk in sarcopenia is mediated by reduced insulin sensitivity and the activation of the muscle-specific isoform of AMP deaminase, AMPD1. By using a high protein-based CKD model of sarcopenia in mice and differentiated human myotubes, we show that urea reduces insulin-dependent glucose and phosphate uptake by the skeletal muscle, thus contributing to the hyperphosphatemia observed in CKD whereas depleting intramuscular phosphate needed to restore energy and inhibit AMPD1. Hyperactivated AMPD1, in turn, aggravates the low energy state in the muscle by removing free adenosine monophosphate (AMP) and producing proinflammatory factors and uric acid which contribute to the progression of kidney disease. Our data provide molecular and metabolic evidence supporting the use of strategies aimed to improve insulin sensitivity and to block AMPD1 to prevent sarcopenia in subjects with CKD.
