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

doi:10.1016/j.isci.2023.106355

Phosphate depletion in insulin-insensitive skeletal muscle drives AMPD activation and sarcopenia in chronic kidney disease

iScience. 2023 Mar 10;26(4):106355. doi: 10.1016/j.isci.2023.106355. eCollection 2023 Apr 21.

Authors

Ana Andres-Hernando^{1

2

3}, Christina Cicerchi¹, Gabriela E Garcia^{1

3}, David J Orlicky⁴, Peter Stenvinkel⁵, Richard J Johnson^{1

3}, Miguel A Lanaspa^{1

2}

Affiliations

¹ Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
² Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
³ Division of Nephrology, Rocky Mountain VA Medical Center, Aurora, CO, USA.
⁴ Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁵ Department of Renal Medicine M99, Karolinska University Hospital, SE-141 86Stockholm, Sweden.

Abstract

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.

Keywords: Biological sciences; Cell biology; Pathophysiology; Physiology.

Abstract

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