Abstract: TH-PO398
A New Deleterious Role for AMPD1 in the Pathogenesis of CKD-Dependent Muscle Waste
Session Information
- Nutrition, Inflammation, Metabolism: Basic Mechanisms
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Nutrition, Inflammation, and Metabolism
- 1401 Nutrition, Inflammation, Metabolism
Authors
- Andres-hernando, Ana, University of Colorado Denver, Aurora, Colorado, United States
- Johnson, Richard J., University of Colorado Denver, Aurora, Colorado, United States
- Lanaspa, Miguel A., University of Colorado Denver, Aurora, Colorado, United States
Background
Chronic Kidney Disease (CKD) reflects an overall catabolic state with significant loss of muscle mass. Mortality in CKD closely relates to muscle atrophy and no reliable methods to prevent CKD-induced muscle wasting currently exist. Proper glucose and phosphate uptake is essential for maintaining muscle mass which is controlled by the regulation of the Akt/As160/glut4 axis. AMP Deaminase 1 (AMPD1) is a muscle-specific protein inhibited by intracellular phosphate that negatively regulates the activation of the energy sensor protein AMPK and thus, AKt-signaling and glucose uptake. Based on this, we hypothesize that AMPD1-deficient mice by having an over-activation of AMPK and glucose uptake in the skeletal muscle will demonstrate a significant amelioration in CKD-dependent loss of muscle mass.
Methods
CKD-dependent muscle waste was induced in wild type and AMPD1 knockout mice by subtotal nephrectomy followed by a 5-week high protein diet. Body weight loss –a marker of muscle mass loss- in sham and nephrectomized mice was monitored weekly and renal function, muscle mass, intramuscular activation of AMPD1 and its signaling –AMPK and Akt activities, phosphate and uric acid levels- determined at sacrifice.
Results
AMPD1 activation in muscle of wild type mice undergoing CKD/High protein feeding is denoted by reduced intramuscular phosphate, increased AMP-dependent ammonia production and accumulation of AMPD-dependent products –uric acid and inosine-. Wild type but not AMPD1 deficient mice on CKD/high protein demonstrated significant weight and muscle –tibialis anterior, gastrocnemius and soleus- loss with elevation of serum creatinine kinase and glutamate –markers of muscle protein loss-. AMPD1 deficiency in mice results in AMPK activation leading to increased energy levels (ATP) and improved glucose uptake as reflected by the activation of the Akt/AS160/glut4 axis thus preventing protein loss and intramuscular catabolic processes. As a result, AMPD1 knockout mice on CKD demonstrated significant improved renal function with lower serum creatinine levels than wild type counterparts.
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Conclusion
AMPD1 activation in the skeletal muscle is a key step in the pathogenesis of CKD-dependent muscle wasting. Thus, AMPD1 blockade represents a new therapeutic approach for the prevention of this condition and to accelerate the recovery of muscle loss in subjects with CKD.
Funding
- NIDDK Support