Sarcopenia (muscle wasting) is a crippling condition that affects 25% of the aging population and even a greater percentage of subjects with chronic kidney disease (CKD), and is disproportionately high among veterans. Now recognized as a disease entity with its own ICD-10 code, it is associated with increased mortality and carries an annual US cost estimated to be more than 11.8 billion dollars and yet there is very little known of its pathogenesis or treatment. Sarcopenia is common in the aging population, especially those with obesity and diabetes. However, one population that commonly suffers from sarcopenia are those individuals suffering from chronic kidney disease, where both young and old are affected. It is now recognized that the disease does not result simply from poor nutrition and physical inactivity, but is often driven by inflammation and oxidative stress that can progress to protein-energy wasting, frailty and cachexia. The biological processes that are involved include effects of metabolic acidosis to stimulate protein catabolism from activation of the ubiquitin system, overexpression of myostatin that inhibits muscle growth, effects of insulin resistance, and other mechanisms. While much has been learned about these basic cellular processes involved in sarcopenia, here we present a novel hypothesis suggesting that the enzyme AMP deaminase 1 (AMPD1) may have a central role in causing sarcopenia by both regulating intracellular energy (ATP) levels and driving inflammation and oxidative stress. Using a model of chronic kidney disease in mice (remnant kidney model on a high protein diet), we have documented that the animals develop sarcopenia and in preliminary studies that sarcopenia does not occur in mice lacking AMPD1 with equivalent kidney damage. Here we will extend our studies to determine the effect of blocking AMPD1 in both male and female and both young and old mice with kidney disease, in association with extensive phenotyping including exercise tolerance, and studies of energy balance and body composition. Second we will explore the mechanisms by which AMPD1 activation causes inflammation, focusing on the role of uric acid and inhibition of AMP activated protein kinase. Finally, we will explore the basis underlying the activation of AMPD1 in chronic kidney disease, with an emphasis on the role of intracellular phosphate depletion and insulin resistance. If we identify activation of AMPD1 as a cause of sarcopenia and show that it is driven by insulin resistance, intracellular phosphate depletion and uric acid generation, we will not only identify a mechanism driving a severe complication of chronic kidney disease but also a potential way to intervene both prophylactically and therapeutically. Such a discovery would be of great help to all individuals with chronic kidney disease, and would have a big impact on Veterans and the Veteran Health Administration.

Public Health Relevance

Sarcopenia (muscle loss and wasting) affects nearly 25 percent of aging Americans and is associated with increased mortality and a yearly cost of 11.8 billion dollars. Sarcopenia is also one of the most serious yet understudied complications of chronic kidney disease (CKD), and has a major role in limiting mobility, causing weakness and inanition, and increasing risks for morbidity and mortality. Here we investigate a novel pathway for sarcopenia in CKD that involves activation of AMP Deaminase 1 isoform in the muscle, resulting in inflammation and oxidative stress that leads to muscle wasting. Here we explore the role of AMPD1, its activation by a decrease in intracellular phosphate, and its downstream pathways that involve generation of uric acid and the inhibition of AMP activated protein kinase. The identification of AMP Deaminase 1 as a new, targetable cause of sarcopenia could lead to significant improvement in the health of our veterans and general population.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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VA Eastern Colorado Health Care System
United States
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