# A Novel Mechanism for Sarcopenia in Chronic Kidney Disease

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2020 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 9882157
- **Project number:** 5I01BX004511-02
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** Richard Joseph Johnson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882157

## Citation

> US National Institutes of Health, RePORTER application 9882157, A Novel Mechanism for Sarcopenia in Chronic Kidney Disease (5I01BX004511-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9882157. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*