# Activation of the Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA) as a Therapeutic Intervention for Sarcopenia

> **NIH VA I01** · OKLAHOMA CITY VA MEDICAL CENTER · 2021 · —

## Abstract

Sarcopenia (loss of muscle mass and function) universally affects the elderly and has a
tremendous impact on quality of life, independent living, and healthcare costs in aging veterans.
The goal of this study is to test a potential new pharmacological approach, activation of the
sarcoendoplasmic reticulum (SR) calcium ATPase (SERCA) that pumps Ca2+ back into the SR
following muscle contraction, to modulate sarcopenia. This work is critically important as no
effective pharmacologic interventions currently exist. Here we have employed a mouse model of
sarcopenia developed by my laboratory (the Sod1-/- mouse lacking the antioxidant enzyme
CuZnSOD) that recapitulates many features of sarcopenia in aging mice and in humans as a
pre-clinical model to test and characterize potential interventions. Successful interventions can
then be tested further in aging wild type mice. Disrupted intracellular calcium homeostasis is a
potential contributor to loss of skeletal muscle mass and force-generating capacity during aging
and impaired SERCA function can lead to elevated cytosolic calcium and deleterious effects on
cellular processes. We hypothesized that increasing SERCA activity to maintain calcium
homeostasis may be an effective mechanism to treat sarcopenia. In support of this, our
preliminary data clearly show that treatment of 2 month old Sod1-/- mice with CDN1163, an
allosteric SERCA activator, increases SERCA activity, blunts muscle atrophy, improves force
generation and reduces muscle mitochondrial ROS production that occurs in the untreated
Sod1-/- mice. CDN1163 has reported beneficial effects on metabolism and cognitive function,
but our study is the first to test its application as a therapeutic intervention for treating
sarcopenia. In this proposal, we will test the hypothesis that SERCA activation can
prevent/reduce muscle atrophy and weakness through regulation of cytosolic calcium signaling,
mitochondrial function and reduced proteolytic activity. First, we will define dose response and
biologic effects of oral administration of CDN1163 in mice through the diet. Once we have
determined an optimal effective dose, we will follow up on our exciting data and test whether
CDN1163 treatment can prevent/reduce age-related loss of muscle mass and weakness in
aging wild type mice in Aim 2. Male and female wildtype C57Bl6 mice will be administered
CDN1163 starting at 15 months of age. We will measure the effect of CDN1163 treatment on
the regulation of cytosolic calcium signaling, mitochondrial function, contractile function, reduced
proteolytic activity and other essential markers of the sarcopenia phenotype at 15, 20, and 28
months of age. SERCA activity is also regulated by an endogenous inhibitor, sarcolipin (Sln).
Our studies have shown that sarcolipin is elevated in muscle during aging and in Sod1-/- mice,
consistent with reduced SERCA activity. In Aim 3, we will test whether activation of SERCA
through depletion of the SERCA inhibitor sarcolipin m...

## Key facts

- **NIH application ID:** 10166596
- **Project number:** 5I01BX004453-03
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** HOLLY VAN REMMEN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166596

## Citation

> US National Institutes of Health, RePORTER application 10166596, Activation of the Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase (SERCA) as a Therapeutic Intervention for Sarcopenia (5I01BX004453-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10166596. Licensed CC0.

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