# STIM1 and its role in regulating cardiac metabolism

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $546,596

## Abstract

Mortality rates associated with cardiovascular disease have decreased significantly; however, the incidence of
heart failure continues to grow and 5-year survival rates remain at ~50%, underscoring the need to improve
our knowledge of the molecular underpinnings of this disease. The heart requires a high level of
metabolic flexibility to enable it to continuously adapt to changing workload demands throughout the day.
Substrate availability and hormone levels also fluctuate with fasting/feeding cycles, further demanding cardiac
metabolic flexibility. Loss of cardiac metabolic flexibility is a recurrent feature of cardiac disease, observed
during hypertrophy, heart failure and diabetic cardiomyopathy. Similarly, dysregulation of Ca2+ homeostasis is
a common element underlying the etiology of many cardiac diseases. Calcium is an established regulator of
cardiac metabolism and mitochondrial function, through direct allosteric interactions, posttranslational
modifications, and transcriptional events. However, despite established roles of Ca2+ in regulating cardiac
energy metabolism, the specific Ca2+ handling pathways involved are not well characterized and their
role in maintaining metabolic flexibility is not known. STromal Interaction Molecule-1 (STIM1) is a
ubiquitously expressed and highly evolutionarily conserved protein located in the ER/SR that is responsible for
regulating diverse Ca2+ signaling pathways in non-excitable cells and is recognized as a core element of all
mammalian Ca2+ signaling systems. Despite discovery of STIM1 in the heart approximately 20 years ago,
our knowledge about the physiological role of STIM1 in adult cardiomyocytes remains unclear and
controversial. We recently reported that cardiomyocyte deletion of STIM1 (crSTIM1-KO) precipitates contractile
dysfunction and dilated cardiomyopathy by 36 weeks of age. In young crSTIM1-KO mice prior to onset of
contractile dysfunction there was impaired glucose metabolism and insulin signaling combined with increased
lipid accumulation and an upregulation of lipogenic proteins. This metabolic phenotype is very similar to the
cardiac metabolic signature observed during diabetes, a well characterized example of metabolic inflexibility.
Collectively, these observations have led to the hypothesis that STIM1 is a previously unrecognized
regulator of cardiac metabolism and mitochondrial function and that decreased STIM1 contributes to
the adverse effects of diabetes on the heart. To test this hypothesis, we will 1) Define fully the extent to
which STIM1 regulates cardiac metabolism; 2) Establish the mechanisms by which STIM1 influences
mitochondrial function in the heart and 3) Determine how diabetes regulates STIM1 levels and whether loss of
STIM1 contributes to the adverse effects of diabetes on the heart. The successful completion of this proposal
will provide significant new insights into the role of STIM1 in regulating cardiac metabolism and mitochondrial
function and provide the fo...

## Key facts

- **NIH application ID:** 10126897
- **Project number:** 5R01HL149354-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** JOHN C CHATHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $546,596
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126897

## Citation

> US National Institutes of Health, RePORTER application 10126897, STIM1 and its role in regulating cardiac metabolism (5R01HL149354-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10126897. Licensed CC0.

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